D

Diabetic Neuropathies
AARON I. VINIK, MD, PHD
MARIE T. HOLLAND, MD
JEAN M. LE BEAU, PHD

FRANCIS J. LJUZZI, PHD

KEVIN B. STANSBERRY, BS
LARRY B. COLEN, MD

Diabetic neuropathy is a common complication of diabetes that may be associated

both with considerable morbidity (painful polyneuropathy, neuropathic ulceration)
and mortality (autonomic neuropathy). The epidemiology and natural history of
diabetic neuropathy is clouded with uncertainty, largely caused by confusion in the
definition and measurement of this disorder. We have reviewed various clinical
manifestations associated with somatic and autonomic neuropathy, and we herein
discuss current views related to the management of the various abnormalities.
Although unproven, the best evidence suggests that near-normal control of blood
glucose in the early years after diabetes onset may help delay the development of
clinically significant nerve impairment. Intensive therapy to achieve normalization of
blood glucose also may lead to reversibility of early diabetic neuropathy, but again,
this is unproven. Our ability to manage successfullly the many different manifestations of diabetic neuropathy depends ultimately on our success in uncovering the
pathogenic processes underlying this disorder. The recent resurgence of interest in
the vascular hypothesis, for example, has opened up new avenues of investigation for
therapeutic intervention. Paralleling our increased understanding of the pathogenesis
of diabetic neuropathy, refinements must be made in our ability to measure quantitatively the different types of defects that occur in this disorder. These tests must be
validated and standardized to allow comparability between studies and more meaningful interpretation of study results.

FROM THE DIABETIC NEUROPATHY STUDY GROUP, EASTERN VIRGINIA MEDICAL SCHOOL,

NORFOLK,

VIRGINIA.
ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO AARON I. VINIK, MD, PHD, THE DIABETES
INSTITUTES, EASTERN VIRGINIA MEDICAL SCHOOL, 855 W. BRAMBLETON AVENUE, NORFOLK, VA, 23510.
I D D M , INSUUN-DEPENDENT DIABETES MELLITUS; N I D D M , NON-INSULIN-DEPENDENT DIABETES MELLITUS; A F T , AUTONOMIC FUNCTION TESTING; N D S , NEUROPATHY DISABILITY SCORE; N S S , NEUROPATHY
SYMPTOM SCORE; DCCT, DIABETES CONTROL AND COMPLICATIONS TRIAL; LDL, LOW-DENSITY UPOPROTEIN; HDL, HIGH-DENSITY LIPOPROTEIN; BMI, BODY MASS INDEX; NCV, NERVE CONDUCTION VELOCITIES;
STZ, STREPTOZOCIN; ARI, ALDOSE REDUCTASE INHIBITOR; DAG, DIACYLGLYCEROL; GAD, GLUTAMATE
DECARBOXYLASE; GABA, T-AMINOBUTYRIC ACID; NGF, NERVE GROWTH FACTOR; DRG, DORSAL ROOT
GANGLION; SP, SUBSTANCE-P; CGRP, CALCITONIN GENE-RELATED PEPTIDE; IGF, INSULINLIKE GROWTH
FACTOR; IGF-I, INSULINLIKE GROWTH FACTOR I; IGF-II, INSULINLIKE GROWTH FACTOR II; B F G F , BASIC
FIBROBLAST GROWTH FACTOR; B D N F , BRAIN-DERIVED NEURITROPHIC FACTOR; C N T F , CILIARY NEUROTROPHIC FACTOR; EGF, EPIDERMAL GROWTH FACTOR; ZE, ZOLLINGER ELLISON; IMCC,

INTERDIGESTIVE

MIGRATING MOTOR COMPLEX; P P , PANCREATIC POLYPEPTIDE; G I P , GLUCOSE-DEPENDENT INSULIN-RELEASING

PEPTIDE; SRIF, SOMATOSTATIN;

EPI, EPINEPHRINE;

NE, NOREPINEPHRINE;

HAFF,

HYPOGLYCEMIA-

ASSOCIATED AUTONOMIC FAILURE; E M G , ELECTROMYOGRAM; Q S T , QUANTITATIVE SENSORY TESTING; C V ,

COEFFICIENT OF VARIATION; T S T , THERMOREGULATORY SWEAT TEST; Q S A R T , QUANTITATIVE SUDOMOTOR
AXON REFLEX TEST.

1926

iabetic neuropathy encompasses a

wide range of abnormalities affecting both peripheral and autonomic
nerve function. The disorder may be
manifested either clinically, through numerous different symptoms, or subclinically, with abnormalities detectable only
by careful testing. Frequently, the diagnosis of diabetic neuropathy is difficult to
make because the manifestations are
nonspecific and may occur in numerous
other conditions. Neuropathy is not confined to a single type of diabetes, but can
occur in IDDM, NIDDM, and various
forms of acquired diabetes (1-3). Although considerable uncertainty exists as
to the prevalence of neuropathy among
diabetic individuals, it is generally accepted that neuropathy is the most common, and often the most troublesome, of
the major complications afflicting those
with diabetes.

CLASSIFICATION Diabetic neuropathy is not a single entity, but rather

a number of different syndromes, each
carrying a range of clinical and subclinical manifestations. Pathologically, the
different syndromes may be distinguished by the type of nerve fiber affected and the site of the lesion. Clinically, each syndrome is associated with a
range of manifestations, many of which
overlap, thus often making it impossible
to classify individual cases (4).
Numerous schemes have been
proposed for the classification of diabetic
neuropathy, with continual revision being made as more is learned about the
epidemiology, clinical course, and etiologies of the different neuropathic syndromes that occur in diabetes. From an
etiological perspective, one useful framework for the classification of diabetic
neuropathy was put forth by Sullivan
(5), who advocated differentiating the
more commonly occurring diffuse symmetrical pattern of neuropathy from the
less commonly occurring focal and predominantly asymmetrically distributed
pattern of neuropathy. Since then, other

DIABETES CARE, VOLUME 15, NUMBER 12, DECEMBER 1992

Vinik and

Table 1Classification and staging of diabetic neuropathy

SUBCUN1CAL NEUROPATHY
ABNORMAL ELECTRODIAGNOSTIC TESTS
DECREASED NERVE CONDUCTION VELOCITY
DECREASED AMPLITUDE OF EVOKED MUSCLE OR NERVE ACTION POTENTIAL
ABNORMAL

QST

VIBRATORY/TACTILE
THERMAL WARMING/COOLING
OTHER
ABNORMAL AUTONOMIC FUNCTION TESTS
ABNORMAL CARDIOVASCULAR REFLEXES
ALTERED CARDIOVASCULAR REFLEXES
ABNORMAL BIOCHEMICAL RESPONSES TO HYPOGLYCEMIA
CLINICAL NEUROPATHY
DIFFUSE SOMATIC NEUROPATHY
DISTAL SYMMETRIC SENSORIMOTOR POLYNEUROPATHY
PRIMARILY SMALL-FIBER NEUROPATHY
PRIMARILY LARGE-FIBER NEUROPATHY
MIXED
AUTONOMIC NEUROPATHY
CARDIOVASCULAR AUTONOMIC NEUROPATHY
ABNORMAL PUPILLARY FUNCTION

Associates

studies included motor- and sensoryevoked amplitudes and conduction velocities from both an arm and a leg. Dyck
et al. (10) subsequently assessed the reproducibility of these suggested measurements over a 5-yr period, as part of
the Rochester Diabetic Neuropathy
Study. The NDS (particularly the weakness subset of the NDS), vibration
thresholds, motor and sensory nerve action potentials, and motor NCVs were
highly reproducible measurements of
neuropathy over time. The least reliable
measurement was the NSS, the assessment of symptoms: among the subsets of
the NDS, the symptoms portion of the
NDS had the worst reproducibility.
Table 1 offers a current classification of neuropathy that clearly will be
modified as our understanding of the
disease process improves.

GASTROINTESTINAL AUTONOMIC NEUROPATHY

GASTROPARESIS
CONSTIPATION
DIABETIC DIARRHEA
ANORECTAL INCONTINENCE
GENITOURINARY AUTONOMIC NEUROPATHY
BLADDER DYSFUNCTION
SEXUAL DYSFUNCTION
HYPOGLYCEMIA UNAWARENESS/UNRESPONSIVENESS
SUDOMOTOR DYSFUNCTION
FOCAL NEUROPATHY
MONONEUROPATHY
MONONEUROPATHY MULTIPLEX
AMYOTROPHY

Based on the San Antonio Convention for neuropathy. To be diagnosed, patients must have a minimum
of a sign or a symptom, and an abnormal electrodiagnostic test.

researchers have emphasized further distinctions among the diffuse symmetrical

neuropathies between those neuropathies that are primarily sensory, and
those that are primarily motor (4,6,7).
On the basis of pathological studies of
actual nerve lesions, Brown et al. (8)
have more recently suggested that sensory neuropathy be subclassified even
further, according to whether primarily
small or large nerve fiber involvement is
observed. The usefulness of this distinction in terms of the pathogenesis of diabetic neuropathy has yet to be determined.

DIABETES CARE, VOLUME 15, NUMBER 12,

In 1988, a consensus statement

from the San Antonio Conference on Diabetic Neuropathy recommended that at
least one parameter from each of the following five categories be measured to
classify diabetic neuropathy: symptom
profiles, neurological examination, QST,
nerve conduction studies, and AFT (9).
The panel recommended that the neurological examination be a systematic assessment "of neuropathic signs and
symptoms, including sensory, motor and
reflex measures in upper and lower extremities, cranial nerves and autonomic
function." Suggested nerve conduction

DECEMBER

1992

PREVALENCE OF NEUROPATHY
Prevalence data for diabetic neuropathy
are sparse, and it is virtually impossible
to obtain reliable estimates of the prevalence of neuropathy among the diabetic
population. Few population-based studies have been undertaken, and because
the prevalence of undiagnosed diabetes
in the general population is estimated to
be at least as great as the prevalence of
diagnosed diabetes (11), most published
studies entail substantial selection biases
because they are limited to that portion
of the diabetic population that has access
to clinical care. In addition, lack of consensus as to the appropriate diagnostic
criteria for diabetic neuropathy has resulted in a wide range of prevalence estimates reported in the literaturefrom
0 to 93% (12).
Probably the best data regarding
prevalence of neuropathy come from the
extensive study of nearly 4500 clinic patients by Pirart (13-15), who reported a
prevalence rate ranging from 7% for individuals within 1 yr of diagnosis of diabetes to 50% for those with diabetes for
>25 yr. In Pirart's study, neuropathy
was defined as loss of Achilles reflexes
with symptoms or objective signs of

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Diabetic neuropathies

polyneuropathy. Comparable prevalence

rates were reported by Franklin et al.
(16), who also used a combination of
symptom and objective information to
diagnose neuropathy in their study of
NIDDM patients in the San Luis Valley
Diabetes Study. Although Brown and Asbury (8) have estimated that >50% of all
patients receiving insulin have symptomatic neuropathy, and Goodman et al.
(17) reported pain and paresthesias to be
present in 62% of all cases in their series,
Boulton et al. (18) have suggested that
most prevalence studies overestimate the
true prevalence of symptomatic neuropathy because their diagnostic criteria are
nonspecific. Thus, these researchers defined symptomatic neuropathy as the
presence of symptoms and signs of nerve
dysfunction in the absence of peripheral
vascular disease and found that 10.4% of
insulin-treated patients <60 yr of age in
their clinic population had symptomatic
neuropathy. An additional 8.9% exhibited absent knee and ankle reflexes in the
absence of significant symptoms, and another 6.3% exhibited absent foot pulses
(18). This estimate is similar to that obtained by Fry et al. (19), who observed
symptoms in association with significant
signs present in 13% of their patients.
Signs of peripheral neuropathy
are frequently demonstrable on clinical
examination in diabetic patients. In a series of 1175 unselected patients from a
diabetes outpatient clinic, Pirart (15)
found that 12% already had signs of diabetic neuropathy at the time of diagnosis of diabetes. Ankle reflexes were absent in 19.6% of a diabetic population
studied by Boulton et al. (18), and Nilsson et al. (20) found that Achilles reflex
was absent in 10.5% of short-duration
diabetic patients and 15.2% of longduration diabetic patients. Interestingly,
though, Nilsson et al. (20) also observed
absence of Achilles reflexes in 8.5% of
nondiabetic control subjects and in 25%
of nondiabetic control subjects >60 yr of
age. Loss of ankle vibration and/or Achilles tendon reflexes was found among
40.8% of 503 Mexican subjects with

1928

NIDDM, although in this group, 32.2%

of subjects had symptoms attributable to
peripheral neuropathy (21). By using a
broader set of criteria, Haimanot and Abdulkadir (22) found that 54% of diabetic
patients had objective sensory deficits in
the extremities, reduction or loss of deep
tendon reflexes, and autonomic disturbances or mononeuropathy without an
obvious alternative cause. Prevalence
ranged from 42% for individuals with
duration of diabetes < 5 yr to 80% for
individuals with duration of diabetes
>15 yr. Moreover, these findings were
present in only 8% of a nondiabetic control population.
Clinically, detectable diabetic
neuropathy is more common than generally thought, if its presence is sought
by careful examination. In a cohort of
278 healthy IDDM subjects enrolled in
the feasibility phase of the DCCT, clinical
peripheral polyneuropathy was detectable in 39% of the subjects on careful
examination, despite the fact that patients with known neuropathy of sufficient severity to require medical attention were excluded (23). Thus, the
prevalence of detectable but subtle (and
often asymptomatic) peripheral somatic
neuropathy in a generally healthy cohort
of subjects with IDDM of <15 yr duration is quite high.
Although uncommon, neuropathy occasionally occurs in diabetic children. Reduction in motor NCVs have
even been documented among diabetic
children (24,25), as have reductions in
vibratory sensation (26). Symptomatic
neuropathy is found only rarely among
young diabetic patients.
Few published estimates exist of
the prevalence of other syndromes of somatic neuropathy, mainly because these
conditions occur so infrequently. In two
African populations, the prevalence of
mononeuropathy (including mononeuropathy multiplex) among patients with
diabetes was reported to be 3.7 (22) and
1.1% (27). Prevalence rates for radiculopathy and amyo trophy in these populations ranged from 0 to <2%. In a sam-

ple of 351 patients admitted to an

inpatient diabetes clinic, we observed
prevalence rates for mononeuropathy,
radiculopathy, and amyotrophy to be
3.0, 3.5, and 2.1%, respectively (A.I.V.,
B.D. Mitchell, unpublished observations).
No adequate studies are available
on the prevalence of symptomatic autonomic neuropathy. A wide range has
been reported in the prevalence rates for
different autonomic symptoms, but these
rates are difficult to interpret because of
the high frequency with which many of
these symptoms can occur in the nondiabetic population. Impotence, for example, may be present in as many as 50% of
diabetic men, although this condition is
not infrequent in the nondiabetic population. In one study, Jeyarajah et al. (29)
found that 38.5% of their patients experienced one or more of the autonomic
symptoms (intermittent diarrhea, sweating abnormality, giddiness on standing,
gastric fullness, or hypoglycemic unawareness), but only 50% had abnormal AFTs.
Estimates of the prevalence of autonomic neuropathy based on the presence of abnormalities of cardiovascular
autonomic reflexes have ranged in the
literature from 14 to nearly 50% (2933). Burke et al. (33), who observed that
14% of their clinic patients experienced
both an abnormal heart-rate variation
during deep breathing and an abnormal
heart-rate response to standing, then observed that 61.9% of these patients also
experienced one or more of the following
symptoms: postural dizziness, chronic
diarrhea, impotence, postprandial sweating, dysphagia, or urinary symptoms. At
the other extreme, Jeyarajah et al. (29)
observed AFT abnormalities in 46.2% of
their diabetic patients, but also in 15% of
their healthy control subjects. The prevalence of AFT abnormalities has been
found to be associated both with duration of diabetes (32) and age (29), although these correlations may not hold
for all indexes of autonomic function.
It formerly was thought that dia-

DIABETES CARE, VOLUME 15, NUMBER 12, DECEMBER

1992

Vinik and Associates

betic autonomic neuropathy was a disease only of 1DDM, but Veglio et al. (34)
have reported, the prevalence is equal or
even greater in NIDDM than IDDM. It
also has been observed that an individual's age is more important a predictor of
the appearance of autonomic neuropathy
than duration of neuropaths to sudden
demise, for which no apparent reason
has been found. Epidemiological data
suggest that autonomic neuro pathy may
cosegregate with factors predisposing to
macrovascular events. A striking association has been found between autonomic
neuropathy and hypertension, elevation
of LDL cholesterol, and a reduction of
HDL cholesterol (35), and somewhat
surprisingly, an increased prevalence
among females and individuals with a
raised BMI (36). Therefore, it is not surprising that these individuals are most
susceptible to an attenuated life span because of cosegregation of all the risk factors for cardiovascular mortality with autonomic neuropathy.

Risk factors
Despite extremely poor control of their
diabetes, up to 50% of all diabetic subjects never develop symptoms of neuropathy, even after >20 yr duration of diabetes ( 1 3 - 1 5 ) . Conversely, some
unfortunate subjects develop neuropathy
soon after the onset of diabetes, even
when glycemic control is relatively good.
These well-known observations implicate the involvement of factors other
than glycemia in the etiology of diabetic
neuropathy.
A genetic predisposition for the
development of diabetic neuropathy has
been sought (13-15,20,37-39) but, as
yet, not identified. At least two studies
have failed to find an association between signs of peripheral neuropathy
and family history of NIDDM ( 1 3 15,20), thus suggesting that a single gene
is not responsible for both NIDDM and
peripheral neuropathy. Chochinov et al.
(39) speculated that other genetic factors
may be involved, so they measured vibration sensation in diabetic subjects,

DIABETES CARE, VOLUME 15,

NUMBER 12,

their immediate family members, and

normal control subjects. The researchers
found that, although vibration sensation
was reduced in the diabetic subjects, sensation in family members was not reduced, and was no different than in normal control subjects. The question that
has not been investigated adequately is
whether genes exist that segregate independently of diabetes, affect susceptibility to neuropathy, but are expressed only
in the presence of diabetes. Heritable defects (i.e., genes) may be present, for
example, that predispose neural (and
vascular) tissue to further injury in the
metabolic milieu of diabetes. A more detailed understanding of the specific biochemical defects present in neuropathy is
required before this issue can be elaborated on further.
The relationship between neuropathy and various constitutional factors has been investigated by several researchers. Gadia et al. (40) recently
reported an inverse correlation between
vibratory sensation and height and between peroneal motor NCVs and height
in a group of subjects with NIDDM.
They suggested that body stature may be
a proxy for neuron length, with larger
neurons being more susceptible to metabolic injury than shorter neurons.
Moreover, a causal relationship between
height and peripheral neuropathy could
explain the association between male
gender and peripheral neuropathy
among subjects with IDDM recently reported in the Diabetes Control and Complications Trial (41). Grenfell et al. (42),
on the other hand, observed an association between the presence of nephropathy and short stature among individuals
with diabetes onset during childhood
and hypothesized that poor diabetic control may retard growth in childhood,
thus making short stature a marker for
the early development of complications.
At least two studies have investigated a
possible relationship between obesity
(percentage of ideal body weight) and
the presence of peripheral polyneuropathy, and both failed to find an association

DECEMBER

1992

(13-15,43), notwithstanding the association of an increased BMI and autonomic

neuropathy (36).
The relationship between pubertal changes and development of neuropathy was investigated by Sosenko et al.
(26), who found that vibration sensation
was significantly reduced in postpubertal
children compared with prepubertal
children. This observation needs to be
confirmed; possibly, the increased physiological stress on the body that occurs
during puberty increases susceptibility to
neuropathy.
Nutritional factors, including vitamin deficiencies, have long been recognized as possible contributing factors
to the development of neuropathy, including diabetic neuropathy (44). Deranged Vitamin B12 metabolism is one
possible pathway that has been implicated theoretically (45), but no data are
available to support this hypothesis.
Some researchers have suggested that the
interaction of malnutrition with diabetes
might account for the high prevalence of
neuropathy seen in the diabetic population in underdeveloped countries (46).
NATURAL HISTORY Slowing of
NCVs is among the earliest neuropathic
abnormalities that occur in diabetes and
often is present even at diagnosis of diabetes (47-50). After diagnosis, slowing
of NCV generally progresses and is correlated with duration of diabetes (51).
Sensory fibers usually are affected first,
followed by motor fibers (52).
Although slowing of NCVs is
common in diabetes and often occurs
early in the course of the disease, considerable uncertainty exists as to the relevance of these abnormalities to the future development of either subclinical
manifestations or clinically apparent diabetic neuropathy. Although most studies have documented that symptomatic
patients are more likely to have slower
NCVs than patients without symptoms
(18,22,27,52-54), NCV does not appear
to be related to the severity of symptoms
(55).

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Diabetic neuropathies

The relationship between the objective signs of neuropathy and neuropathic symptoms is also not well defined.
The observed manifestations of neuropathy are thought to depend on the type
of nerve fiber affected. Small nerve fiber
damage, which usually, although not always, precedes large nerve fiber damage,
is manifested first in the lower limbs,
with a loss of thermal sensitivity, and
reduced light-touch and pin-prick sensation occurring early (J. Jaspan, unpublished observations). When pain occurs,
NCV is often normal or only minimally
reduced (57), suggesting that pain is an
early (small fiber) manifestation of diabetic polyneuropathy. When pain is
present, it typically resolves on its own,
but whether this is reflective of the reversibility of early nerve damage or progression to nerve death is not clear. Large
fiber neuropathies are manifested by reduced vibratory sensation and depressed
tendon reflexes. In two follow-up studies, progressive reduction of vibratory
sensation and loss of tendon reflexes
have been observed in patients who at
the same time reported an improvement
in pain symptoms (58,59). The situation
is further complicated by the fact that
most diabetic peripheral neuropathy is of
mixed variety, with both large and small
nerve fiber involvement. In our own
clinic population, only 15.0% of diabetic
subjects with clinically confirmed symptoms of neuropathy had no objective
signs of neuropathy, and 63.7% of patients with signs had no symptoms (28).
Other investigators have reported even
smaller proportions of pure small nerve
fiber and pure large nerve fiber neuropathies (8,56).
Autonomic neuropathy may be a
prerequisite in the development of foot
ulceration in diabetes that is conventionally classified as a manifestation of distal
symmetric polyneuropathy (60,61). Animal studies have suggested that autonomic neuropathy alone may precipitate
plantar ulceration (62). Callus formation,
which predates plantar foot ulceration,
may arise in part from excess blood

1930

flowas it disappears if peripheral vas- thetic integrity, but researchers now apcular disease develops (63). Hariot ar- preciate that the autonomic pathways inthropathy (neuroarthropathy) is an un- volved in these reflexes are complex and
derdiagnosed complication of the these that tests may reflect both parasymdiabetic neuropathic foot in which bone pathetic and sympathetic innervation
fractures occur and are followed by bone (70). Once these tests become abnormal,
disorganization and increased risk of sec- they usually remain abnormal (71,72).
ondary ulceration. This traditionally is
Sympathetic failure usually folascribed solely to distal symmetric poly- lows vagal denervation and may involve
neuropathy in diabetes. High peripheral the following processes: cardiac denervablood flow, which causes weakening of tion (in combination with parasympabones in the foot, may predispose to frac- thetic denervation), loss of peripheral
tures in the insensitive foot (64,65).
and splanchnic (visceral) vasoconstricMuch remains to be learned of tion, loss of vasomotor control, and inthe natural history of diabetic autonomic crease in peripheral blood flow (68).
neuropathy. Testing of cardiovascular re- Among the symptoms that may be manflexes has revealed that signs of auto- ifested by these defects are postural hynomic neuropathy may occur relatively potension, sweating disturbances, and
early in the course of diabetes (29,32, hypoglycemic unawareness. Direct in66). Both sympathetic and parasympa- jury to small myelinated and unmyelithetic nerve fibers may be affected, with nated sympathetic nerve fibers signaling
parasympathetic dysfunction preceding pain and temperature also may occur,
sympathetic dysfunction (32,66,67). Im- leading possibly to painful peripheral
provements in the methods to measure neuropathy.
sympathetic function have now shown
Although symptomatic periphthat sympathetic damage may occur ear- eral neuropathy usually precedes the delier than previously thought (68). By us- velopment of symptomatic autonomic
ing infrared pupillometry, Ziegler et al. neuropathy (6,73), signs of parasympa(50) have demonstrated that the speed of thetic neuropathy sometimes may appear
pupillary dilation may be slowed even at before signs of peripheral neuropathy
the diagnosis of IDDM.
(74). In contrast, sympathetic nerve abOf all parasympathetic nerve fi- normalities are rarely found in the abbers, 75% are in the vagus nerves sence of signs of peripheral neuropathy
(10th cranial nerve), where they pass to (74). Isolated abnormalities on autothe entire thoracic and abdominal re- nomic function tests are occasionally
gions of the body. Early autonomic nerve found, however, in nondiabetic individdysfunction has been attributed to vagal uals (29).
damage, with manifestations appearing
The mortality for diabetic autoin several organ systems. A battery of nomic neuropathy has been estimated to
diagnostic tests to assess cardiovascular be ~44% within 2.5 yr of diagnosis of
autonomic function have been devised symptomatic autonomic neuropathy
that measure heart-rate responses under (66). Early studies by Ewing et al. (70) in
various conditions. Among the defects Scotland caused much concern because
indicative of cardiac autonomic damage most people died of conditions other
demonstrable by these tests are: an in- than autonomic neuropathy, such as recrease in resting heart rate (tachycardia), nal failure, and the only patients folabnormal heart-rate response to the Val- lowed were those who were symptomsalva maneuver, loss of beat-to-beat vari- atic. Table 2 is a summary of available
ability in heart rate, and loss of the im- data on the influence of autonomic neumediate heart-rate response to standing ropathy on mortality and IDDM. As this
(32,66,69). These tests were initially summary shows, although Ewing's obthought to reflect cardiac parasympa- servations were thought to be an overes-

DIABETES CARE, VOLUME 15,

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Vinik and Associates

Table 2Influence of autonomic neuropathy on mortality in IDDM

REFERENCES

482.

EWING ET AL.,

1980

LENGTH OF

OVERALL

FOLLOW-UP

MORTALITY

SELECTION CRITERIA

(YR)

(%)

40

AUTONOMIC SYMPTOMS AND

19 MO-5

53

3-5

27

5
5
5
5

19
24
46
27

ABNORMAL A F T

71.

WATKINS,

64

1980

AUTONOMIC SYMPTOMS AND

ABNORMAL A F T

74A. HASSLACHER,

1983

246. SAMPSON, 1990

245. KAHN AND VINIK,
10. O'BRIEN, 1991

1987

16
41
30
84

ABNORMAL BEAT-TO-BEAT
ABNORMAL

AFT

ABNORMAL

AFT

ABNORMAL

AFT

timate, it is apparent that based on

asymptomatic subjects with only abnormalities in AFTs, the overall mortality
rate may be as high as 25-40% (75).

PATHOGENESIS Table 3 and Fig. 1

summarize the current theories of pathogenesis of diabetic neuropathy. The most
important pathological change in diabetic
polyneuropathy is loss of myelinated and
unmyelinated nerve axons. Distal nerves
are more affected than proximal nerves, as

Table 3Factors that have been implicated

in the etiology of diabetic complications
METABOLIC CONSEQUENCES OF HYPERGLYCEMIA
POLYOL PATHWAY ABNORMALITIES
MYO-INOSITOL DEFICIENCY
NA+-K+-ATPASE

DEFICIENCY

ENZYMATIC GLYCATION OF PROTEINS

NONENZYMATIC FATTY ACID AND
PROSTAGLAND1N ALTERATIONS
PROTEIN KINASE C ALTERATIONS
GROWTH HORMONE EXCESS
VASCULAR COMPLICATIONS OF HYPERGLYCEMIA
EPINEURAL VESSEL ATHEROSCLEROSIS
ENDONEURIAL MICROVASCULAR DISEASE
ALTERED ENDOTHEUAL CELLS
THICKENED BASEMENT MEMBRANES
MICROVASCULAR OCCLUSIONS
DECREASED ERYTHROCYTE DEFORMATION
DISORDERED HEMOSTASIS (PLATELET
HYPERAGGREGABIUTY)
AUTOIMMUNITY
DISORDERED NERVE SURVIVAL AND REGENERATION
ALCOHOL AND TOBACCO
HYPOGLYCEMIA

DIABETES CARE, VOLUME 15,

NUMBER 12,

determined by postmortem nerve fiber

density determinations (76) and electrophysiological observations (77).
This axon loss is also accompanied by demyelination, as shown by
Thomas and Lascelles (78) with teasedfiber preparations 25 years ago. Segmental demyelination in diabetes may be primary, from loss of individual Schwann
cells, or secondary, the result of responses
to changes in axonal caliber (79).
Recently, Sima et al. (80) described subtle changes at the nodes of
Ranvier along human diabetic nerves, including paranodal swelling and alterations of Schwann cell attachments to
paranodal axons, termed axo-glial dysjunction. This anatomical abnormality is
associated with nerve-conduction slowing that improves with therapy (81). The
defect is still inadequate to account for a
major portion of the nerve-conduction
slowing in diabetes that is not explained
by loss or demyelination of the large caliber axons (82). However, it does occur
with other experimental metabolic neuropathies (83,84) and, therefore, may
not be unique to diabetes.
For at least 60 years, pathologists
have known that patients with diabetes
have abnormal nerve blood vessels.
Fagerberg (85) called attention to the
parallel between the severity of neuropathic abnormalities and endoneurial
basement membrane thickening. Numerous other researchers have now confirmed this relationship (86,87), although the observations do not prove a

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1992

direct causal relationship between abnormalities in vasa nervorum and the severity of neuropathy. Others have demonstrated focal infarctive lesions in
proximal diabetic nerves obtained from
patients who appeared to have a lengthdependent polyneuropathy (88,89).
Acute ischemia has been implicated in certain mononeuropathies, but
also may participate in the development
of polyneuropathy. An acute multifocal
ischemic basis for diffuse polyneuropathy is unlikely because nerves are highly
resistant to ischemia and have a rich collateral circulation with low metabolic requirements (83,90). Furthermore, acute
vascular insufficiency causes focal, not
diffuse, injury (91). Nonetheless, multifocal ischemic lesions could have a pathogenic role in diabetic polyneuropathy.
Indeed multifocal infarcts have
been found in proximal nerves of patients with diabetic polyneuropathy
when such changes were sought at autopsy (88,89). The ischemic lesions
resemble those found in the case of proximal motor neuropathy (92).

Microvascular theory of
pathogenesis of neuropathy
It is now widely accepted that mononeuropathy is a vascular disease. The acute onset independent of relationship to diabetes
control and the spontaneous resolution
without treatment testify to a vascular nature. Occlusion of vasa nervorum has been
documented in isolated third nerve pulses
supporting the contention (92).
That microvascular disease plays
a primary role in the pathophysiology of
distal symmetric diabetic neuropathy has
been postulated for various reasons; this
theory has gained increasing support
among its believers, and it is a hotly
debated issue among metabolists. Arguments in support of the vascular theory
are: 1) the strong association between the
presence of neuropathy and microvascular disease in diabetes (20,93-95); 2) the
basement membrane abnormality that is
characteristic of diabetes, which has been
reported by several authors to involve

1931

Diabetic neuropathies

Metabolic
Axonal Atrophy
Demyelenation

^polyols, sorbitol
+ fructose
r
f

DIABETES
+
Genetic/
Environmental
(Alcohol,
Tobacco)

myoinositol

Na+/K+ ATP

Autoimmune

-Clinical
Neuropathy

Anti Ganglioside
AntiGAD

Segmental
Demyelination
height

Vascular
Closure of

Endoneurial
Hypoxia

Vasa Nervorum
Trauma

Other Hemoglycemic Abnormalities

Platelet Aggregation
rbc deformability
Circulating Immune Complexes
He mato logic
Advanced Glycosylation Endproducts (AGE)
Figure 1Model for pathogenesis of diabetic neuropathy.

the vasa nervorum in diabetes (82,87,

96); 3) reports of thrombosis in mediumsized intraneural arterioles (92); 4) axonal stasis, swelling, and secondary demyelination in the rat sciatic nerve
secondary to acute ischemia (97); 5) reduced nerve blood flow, and decreased
nerve oxygen tension and increased vascular resistance in STZ-induced diabetic
rats (98); 6) the prevented-by-oxygen
supplementation of the nerve conduction abnormality in STZ-induced diabetic rats (99), reduced sural nerve oxygen tension, and increased vascular
resistance in diabetes (100); 7) sural
nerve biopsies from patients with diabetic polyneuropathy reveal an increase
in the number of endothelial nuclei per
capillary closure in patients with neuropathy, which also positively correlates
with the severity of neuropathy (101).

1932

Careful clinical examination often

suggests a patchy multifocal distribution of
the sensory loss unlike that of a metabolic
disease but more compatible with a vascular etiology. Our own studies that link tobacco smoking (102) and other evidence
of microvascular disease also favor this.
Furthermore, several pathological studies
support an ischemic mechanism as a cause
of loss of nerve fibers (103). Disordered
hemostasis is the hallmark of diabetes,
with an increased propensity to platelet
aggregation (104,105) and abnormal hemorrheology decreased erythrocyte deformability. A verifying theory for the pathogenesis of neuropathy, retinopathy,
nephropathy, and macrovascular disease
would require consideration of a generalized small vessel disease. Thus, microvascular pathological abnormalities and
ischemia may be involved in the patho-

genesis of diabetic polyneuropathy. They

may not represent the cause(s) of all
forms nor contribute to every variety, but
they may be of great significance in certain subsets of patients with neuropathy.
More recent studies have shown
that within 2 - 3 wk of STZ-induced diabetes in the rat, if glycemic control is
poor, a diffuse distal nerve fiber loss occurs with multiple proximal nerve infarcts, giving the erroneous impression
that the disorder is one of a distal axonapathy, as is nerve fiber loss in diabetes
in humans. Waxman (91) has discussed
the theoretical explanation of a diffuse
process that causes predominantly distal
symptoms as a result of excess vulnerability of the longest fibers to injury. Focal
nerve destruction restricted to proximal
segments also could produce diffuse distal fiber loss. The interweaving axons descending down a nerve change the appearance to a homogeneous pattern that
mimics a dying-back neuropathy.
Epidemiological laboratory evidence implicates hyperglycemia and other
consequences of insulin deficiency in the
pathogenesis of neuropathy. The putative
mechanism by which hyperglycemia initiates or sustains tissue damage in diabetes
remains controversial. Several glucoseinduced metabolic abnormalities, including nonenzymatic protein glycation (106),
glucose-dependent gene induction (107),
and polyol pathway activation (108,109),
have been invoked as potential tissuespecific mediators of glucose toxicity.
A relationship between polyol
pathway activation and the acutely reversible slowing of nerve conduction was
initially described in diabetic rodents by
Gabbay (110). Activation of the polyol
pathway by glucose is a prominent
metabolic feature of peripheral nerve in
animals with acute diabetes, where it
promotes sorbitol and fructose accumulation, myo-inositol depletion, and slowing of nerve conduction (110-112).
Similar, although not identical, metabolic changes have been noted in peripheral nerves from diabetic humans (113-

DIABETES CARE, VOLUME 15, NUMBER 12, DECEMBER 1992

Vinih and Associates

116); and where ARls diminish sorbitol

accumulation (113,115), an increase in
nerve conduction also occurs (117). Furthermore, the accumulation of sorbitol
and depletion of myo-inositol are accompanied by a secondary abnormality in
phosphoinositide metabolism and a decrease in Na+-K+-ATPase pump regulation and hence, signal transduction,
which in turn may contribute to functional and structural abnormalities
within the peripheral nervous system
(118). The acutely reversible component
of nerve-conduction slowing has been
attributed to reduction in the resting
membrane potential that corresponded
to a four- to fivefold increase in intraaxonal Na + , consistent with a reduction
in activity of the electrogenic Na + -K + ATPase (81,119,120).
Taken together, these studies attribute the rapidly reversible component
of nerve-conduction slowing in the
acutely diabetic rats to polyol pathwayinduced myo-inositol-related alteration
in neural Na+-K+-ATPase activity. An
important effector limb of the phosphoinositide signal transduction system (121)
is endogenous DAGs, largely derived
from ntyo-inositolcontaining phospholipid. Impairment in phosphoinositide
turnover with a reduction in the generation of DAGs may be responsible for the
decrease in activation of the Na + -K + ATPase, as has been observed in erythrocytes from STZ-induced diabetic rats
(122). These observations are consistent
with the notion that a component of phosphoinositide turnover is involved in protein kinase C-mediated regulation of Na + K+-ATPase activity and the altered polyol
pathway activity in peripheral nerve.
However, structural and functional defects in nerve fibers appear to be
responsible for the majority of the clinically significant effects in diabetic neuropathy. Ward et al. (123) report elevated nerve sorbitol levels but normal
myo-inositol levels in peripheral nerve
tissue from diabetic patients. Dyck et al.
(124) found no increase in sorbitol or
fructose in nerves taken from maturity

DIABETES CASE, VOLUME 15,

NUMBER 12,

onset diabetic subjects. In contrast, Mayhew et al. (114) found markedly elevated
sorbitol levels and diminished myoinositol levels in femoral nerve specimens obtained at autopsy from diabetic
subjects. Dyck et al. (113), in a wide
variety of patients with diabetes, found a
rise in nerve sorbitol that was not statistically significant, but no reduction in
myo-inositol levels. Numerous explanations have been suggested for these discrepancies, including differences between fresh and autopsy material and the
cross-section of sample measured. Differences may exist between tissues obtained
from IDDM and NIDDM subjects. For
example, sorbitol levels were found to be
higher in IDDM subjects compared with
NIDDM subjects, despite comparable
nerve glucose levels, and myo-inositol
was consistently decreased in both
groups of diabetic subjects (114,125).
In diabetes in humans, the expected decrease in myelinated nerve fiber
density and morphometric evidence of
nerve fiber atrophy and Wallerian degeneration (80) has been found, but, contrasting with the animal studies, axoglial dysjunction is not uniformly found
in NIDDM and is not statistically increased over age-matched control subjects, although it appears to be a significant abnormality in nerves of IDDM. On
the other hand, Wallerian degeneration
is increased in the NIDDM group (80).
The nonrandom distribution pattern of
nerve fiber loss has been interpreted by
some authors (126,127) as indicative of
vascular ischemic damage that may be a
function of age, duration of diabetes, and
type of diabetes, but this has been contested by others (80)
Hypoglycemia
Hypoglycemia also has received attention
for its possible role in the development
of diabetic neuropathy. The development of peripheral neuropathy associated with insulinoma-related hypoglycemia was documented by Jaspan et al.
(128) in 1982. Although the pathway
through which hypoglycemia leads to

DECEMBER

1992

nerve damage in this disorder is unclear,

this association has led to the hypothesis
that hypoglycemia, and hyperglycemia,
may contribute to nerve injury in diabetic individuals. Frier and Hilsted (129)
have hypothesized the involvement of a
vascular pathway, whereby hypoglycemia induces an increase in hematocrit
and blood viscosity, a decrease in capillary blood flow, and subsequent hypoxia
and ischaemia to already threatened microvasculature. The importance of hypoglycemia as a contributing factor to diabetic neuropathy is probably not great,
although no experimental or clinical data
are available.
Alcohol
Mounting evidence indicates that alcohol, a known neurotoxin, may play a role
in the initiation or exacerbation of symptomatic diabetic neuropathy. McCulloch
(130) observed that the prevalence of
neuropathic symptoms increased with
increasing levels of alcohol among diabetic males in his clinic population. We
previously reported a threefold increase
in the prevalence of symptomatic neuropathy among drinkers compared with
nondrinkers, although no dose-response
relationship was apparent, and the association was observed among IDDM males
only (131).
Autoimmunity
Awareness of the possible contribution of
autoimmunity to the development of diabetic neuropathy has increased. We
have reported on the presence of autoantibodies in the circulation of diabetic
patients to sciatic nerve, postganglionic
sympathetic neurons, and structures
within the vagus nerve (132). Whether
or not these contribute to the pathogenesis of this disorder or are simply markers of neuronal destruction remains to be
elucidated.
It long has been recognized that
autoimmune pancreatic P-cell destruction, which is attributable to loss of immunological tolerance to self-antigens
present in insulin-secreting

1933

Diabetic neuropathies

within the pancreatic islets, is a major

event in the pathogenesis of insulin deficiency in IDDM (133-135). One or
more susceptibility factors are encoded
by the major histocompatibility complex
on chromosome 6, probably by the DQ
Al and Bl loci (136,137). The nature of
the antigen has, however, been elusive,
and whether or not the (3-cell is the culprit or the victim of the autoimmune
response has not been resolved. One of
the identified antigens is a 64,000-Mr
islet protein.
Autoantibodies to a 64,000-Mr
islet cell protein are associated with
IDDM and have been detected years before the onset of symptoms (138-140).
In addition, other IDDM-associated autoantibodies, such as those against insulin and cytoplasmic gangliosides of islet
cells, appear later, possibly as a consequence of the release of these antigens
(or their precursors) from the damaged
islet cells. The identification of autoantibodies to GAD in the stiff man syndrome
(141), a disorder associated with IDDM,
led to a search for the possible identity of
GAD antibodies with those to the
64,000-Mr islet cell autoantigen.
Baekkeskov et al. (142) reported
that the 64,000-Mr islet cell autoantigen
is indeed a form of GAD, the enzyme
responsible for the synthesis of GABA in
the brain, peripheral neurons, pancreas,
and other organs (143). Tobin et al.
(144) have identified two GADs, a
65,000 Mr and 67,000 Mr, which differ
in molecular size, amino acid sequence
(with 30% sequence divergence), and
in their intracellular distributions and interactions with GAD cofactor pyridoxal
phosphate (144-147). In the brain neurons, GAD65 is preferentially associated
with axon terminals, whereas GAD67 is
present in both terminals and cell bodies
(144).
Recently it has been suggested
that autoantibodies to one or both forms
of GAD are present in the sera of IDDM
patients long before symptoms of neuropathy appear. Individual sera showed
distinctive profiles of epitopic recogni-

1934

tion, and antibodies to GAD tend to de- macroglobulinemia, lymphoma, and cercline after diabetes onset but appear to tain leukemias (151) and antibodies to
persist in those individuals who have gangliosides; anti-GMl and anti-asialo
neuropathy. Attempts to define an etio- GM1 antibodies are associated with inlogical role for these antibodies is based flammatory neuropathy and paraproteinemia. We therefore studied 46 submainly on circumstantial evidence.
jects,
26 IDDM and 20 NIDDM, with
Hirsch and Shamoon (148) have
mild
peripheral
neuropathy compared
noted a selective defect in EPI secretion
with
26
nondiabetic
control subjects and
in response to hypoglycemia with presshowed that 33% of diabetic patients
ervation response to exercise.
Cross-sectional studies have had antibodies concentrations >5 SD
noted the presence of complement-fixing above the nondiabetic control subjects for
antiadrenal medullary antibodies in 30% GM1 and asialo GM1, and that a signifiof IDDM patients, which decreases after cant correlation was observed between the
16 yr of diabetes (149), suggesting that antibody level and sural amplitudes.
the antibodies may play a causative role
These studies on the presence of
in the development of neuropathy of the antibodiesto GAD and various glycoadrenergically innervated adrenal me- proteins and nervous tissueraise the
dulla. Furthermore, we have previously interesting question of whether these
described antisympathetic ganglia au- simply are attributable to damage resulttoantibodies in IDDM (135), which may ing in an antigen leak provoking an imbe associated with the diminished cate- mune response, or whether they play a
cholamine response to a change in pos- primary role in the development of neuture (150) and orthostasis, further sup- ropathy. Further studies clearly are
porting the notion that the adrenergic needed to determine the natural history
nervous system is indeed a target for of the antibodies in relationship to neuropautoimmune destruction.
athy and examination of various models of
We have hypothesized that the neuropathy to establish the pathogenetic
increased prevalence of complement- capabilities. This will be of vital imporfixing adrenomedullary antibodies in tance in future directions for managesubjects with diabetes of <16 yr dura- ment of neuropathic complications attion may precede the onset of autonomic tributable to an autoimmune, as opposed
neuropathy, but a cause and effect rela- to metabolic or vascular, etiology.
tionship between the presence of these
antibodies and neuronal dysfunction has DISORDERED NERVE SURVIVAL
not been clearly established.
AND REGENERATION IN
More recently, we examined the DIABETES Any hypothesis directed
sera of 120 IDDM patients for the pres- at the pathogenesis of neuropathy must
ence of complement-fixing antisciatic address the characteristics of axonal denerve antibodies (135): 26 of 120 (22%) generation, demyelination and atrophy,
had fluorescent scores exceeding any and and decreased NCV, which typify the
all of those in 66 normal control sub- disease (4). Recently, some attention has
jects. Surprisingly, 3 of 12 (25%) been directed to the role of growth facNIDDM patients were also positive for tors in diabetic neuropathy, with particcomplement-fixing antibodies, and a ular attention to NGF. Because neuronal
possible role in the pathogenesis of so- growth factors can promote the survival,
matic neuropathy was raised. The anti- maintenance, and regeneration of neubodies found in our studies differed from rons subject to the noxious effects of dithose reported above. It is well estab- abetes, the relative success of diabetic
lished that circulating antibodies may patients in maintaining normal morpholhave a pathogenetic role in neuropathies ogy and function of their nerves ultiassociated with amyloidosis, myeloma, mately may depend on normal expres-

DIABETES CARE, VOLUME 15, NUMBER 12,

DECEMBER

1992

Vinik and Associates

sion of these factors. Many of the

neuronal changes characteristic of diabetic neuropathy are similar to those observed after removal of target-derived
growth factors by axotomy or depletion
of endogenous NGF by experimental induction of NGF autoimmunity. Current
knowledge of growth factors and their
possible role in the pathogenesis of diabetic neuropathy will be discussed.
Throughout life, an intimate neuron-target interaction occurs that affects
the normal functioning of both neuron
and target for their survival and maintenance. One aspect of this interaction is a
neuronal dependence on retrogradely
transported, target-derived growth factors. In the cell body, these growth factors regulate neuronal gene expression,
and consequently protein synthesis, and
thereby play a role in cell survival and
maintenance of the cell and its processes.
Moreover, during development or after
axonal injury, various grow factors enhance axonal growth.
NGF, discovered nearly 50 years
ago, is the most thoroughly studied of a
growing list of NGFs. It has been known
since the pioneering work of LeviMontalcini (152-154) that neural crestderived cells, sympathetic neurons, and
DRG neurons, are developmentally dependent on NGF. More recently, it has
been shown that adult DRG and sympathetic neurons, both of which are populations of neurons affected in diabetic
neuropathy, are dependent on NGF either for their maintenance (155) or their
survival (156).
Faradji and Sotelo (157) have
shown a decline in serum NGF levels in
diabetic patients compared with normal
control subjects. Moreover, the decline
in serum NGF levels was greater in patients with greater neurological impairment. Although these data suggest a decline in NGF synthesis in diabetes as a
causative factor in diabetic neuropathy, a
recent study of STZ-induced diabetic rats
reported increases in NGF levels in most
NGF-producing tissues (158). Yet, despite the increases in target-tissue NGF

DIABETES CARE, VOLUME 15,

NUMBER 12,

levels in this study, NGF levels in the

superior cervical ganglion, an NGFdependent population of neurons, was
reduced dramatically.
Moreover, Hellweg et al. (159)
showed that retrograde transport of NGF
in the sciatic nerve was reduced in STZinduced diabetic rats. Decreased retrograde NGF transport in axons of the
STZ-induced diabetic rat ileal mesenteric
nerves has been reported by Schmidt et
al. (160) preceding the development of
frank distal axonopathy.
After sciatic nerve section in normal adult rats, a significant number of
the axotomized neurons in the involved
DRGs die (156,161,162). This cell loss
can be completely eliminated by the application of exogenous NGF to the cut
proximal end of the nerve (156). Moreover, those DRG neurons do not die after
sciatic nerve section (156) or in vivo. NGF
depletion (155) exhibits significant atrophy of their cell bodies and axons. This
atrophy is reversed at least partially by the
application of exogenous NGF (156).
One possible mechanism underlying the NGF-induced reversal of DRG
neuronal atrophy was demonstrated recently by Verge et al. (163). They
showed that an axotomy-induced downregulation of neurofilament gene expression in DRG neurons that express NGF
receptors was reversed by intrathecal infusion of NGF. Neurofilaments are believed to be important in maintaining cell
body size and axon diameter (164,165);
and therefore, by controlling neurofilament gene expression, NGF can regulate
cell size and axonal diameter. NGF affects neurofilament gene expression only
in DRG neurons with NGF receptors
(163).
Atrophy of DRG neuronal cell
bodies in experimental diabetes has been
reported (166). Moreover, considerable
evidence indicates reduced axonal diameters and concomitant slowed conduction velocities in diabetic patients and in
animal models of diabetes (167,168). A
role for NGF in the maintenance of normal axon diameter by its effect on neu-

DECEMBER

1992

rofilament gene expression has been discussed above, however, neurofilament

synthesis in large, light DRG neurons
apparently is regulated by other, nonNGFs derived from skeletal muscle
(169). It is reasonable to expect that retrograde transport of these factors also
might be disturbed in diabetes and hence
lead to a downregulation of neurofilament gene expression in non-NGFreceptive neurons.
A study by Larsen and Sidenius
(170) supports, in part, the idea of a
downregulation in neurofilament gene
expression in STZ-induced diabetic rats.
They showed a reduction in the amount
of high molecular neurofilament protein
transported by slow axonal transport in
diabetic rats. This reduction could reflect
a reduced synthesis of the protein caused
by a downregulation of the gene.
NGF is also important in the regulation of SP synthesis in adult DRG
neurons (171,172). SP is found in the
sympathetic nervous system and in a subpopulation of DRG neurons (173). It has
been implicated in diverse and widespread
activities, including vasodilation, gut motility, and nociception (173), all of which
are perturbed in diabetic neuropathy.
Lindsay and Hamar (172) have
shown that NGF is involved in the regulation of mRNAs that encode the precursor molecules of SP and CGRP. They
showed that in vitro NGF deprivation
caused cultured adult DRG neurons to
downregulate the mRNAs for the SP and
CGRP precursor molecules. Moreover,
when adult rats are immunized against
mouse NGF, a procedure that causes an
autoimmune depletion of NGF, SP levels
are reduced in the DRG, spinal cord, and
skin by - 6 5 % (171).
Perturbations of pain sensation is
characteristic of diabetic neuropathy,
and the levels of SP, which has been
implicated as a nociceptive transmitter
(173), are reduced in diabetic rats. Calcutt et al. (174) have reported a slight
reduction in SP levels in DRG neurons.
In addition, the amount of anterogradely
transported SP is reduced in STZ-in-

1935

Diabetic neuropathies

duced diabetic rats (174-176). Neither

treatment with an ARI (sorbinil) alone
nor with gangliosides affected the
amount of SP transported in sciatic
nerves of diabetic rats (174-176). From
their observations, Calcutt et al. (174)
concluded that a selective downregulation of SP precursor gene expression
caused by a decline in NGF reaching the
ganglia via retrograde transport could explain a reduction in SP synthesis and
transport in STZ-induced diabetic rats. It
remains to be established that the reduction in SP is pertinent to the symptom
complex of neuropathy.
IGFs also may be implicated in
the pathogenesis of diabetic neuropathy
because of their shared structural homology with insulin, widespread distribution throughout the nervous system, and
profound effect on developing neurons.
IGF-I and IGF-II are known growth factors that have been implicated in the
growth and differentiation of neurons.
Both insulin and IGF-II can promote
neurite outgrowth of neuroblastoma cells
in vitro (177,178), and IGF-I has been
implicated in the survival and differentiation of fetal rat brain neurons in culture
(179).
Kanje et al. (180, 181) have
shown that IGF-I is important in determining successful peripheral nerve tissue
in vivo. They showed that administration
of exogenous IGF-I to nerve repair sites
via miniosmotic pumps significantly enhanced nerve regeneration. Likewise, regeneration was inhibited if the nerve was
perfused with antibodies directed against
native IGF-I.
To date, little research has been
conducted that associates reduced IGF
protein levels, whether attributable to
impaired transport or synthesis, with the
occurrence of diabetic neuropathy. One
study showed that animals with decreased plasma levels of IGF-I because of
experimentally induced diabetes show a
marked impairment in peripheral nerve
regeneration (182). Interestingly, previous studies that examined peripheral
nerve regeneration in animals with ex-

1936

perimentally induced diabetes also

showed an impairment in nerve regeneration (183). The molecular basis of this
impairment is at present unknown.
However, given that unidentified soluble
neuronal and Schwann cell-promoting
factors are produced and released during
normal conditions of peripheral nerve
repair (184,185), it is possible that the
expression of these factors is compromised in a diabetic state similar to that
reported for IGF-I.

Neurotrophic factors and

neuropathy
With our new understanding of the role
of growth factors in the control of growth
initiation, proliferation, and the apoptotic process whereby remodeling of
neurons occurs, it becomes possible to
consider the use of neurotrophic factors
in the treatment of diabetic neuropathy.
Aided by the availability of large quantities of recombinant neurotrophic factors,
it is feasible to consider their possible
place in the management of diabetic neuropathy. The choice of the optimal neurotrophic factor is dependent on an
awareness of the neuronal population involved in the disease process and an understanding of the specificity of each factor for a specific neuronal population
affected by the disease process. This emphasizes the need for more specific delineation of the neuronal population involved in the disease process and the
specific syndrome present in a particular
patient.
Sympathetic and DRGs express
receptors for the neurotrophins, NGF,
bFG, and BDNF; thus, these agents may
prove efficacious for the treatment of the
small fiber sensory and autonomic neuropathies (186,187). The motor neuropathies are candidates for treatment with
various growth factors, including CNTF,
IGF-1, bFGF, and certain other musclederived growth factors (188-190).
The optimum approach to mixed
sensory neuropathies may be the use of
factors with less specificity for motor or
sensory neurons. Some factors, such as

CNTF, exert trophic actions on both sensory and motor neurons (191,192) and
will be worthy of trial in mixed neuropathies. Alternatively, the use of combinations of growth factors, each with actions
on a component of the neuropathic process, may prove to be the appropriate
approach.
Stimulating nerve growth and regeneration as well as remodeling growth
factors that target neurons may decrease
the vulnerability to damage by the diabetic disease process and may enhance
neuronal ability to compensate for recovery from the regenerative process. NGF
has been considered for the treatment of
Alzheimer's disease because of the loss of
cholinergic neurons in this disease and
the pronounced and selective trophic action of NGF on cholinergic neurons
(193). Recombinant NGF has been
shown to reverse experimental cholinergic injury in animals (194,195). bFGF
and BDNF also protect cholinergic cell
bodies, although not as well as NGF
(196,197).
Evidence also indicates that
dopaminergic neurons may be responsible to treatment with growth factors.
BDNF, bFGF, IGF-1, and EGF promote
developmental differentiation of the
dopaminergic neurons affected in Parkinson's disease (198-201).
Even motoneurons may be protected from cell death. CNTF rescues
motoneurons from naturally occurring
cell death during chick embryo development and may retard motoneuron degeneration in the adult (190,192).
Early results of treatment of toxic
neuropathies with growth factors are encouraging. The small fiber sensory neuropathy induced by taxol can be prevented by the administration of NGF
(202). The large fiber neuropathy induce
by the antitumor agent cisplatinum with
prominent propioceptive deficits can be
prevented in rodents (203) treated with
NGF (204), which also has been shown
to prevent or delay the development of
sensory neuropathy in STZ-induced diabetes. CNTF supports the survival of cul-

DIABETES CARE, VOLUME 15,

NUMBER 12,

DECEMBER

1992

Vinik and

Table 4Neurotrophic factors and possible therapeutic strategies for diabetic neuropathies
AUTONOM1C

SOMATIC
MOTOR

SENSORY

MIXED

ADRENERGIC

CHOLINERGIC

DOPAMINERGIC

+
+

+
-

+
-

+
+

+
+

+
+

+
+
-

+
+

GROWTH FACTORS

CNTF
1GF-1
BFGF
MUSCLE-DERIVED

NGF
BDNF
EGF
COMBINATIONS

tured neurons and promotes motor neuron survival after axotomy (190,192) and
thus shows special promise for the treatment of the pure motor neuropathies in
diabetes. A table is included that shows
the prospective uses of growth factors in
nerve damage (Table 4).
The question as to how growth
factors will gain access to neurons may
not be as difficult as once believed. 1mplantable pumps, now used extensively
in the treatment of diabetes, may permit
delivery of adequate concentrations of
growth factors to peripheral nerves
where they may act locally. The future is
also promising for the implanting of genetically engineered cells (205,206). It is
also within the realms of possibility that
pharmacological agents will be able to
selectively modify the activity of neurotrophic agonists (207,208), as has been
shown for certain alkaloidlike compounds.
In summary, although the mechanism of action remains unknown, the
current knowledge of growth factors and
their relationship to diabetic neuropathy
suggests a pathophysiological role for reduced levels of NGF and possibly the
IGFs available to neuronal cell bodies. In
this regard, it is now conceivable that
neuronal function, atrophy, and possibly
cell death may be compromised in diabetic neuropathy by this reduction.
Whether the growth factor deficiency is
caused by decreased synthesis, an inabil-

DIABETES CARE, VOLUME 15,

NUMBER 12,

ity of the factor to bind to its receptor,

disturbances in retrograde axonal transport, or intraneuronal processing remains to be established. However, further studies aimed at understanding the
gene and protein expression of potential
peripheral NGFs during diabetic neuropathy, and their receptor-binding and
subsequent transport from sites of synthesis to sites of action should shed considerable light on the relationship between growth factor expression and
diabetic neuropathy.
CLINICAL MANIFESTATIONS
From a clinical perspective, it is useful to
classify diabetic neuropathy into the two
broad categories of somatic and autonomic neuropathies, each with its own
further subdivisions. The somatic neuropathies tend to fall into three major
subdivisions: symmetric distal polyneuropathies, proximal motor neuropathies,
and focal neuropathies. Although it is
convenient to consider these separately,
in practice, observed patterns often overlap and involvement of sensory, motor,
and autonomic nerves usually coexist
(8,209,210).
Although cooling-detection
thresholds are advocated by some as a
sensitive and reproducible assessment of
peripheral small fiber function (211), a
practical and reproducible method of assessment is not yet readily available. This
is disappointing because small fiber de-

DECEMBER

1992

Associates

fects may occur early in diabetes, and

may be the first sign of the development
of neuropathy (68). Defects of peripheral
thermal sensation may occur independently of vibration perception and may
reflect similar defects in the small peripheral autonomic fibers (212-214).
CLINICAL PRESENTATION
Somatic neuropathies
Symmetrical distal polyneuropathy.
This is the most common and widely
recognized form of diabetic neuropathy.
The onset is usually insidious but occasionally acute, and it follows stress or
initiation of therapy of diabetes. The deficit is predominantly sensory with lesser
involvement of motor fibers. Signs include depression or loss of ankle jerks
and vibratory sensation with calf tenderness and hyperalgesia in some patients.
The neurological deficit is peripheral, involving the distal sensorimotor nerves in
a glove and stocking distribution. The
lower extremities receive the major brunt
of the affliction. The stocking is not a
single line of loss of one modality of
sensation but rather multiple gloves and
stockingsare noted, one for each modality. In general, the long fibers that are
affected most severely, such as those for
position, sense, and touch, have the
highest stocking and the short pain fibers
the lowest stocking. If all the levels coincide, then one must be alert to the
possibility of a conversion reaction or
hysteria. The long and short fibers are
affected differentially. The condition
starts distally and proceeds proximally.
The type of neuropathy varies with the
type of nerve fiber involved. Large fibers
are associated with loss of position and
vibration sense, and half of light touch
and sensory ataxia with loss of ankle
reflexes. The symptoms may be minimal,
such as sensations of walking on cotton
wool and floors feeling strange; or they
may be more severe, such as the inability
to turn the pages of a book or discriminate coins. In contrast, the small fiber
neuropathy is associated with a loss of

1937

Diabetic neuropathies

pain sensation and loss of the awareness

of temperature differences.
Painful neuropathySome patients may develop a predominantly
small fiber neuropathy, which is manifested by pain and paresthesia. Symptoms are often exacerbated at night and
are manifested in the feet more than the
hands. Spontaneous episodes of pain
may be severely disabling. The pain varies in intensity and character. In some
patients, the pain has been described as
burning, lancinating, stabbing, tearing,
aching, or like a dog gnawing at the
bones. In others, it has been described as
dull, like a toothache in the bones of the
feet, or even crushing or cramp-like. Pain
often is accompanied by paresthesia or
episodes of distorted sensation, such as
pins and needles, tingling, coldness,
numbness, or burning (79). The lower
legs may be exquisitely tender to touch,
with any disturbance of the hair follicles
resulting in excruciating pain. Because
pain may be aggravated by repeated contact of the lower limbs with foreign objects, even basic daily activities such as
sitting at a desk may be disrupted. Pain
often occurs at the onset of the disease
(57) and often times is made worse by
initiation of therapy with insulin or sulphonylureas (215-217). In this early
form of the painful syndrome, the condition often remits spontaneously and
the management entails supportive therapy. It may be associated with profound
weight loss and severe depression and
has been termed diabetic neuropathic cachexia (218). The syndrome occurs predominantly in males and may occur at
any time in the course of both IDDM and
NIDDM.
Unfortunately, another variety of
painful polyneuropathy exists with onset
occurring later in diabetes, often years,
and in which the pain persists and becomes quite debilitating.
This condition may lead to habituation to narcotics and analgesics and
finally addiction. This latter variety, although relatively infrequent, is inordinately resistant to all forms of interven-

1938

Pain

Threshold

No Pain
Good

Neural

Function

Bad

Figure 2Starling's curve for pain in diabetic neuropathy.

tion and can be most trying to patients

and their physicians.
The mechanism for acute pain in
small fiber neuropathy is not well understood. In some patients, the heralding
features of their diabetes may be the onset of acute painful neuropathy (218),
whereas in others the condition appears
soon after initiation of therapy (217).
Hyperglycemia per se may be a factor in
lowering the pain threshold (219), however, in others a striking amelioration of
symptoms has been observed with the
lowering of blood glucose (57,216). A
plausible theory relates to the regeneration of small, unmyelinated fibers causing spontaneous discharges of impulses
that subserve pain (215,220). It is also
feasible that with the recovery from the
initial episode of hyperglycemia, these
small fibers grow and cause pain (Fig. 2).
This hypothesis, however, may not be
compatible with the observation that regeneration of all nerve fibers has been
found with both the painful and painless
varieties of neuropathy (221). It is also
feasible that with loss of the balancing
influences of large fibers comes a predominant effect of small fiber signal
transmission, which then is associated
with pain; in other words, a large fiber
neuropathy theoretically could generate
pain, even with intact small fibers. This
hypothesis remains, however, to be

proven. On the other hand, pain not

infrequently occurs when objective measures suggest actual recovery from the
neuropathy, implying that regrowth of
small fibers is an important constituent
of this syndrome. Indeed, loss of pain
with evidence of progression of the disease may be indicative of nerve death,
and thus may not be a welcome occurrence.
Motor weakness may occur in the
peripheral symmetric neuropathies, but
wasting of the small muscles of the hands
and feet is characteristic. This usually
occurs in very advanced cases and may
resemble motor neuron disease, although the latter has no sensory component. Loss of the deep tendon reflexes is
a hallmark of peripheral symmetrical
neuropathy, and when pure motor neuropathy is found, causes other than diabetes must be excluded. A similar neuropathy has been described in patients
with insulinomas (128), and the possibility that this syndrome is related to
overzealous treatment with insulin has
yet to be excluded.
Neuropathic (perforating) ulcerFoot ulcer constitutes a major source of morbidity among individuals with diabetes. Loss
of protective sensation and repetitive
trauma, such as walking, are the major
causes. Ulceration occurs most frequently over the metatarsal heads, but

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Vinik and Associates

also appears at other areas of increased

pressure. Loss of tone in the small muscles of the feet leads to an imbalance
between the flexors and extensors, ultimately resulting in the classic hammerclaw toe. The altered architecture of the
foot is associated with increased pressure
over the ball of the foot, which corresponds to the heads of the metatarsals.
Also, the normal person constantly shifts
the area of pressure in the foot while
walking or running, whereas the diabetic
individual with neuropathy is unable to
do so because of lack of the sensory input from the soles of the feet. This constant pressure causes calluses with increase in pressure and ultimately
ulceration in the high pressure areas. Infection develops after the skin breaks
down. Infection in the milieu of ischemia
can eventually lead to gangrene. Thus,
the three important factors in foot ulceration in the diabetic individual are vascular disease, neuropathy, and infection
(222).
Recently, the role of the autonomic
nervous system in the pathogenesis of
neuropathic ulcers has been increasingly
recognized. The hyperhydrosis, the
cracked dry skin, and the increased small
blood vessel flow create an excellent milieu for infection to take hold and proliferate (223).
Neuropathic arthropathy (Charcot's joints)

Neuropathic arthropathy, or Charcot's

joints, occurs in the presence of impaired
sensations of pain and proprioception,
intact motor power, and repeated minor
trauma and occurs usually in feet with
normal pulses and warmth. The clinical
course is painless and is characterized by
nonedematous swelling of the foot so
that the foot becomes shorter, wider,
everted, and externally rotated with a
flattening of the arch. The gait becomes
abnormal, and the clubfoot develops. It
is practically limited to the ankle and
tarsal joints in diabetes. Pathological
roentgenographic features include bone
lysis, fragmentation, and eburnation.
Disarticulation and dissolution of the
joints occurs with bony overgrowth and

DIABETES CARE, VOLUME 15,

NUMBER 12,

calcification in and around the joints following. Eventually pressure ulcers, infection, and osteomyelitis develop. The feet
of diabetic individuals often have bounding pulses that suggest an adequate large
blood vessel supply. The impression is
erroneous, however, and the bounding
pulses are now thought to be caused by
the shunting of blood through the small
arteriovenous fistulae normally regulated
by the sympathetic nervous system. The
enhanced blood flow may be conducive
to excessive bone resorption, fractures,
and osteoarthropathy (224,225).
Proximal motor neuropathies.
Diabetic amyotrophyThis syndrome
may be recognized by the triad of pain,
severe muscle atrophy in the limb girdle
distribution, and fasciculation of the
muscles. The onset is usually acute
(226), but it may be subacute and gradually evolve over weeks (227). Patients
also experience generalized weight loss
and diabetic cachexia. Asymmetrical,
proximal muscle weakness and wasting
of lower extremities, involving predominantly the iliopsoas, quadriceps, and adductor muscles, occur. Patients often
cannot stand unsupported, climb stairs,
or rise from the kneeling or sitting position. The differential diagnosis is Cushing's syndrome, thyrotoxicosis or a neoplasm, all of which produce a proximal
myopathy without evidence of nerve lesions and are characterized by intact reflexes. Other differential diagnoses include the proximal neuropathies in
which no pain or fasciculation is observed, such as Guillain Barre syndrome.
Diabetic amyotrophy often is accompanied by pain in the thigh muscles and
sometimes lumbar or perineal regions.
The knee jerks are depressed, but little or
no sensory involvement is found. The
anterolateral muscle group in the lower
leg also may be involved, producing the
anterior compartment syndrome. Occasionally, the upper limb girdle also is
affected, and wasting of the deltoids is
seen. The syndrome occurs primarily in
older NIDDM patients who frequently
have only mild diabetes. It has been pos-

DECEMBER

1992

tulated that the acute and chronic varieties of the syndrome derive from differences in pathogenesis, with the acute
variety being attributable to multiple infarcts in the proximal nerve trunks and
the lumbosascral plexus, whereas the
slowly evolving variety may be attributable to metabolic factors alluded to
above (228). The condition resolves
spontaneously but this may take from
1-3 yr.
Truncal mononeuropathy (or radiculopa-

thy)This syndrome is primarily a sensory neuropathy affecting the root distribution, which is almost always unilateral
and asymmetrical. The sex distribution is
equal, with primarily older patients being affected. Occasionally, young patients with IDDM of long duration also
may be affected. It usually is associated
with peripheral neuropathy and may resemble diabetic cachexia. Hyperaesthesia
often is found in the root distribution,
and the clinical presentation may mimic
acute abdominal or thoracic crisis resulting in unnecessary invasive procedures.
Denervation of muscles in the root segment also may occur (229-233). This
syndrome may resemble Herpe's Zoster
infection in the prevesicular phase and
occasionally spinal cord compression
from neoplasms or other causes. Nocturnal exacerbation of pain is troublesome,
but spontaneous clearing occurs, usually
within 3 mo of the onset.
Focal neuropathies. Focal and multifocal diabetic neuropathies cause neurological deficits that are confined to the
distribution of a single nerve (mononeuropathy) or multiple single nerves
(mononeuropathy multiplex). The onset
is typically acute, often heralded by severe pain, and the differential diagnosis
must generally exclude a vascular catastrophe. No clear relationship has been
determined with the age or sex of the
patient nor is a relationship apparent
with the type of diabetes, its duration,
the degree of diabetes control, or treatment.

1939

Diabetic neuropathies

Table 5Autonomic neuropathy clinical manifestations

SYSTEM INVOLVED
PUPILLARY ABNORMALITIES

oneal nerves (236,237). Again, these lesions are self-limiting but may take
somewhat longer to resolve than the cranial nerve lesions.

MANIFESTATIONS
DECREASED DIABETER OF DARK-ADAPTED PUPIL
ARGYLL-ROBERTSON TYPE PUPIL

CARDIOVASCULAR

ABNORMALITIES

Autonomic neuropathies

TACHYCARDIA, EXERCISE INTOLERANCE

CARDIAC DENERVATION
ORTHOSTATIC HYPOTENSION
HEAT INTOLERANCE
SKIN TEMPERATURE REVERSAL, DRY SKIN, AND DEPENDENT EDEMA

MOTOR DISTURBANCES OF
GASTROINTESTINAL TRACT

ESOPHAGEAL ENTEROPATHY
GASTROPARESIS

DIABETICORUM

CONSTIPATION
DIARRHEA
FECAL INCONTINENCE
GENITOURINARY TRACT DISTURBANCES

NEUROGENIC VESICAL DYSFUNCTION

SEXUAL DYSFUNCTION
MALE
IMPOTENCE
RETROGRADE EJACULATION
FEMALE
DEFECTIVE LUBRICATION

SWEATING DISTURBANCES

AREAS OF SYMMETRICAL ANHIDROSIS

METABOLIC

HYPOGLYCEMIA U N A W A R E N E S S , HYPOGLYCEM1A UNRESPONSIVENESS,

GUSTATORY SWEATING

AND HAAF

Cranial nerve lesionsLesions in the cra- within 6 - 8 wk and does not appear to
nial nerves are manifested as isolated or be a function of changing diabetes conmultiple palsies, which occur primarily trol.
in the older age-group and may occur in Isolated peripheral nerve lesionsIsolated
the absence of other evidence of neurop- peripheral nerves involve particularly the
athy. The onset is generally abrupt, and ulnar, median, radial, femoral, and latalthough painless in 50% of patients, eral cutaneous nerves of the thigh. Carmay be extremely painful in others for pal tunnel syndrome occurs twice as frereasons that are not understood (234). quently in a diabetic population
The III nerve lesion is most common. It compared with a normal healthy popucharacteristically presents as sudden on- lation, and its increased prevalence in
set with a severe ipsilateral headache of- diabetes may be related to repeated unten preceding the neurological deficit by detected trauma, metabolic changes, or
several days. Ptosis and ophthalmoplegia accumulation of fluid or edema within
are found, but, in contrast with the an- the confined space of the carpal tunnel.
terior communicating aneurysm rupture, The nerves involved are usually motor,
the pupils usually are spared (235). Of but pure sensory lesions occasionally octhe other extraocular ophthalmoplegias, cur. Nerves that are at risk for compresthe VI nerve is less commonly involved, sion are the peroneal nerve at the head of
and the IV nerve seldom is involved. The the fibula, ulnar nerve at the elbow, the
VII nerve is not infrequently affected, re- median at the wrist, and the lateral cutasulting in an isolated Bell's palsy. All neous nerve of the thigh. Affected paother cranial nerves have been reported tients may present with unexplained
to be involved but much less commonly. pain and hyperaesthesia in the upper
Recovery is generally complete outer quadrant of the thigh and the per-

1940

Diabetic autonomic neuropathy may involve any system in the body. Its manifestations are protean, and the onset is
often insidious. Subclinical abnormalities
in cardiovascular (238) and gastrointestinal function (239) may be found at
diagnosis (47) or even in teenage diabetic patients (240). The clinical features
are often unsuspected and, without careful scrutiny, may go undetected. By using cardiovascular reflex tests, the prevalence is reported to be 17-40% (240244). Of teenagers with IDDM, 31%
have abnormal tests (240). The relationship with sensorimotor neuropathy is
variable, but, in general, autonomic and
sensory motor abnormalities coexist. In
people with peripheral neuropathy, 50%
will have asymptomatic autonomic neuropathy. When symptoms of autonomic
neuropathy are present, the anticipated
mortality is 15-40% within 5 yr (72,75,
245,246). With gastroparesis, 35% die
within 3 yr, usually of aspiration pneumonia. Reduced exercise tolerance,
edema, paradoxical supine or nocturnal
hypertension (247), intolerance of heat
due because of defective thermoregulation, silent myocardial infarction, respiratory failure, and sudden death are hazards for the diabetic patient with cardiac
autonomic neuropathy (248-251). It is,
therefore, vitally important to make this
diagnosis early, so that appropriate intervention can be instituted. In the section
that follows, the clinical presentations of
autonomic neuropathy, the diagnostic
tests, and the various forms of management currently available will be discussed.
Table 5 lists a current approach
to the differential classification of autonomic neuropathy.
Pupillary abnormalities. Pupillary abnormalities may proceed all other evidence of autonomic dysfunction, if careful pupillometry testing is conducted

DIABETES CARE, VOLUME 15,

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1992

Vinik and Associates

(250). In affected subjects, Argyll-Robertson-type pupillary responses in which

the pupils react slowly to light if at all
and accommodate normally may be
found. The pupillary abnormalities do
not tend to produce any significant functional deficit, however, unless associated
with failure of dark adaptation and difficulty with driving at night (251).
Orthostatic hypotension without compensatory tachycardia. Orthostatic hypotension is defined as a fall in the systolic blood pressure of >30 mmHg
within 2 min of standing. This defect
tends to occur late in the course of diabetes and signifies advanced involvement
of the autonomic nervous system. It often is found incidentally and is not always symptomatic. After treatment, the
symptoms often abate without any real
change in the blood pressure. The defect
is thought to be attributable primarily to
involvement of the sympathetic nervous
system, which provides vasoconstrictive
input into the skeletal muscle and
splanchnic bed as well as inotropic and
chronotropic stimulation of the heart.
Because blood pressure is maintained by
a product of the cardiac output and peripheral vascular resistance, loss of adrenergic input anywhere along the path
may have pathogenetic significance, although the nature of autonomic involvement in this syndrome is obscure. A hypoadrenergic variety has been described,
ostensibly attributable to disease of the
autonomic nervous system involving the
peripheral nerves (252,253) with a reduction in the synthesis and release of
NE at postganglionic sympathetic neurones (254). A hyperadrenergic variety
also has been described, which is attributable to a reduction in the plasma volume with loss into an edema compartment, the presence of which is not
unusual in patients with autonomic neuropathy (255). Abnormalities in plasma
catecholamines have not been universally found (256), although we have
shown that a progressive decrease in a-2
adrenergic receptors occurs with worsening of the neuropathy, with the greatest

DIABETES CARE, VOLUME 15,

NUMBER 12,

deficit occurring in those patients with

postural hypotension. If this phenomenon reflected the loss of the postganglionic a-2 vasoconstricting receptor, it
might explain the postural hypotension.
On the other hand, this observation may
simply reflect an adaptive response, because in diabetic subjects with autonomic neuropathy, a 10-fold increase in
the sensitivity to NE occurs (257), as in
other conditions associated with sympathetic denervation. Nonetheless, in patients with deficient a-adrenoreceptors,
a paradoxical rise in blood pressure is
found when treated with the a-2 adrenergic agonist clonidine (258).
The loss of adrenergic a-receptors may in some instances be associated
with an excess of adrenergic f$-receptors,
hence the occasional successful outcome
of treatment with (3-receptor blocking
drugs. There may also be a cardiac element with decrease in inotropic and
chronotropic responses of the heart because of a cardiopathy involving the autonomic nervous system (258-260).
One especially prominent feature may be
the provocation of hypotension soon after the administration of insulin
(261,262), and this may be mistakenly
diagnosed as hypoglycemia and exacerbated by meal ingestion (263) or drugs
that accentuate hypotension, such as nitroglycerine, ganglion-blocking drugs,
and diuretics used in the treatment of
hypertension. Patients may even display
the paradoxical features of supine hypertension, rises in blood pressure with
REM sleep (264), and failure of the natural rise in pressure as the day progresses
(75).
Vasomotor instability.
Skin-temperature reversalA result of
loss of the sympathetic fibers in the feet
may be sweating in the upper body as a
means of dissipating heat. In some instances, this can prove uncomfortable
and can mimic the flushing episodes
found in patients with the carcinoid syndrome, unless the observer is aware of
the condition. Loss of the sympathetic
innervation of the small peripheral blood

DECEMBER

1992

capillaries in the feet leads to loss of

vasomotor tone, arteriovenous shunting,
and diapedesis with resultant dependent
edema, and drying and cracking of the
skin (65,224,264); it also may predispose the individual to foot ulceration and
ultimately gangrene and limb loss. The
edema may respond to treatment with
the adrenergic agonist, ephedrine (265).
Cardiac denervationAutonomic neuropathy has now been reported as involving the cardiovascular system with
resting tachycardia, dysfunction of both
left ventricular diastolic filling and systolic ejection, and painless myocardial
infarction. Patients with autonomic neuropathy have high sleep and waking resting heart rates that are unresponsive to
vagotonic maneuvers, such as the Valsalva and deep, slow respiration (266).
In the absence of other causes of tachycardia such as fever, anemia, thyrotoxicosis, and pheochromocytoma, the
above signs suggest vagal neuropathy.
Because these abnormalities are found
early in the course of diabetes, it was
speculated that they were attributable to
loss of the relatively long vagal fibers
compared with the short fibers (245).
More recently, this new notion has been
disputed (246). With progression of the
disease, complete cardiac denervation
ensues, and the heart rate returns to normal but does not regain the reflex responses to breathing and to change in
posture. We have shown previously that
33% of patients with diabetic autonomic neuropathy have depressed left
ventricular systolic function on radionuclide ventriculography in the absence of
ischemic heart disease, and this correlates with the severity of the neuropathy
(267). We have further demonstrated
that left ventricular diastolic filling is abnormal in those patients with the most
severe neuropathy, and that the degree of
abnormality correlates with a reduction
in circulating catecholamines and postural hypotension (260). In 30 subjects
attending a diabetes clinic, we examined
the effects of maximal treadmill response
to exercise and measured the pressure-

1941

Diabetic neuropathies

rate products at rest and maximal exercise. Of the subjects who were found to
have autonomic neuropathy, 17 had
higher resting pressure-rate products, a
function of the resting tachycardia, but
impaired responses to exercise. Thus,
cardiac autonomic neuropathy is associated with impairment of the hemodynamic responses to exercise in the absence of ischemic heart disease. On the
basis of this observation, we now caution
patients against embarking on aggressive
exercise programs without first having
a cardiovascular work-up to exclude occult autonomic cardiomyopathy.
Whether autonomic cardiomyopathy
leads to impaired exercise tolerance or
dysrhythmias is not known.
The cardiac denervation also may
predispose to painless myocardial infarction, with a risk of sudden death
(100,249,250,268-270). It has been reported that silent myocardial infarction
occurs 6-7 times more frequently in the
diabetic population than the population
at large (100). We also have found a
positive correlation between autonomic
neuropathy, prolongation of the QT interval, and sudden death (245). We have
in unpublished observations noted that
individuals with decreased uptake of the
adrenergic screening agent metaiodobenzylguanidine by the heart are at greater
risk of sudden death (245).
Respiratory dysfunctionClinical abnormalities in respiratory function do not
appear to derive from autonomic neuropathy. As reviewed by Ewing and
Clarke (244), numerous of conflicting
reports have been made on abnormalities
in airways resistance, sleep apnea, and
the response to hypercarbia. It is also
doubtful that these abnormalities contribute to the sudden death phenomenon
of diabetic autonomic neuropathy. Our
observations indicate that the respiratory
dysfunction in patients with autonomic
neuropathy comprises the failure of initiation of respiratory drive under conditions of hypoxia (271). Thus, patients
have to rely on the hypercarbic drive, a
situation that presents a real danger dur-

1942

ing anesthesia when oxygen levels are (280). Diabetic pseudo-ZE syndrome is
maintained, and CO2 is driven off. Im- readily distinguished from ZE syndrome
paired hypoxic respiratory drive also by a measurement of the gastric acid,
may account for sleep apnea and for which is low in the former and high in
some of the unexplained deaths. This the latter syndrome. In normal humans,
hypothesis has not, however, been estab- an agastric pacemaker initiates the
lished irrefutably.
IMMC, and a pressure wave proceeds
Motor disturbances of gastrointestinal from the region of the esophagogastric
tract. The gut is a prime focus of auto- junction towards the duodenum and
nomic neuropathy and may be affected small intestine. In patients with gastroin its entirety. Abnormalities may be ex- paresis, the IMMC is lost. Reappearance
pressed both in motor function and in of the IMMC with the administration of
the regulation of gastrointestinal hor- metoclopropamide by the intravenous
route generally heralds a good clinical
mone secretion.
Esophageal enteropathyDisturbances in response to the drug (281). Hyperglyceesophageal function in diabetes are ex- mia per se abolishes the IMMC and
tremely common but probably of no causes a profound delay in gastric empgreat consequence. Esophageal enterop- tying. Thus, it is important when meaathy is frequently detectable through so- suring gastric emptying to do the study
phisticated upper GI series and dynamic only after the glucose is marked normal.
scintiscanning in diabetic patients. Only The major nonnutritional problem with
rarely, however, do patients present with gastroparesis is the irregular absorption
dysphagia, retrosternal discomfort, and of fuels, which accentuates poor diabetes
control. A significantly prolonged gastric
heartburn (244).
emptying time has been observed in peoGastroparesis diabeticorumThis clinical
ple with brittle diabetesno person
syndrome was described initially by Kasshould be labeled as brittle until the gassander (272) and comprises anorexia,
tric emptying study has been completed.
nausea, vomiting, fullness, and early saIn addition, the risk is present with the
tiety. These are general symptoms and
ingestion of soluble fibers, such as guar
are more frequently found among deand pectin, of developing fiber bezoars
pressed people with gastroparesis. For
(282). Thus, extreme care must be exerthis reason, the suspicion of a lesion
cised in prescribing fiber in the diet. Gasmandates an emptying study. Not infretroparesis may become an intractable
quently, however, patients will complain
problem with persistent anorexia, nauof vomiting of meals that were ingested
sea, abdominal pain, and weight loss and
some days beforehand. Meals, such as
may present a near insurmountable
those containing garlic, sausage, or seaproblem in clinical management.
soning, may be tasted on their breath for
Diabetic enteropathyEnteropathy indays after the meal. Physical examination
volving the large colon is common and
of affected patients often reveals a hipmay produce constipation in up to 66%
pocratic succussion splash in which an
of patients with long-standing diabetes
initial delay of emptying of solids occurs
(239). The opposite symptom complex
(273-276) and subsequently of liquids
also may occur, the outcome of which is
(239). The gastric acid secretory retroublesome and explosive diabetic diarsponse to insulin-induced hypoglycemia,
rhea, which has been called paroxysmal
as well as that to sham feeding, is renocturnal diarrhea. The paroxysms occur
duced (276,277), and gastrin levels may
explosively and without warning, and
be elevated, presumably because of the
the patients may produce pools of liquid
autovagotomy (278,279). Indeed, pafeces in embarrassing situations. With
tients may be diagnosed mistakenly with
the associated loss of perirectal and perithe ZE syndrome, leading us to term the
anal sensation that occurs, the patients
condition diabetic pseudo-ZE syndrome

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Vinik and Associates

may not be aware of soiling themselves.

Anal sphincteric control and tone is lost
(283,284) and with it the ability to retain
feces. The condition often fluctuates
from day to day, may occur at night but
may occur at any time of the day or
night, and may exhibit seasonal fluctuation (285). Proximal small intestinal motility disturbances may be found during
the episode, and the gastrointestinal
transit time becomes prolonged in the
remissions (286). In addition, a number
of factors may contribute to the diarrhea,
which include stasis of bowel contents
with bacterial overgrowth (286), bile acid-induced intestinal hurry and malabsorption (287,288), and a diminution in
pancreatic exocrine secretions, presumably due both to the need for insulin to
maintain exocrine pancreatic function
and the vagal pancreatic neuropathy
(289). A further defect in a-2 adrenergic
receptor function has been postulated
and forms the basis of recommended
treatment with adrenergic agonists (290,
291). However, no evidence has suggested a secretory component to the diarrhea, although it has been shown to
respond to antisecretory agents (292,
293).
Gut neuroendocrine abnormalitiesAlthough it is clear that the abnormalities
in the autonomic nerves per se contribute to the extensive dysfunction of the
gut, the autonomic nervous system is
intimately involved in the regulation of
many gut neuroendocrine hormonal
peptides, including gastrin, PP, SRIF,
glucagon, GIP, and motilin, among others. These peptides have important functions in regulating insulin secretion, glucose counterregulation in response to
hypoglycemia, gut motility, intestinal secretions, and digestion and absorption of
nutrients. The clinical consequences of
gastroparesis, diarrhea, and constipation
derive from disease of the autonomic
nerves; and the abnormalities in peptide
secretion appear to be secondary to the
neuropathy. Notwithstanding, the abnormalities in peptide secretion may play
an important role in perpetuating the

DIABETES CARE, VOLUME 15,

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disorder and initiating a vicious cycle of

neuropathy, gut dysfunction, peptide
abnormality, and further gut dysfunction. Even if the abnormalities in these
peptides have no biological consequence, detection of these abnormalities
has provided investigators with useful
tools to detect the failure of autonomic
function early in the course of the disease
(294,295).
Of all the gut hormones measured, PP may be the most useful, because its release from the pancreas is
under exquisite cholinergic, if not vagal,
control (296,297). The PP response to
hypoglycemia (295,298), meal ingestion
(297), and sham feeding (295) all are
abolished by atropine and are markedly
reduced by vagotomy performed within
the preceding 6 mo. We originally
showed that the PP response to hypoglycemia was impaired in diabetic patients
with impaired cardiovascular autonomic
reflexes and proposed this as a test of
vagal integrity (299). Krarup et al. (300)
have shown that the response to hypoglycemia becomes progressively reduced
with increasing duration of diabetes, presumably because of worsening of the autonomic dysfunction. More recently, the
PP secretory response has been used to
determine those patients at risk for hypoglycemia during intensive diabetes
control (301). Current studies are aimed
at determining the earliest and most sensitive indicator of paraympathetic dysfunction, and the PP response to hypoglycemia is a prime candidate. In the
years before the advent of human insulins, the measurement of PP as a marker
for progress of the neuropathy was hampered by the presence of PP antibodies in
the serum of many patients treated with
crude insulins. The PP antibodies were
presumably attributable to the contamination of the crude insulins with porcine
or beef PP. Today crude insulins are no
longer used in many institutions, and it
should be possible to monitor the natural
history of vagal neuropathy by measuring PP responsiveness serially. A test involving hypoglycemia is unfortunately

DECEMBER

1992

not well-tolerated by most subjects, and

it may be that the early response to food
ingestion (244) or sham feeding (295)
may be less traumatic for the subject and
both are reduced in patients with autonomic neuropathy, as is the response to
exercise (302), which may, however, reflect both parasympathetic and sympathetic dysfunction (296).
Glucagon secretion may become
distinctly abnormal in patients with autonomic neuropathy. It is established
that the neural system is involved in the
regulation of glucagon secretion
(303,304) with the response to hypoglycemia impaired in diabetic individuals
with established autonomic neuropathy
(305,307); a deficiency may impair the
ability to recover from hypoglycemia.
The glucagon response to hypoglycemia
may, however, be attenuated as a consequence of neuropathy (308-310). In our
view, this observation should not question the role of the autonomic nervous
system in glucagon regulation but rather
should alert diabetes experts to exercise
caution in selecting individuals appropriate for intensive therapy. In contrast to
the diminished glucagon responses to
hypoglycemia are the exaggerated responses of glucagon to meal ingestion
and to arginine infusion observed among
NIDDM patients with autonomic neuropathy (306). Possibly, these elevated
secretory responses may be a function of
the rate of gastric emptying. This unusual combination of deficient responses
to hypoglycemia and exaggerated responses to food may contribute significantly to the apparently brittle diabetes
encountered in these individuals (300).
Other hormonal peptides under
neural control also affect insulin secretion. GIP secretion, for example, is diminished in response to meal ingestion
in patients with autonomic neuropathy
(311). Because GIP may be a major gut
factor enhancing the insulin response to
glucose, a function known as an incretin,
deficiency may compromise insulin secretion in NIDDM and contribute in part
to the severity of the diabetes. Further

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Diabetic neuropathies

complexity is added by the observation

that secretion of SR1F (an inhibitor of
insulin and glucagon secretion) is also
under vagal control (312) and may be
diminished in autonomic neuropathy
(307,309). Ultimately contributing, in a
complex manner, to dysregulation of diabetes and its instability of control.
The clinical disorders of gastric
secretion and motility, which have been
discussed above, are largely mediated by
the hormone gastrin, which is central to
the control of acid secretion, the growth
and replication of cells in the stomach
and upper small bowel, and motility of
the stomach. In humans, gastrin secretion is regulated partly by the sympathetic nervous system (300) but is also
under tonic inhibitory control by the vagus (313). High fasting and postprandial
concentrations of this hormone are observed in diabetic patients with cardiac
autonomic neuropathy (279,313) and
gastroparesis (276). The consequences of
these findings are not clear, but mistaken
diagnoses of a gastrin secreting tumor is
not unusual. High gastrin levels also may
be attributable to loss of acid secretion,
which is found in patients with the variety of IDDM associated with autoimmunity, antibodies to gastric mucosa, and
atrophic gastritis.
The rhythmic neuronal discharge
coupled with pressure waves known as
the interdigestive myoelectric complex is
lost in patients with gastroparesis and
diabetic enteropathy (281). Coupled
with this rhythmic pressure change,
which proceeds from the esophagogastric junction distally, is a rhythmic release of PP and motilin. This latter hormone qualifies as the "sweeper of the
gut" and may have an important role in
clearing the intestine during the interdigestive period. Although we reported
that the responses to hypoglycemia were
impaired in diabetic patients with autonomic neuropathy (314), thus resembling the observations in vagotomized
people, more striking was the observation that the rhythmic oscillations persisted in the hormone at levels consider-

1944

ably higher than those in normal subjects

(281,300). This is one of the rare situations in which a gut hormone is oversecreted in autonomic neuropathy, and its
rhythmicity is retained. The heightened
secretion rhetorically seems to be an attempt of the body to increase the secretion of the motility factor when intrinsic
neuronal control is failing. However, an
important regulation by insulin occurs
(315), and the flacid bowel found in uncontrolled diabetes may be a consequence of this effect of insulin on gut
hormone secretion. The impact of insulin and hyperglycemia on neurohormonally mediated gut function is fascinating
and deserves further investigation.
Genitourinary tract disturbances

a reflex contraction of the anal sphincter.

These reflexes and sensations are lost in
autonomic neuropathy because of parallel loss of somatic and autonomic sacral
segments 2, 3, and 4.
Retrograde ejaculationRetrograde

ejacu-

lation may be diagnosed by the presence

of azoospermia in the ejaculate or the
finding of live motile sperm in the urine
postcoitus. This diagnosis may be important to the relatively young diabetic patient who desires to procreate, in which
instance, sperm may be recovered from
the urine, and artificial insemination of
the prospective mother conducted.
Sweating disturbances. This is a sudomotor dysfunction characterized by distal anhidrosis and bilateral symmetrical
Neurogenic vesical dysfunctionThe earli- loss of the thermoregulatory response.
est and most frequent form is loss of This may be troublesome to patients who
bladder sensation, and the patient is un- do not perspire in their lower limbs and
aware that the bladder is full. Motor have as a reflex excessive perspiration of
function tends to remain intact, and the the upper body and face.
usual problem is dribbling with overflow Hypoglycemia unawareness and unrecontinence. One often is surprised when sponsiveness. In nondiabetic individuexamining such people to find a bladder als, a fall in blood glucose concentration
at the level of the umbilicus of which the is attended by an outpouring of EPI, glucagon, growth hormone, and cortisol
patient is entirely unaware.
ImpotenceThe most common form of (314). The initial response to hypoglyceorganic sexual dysfunction in male dia- mia is bradycardia and a slight fall in
betics is erectile impotence. Unfortu- blood pressure, followed by a sympanately, many physicians shy away from thetic discharge and the appearance of
asking about the issue. Up to 75% of adrenergic symptoms such as sweating,
male patients who have had diabetes for diaphoresis, and palpitations. In 1963,
15-20 yr suffer some degree of erectile Sussman (316) observed that patients
impotence. In evaluating such patients, it with long-standing diabetes may lose
is important to exclude pyschogenic their sensitivity to hypoglycemia and
causes. Impotence associated with or- coined the term hypoglycemia unresponganic causes may be differentiated by its siveness. Unawareness of a severe hypogradual onset, association with the loss glycemic reaction is because of blunting
of nocturnal erections, and uniformity of the EPI responses to hypoglycemia, a
with all partners. Vascular causes can be consequence of autonomic neuropathy
excluded by a history of buttock claudi- (306,307,310,317,318). Affected pacation and by using Doppler ultrasound tients lose their early warning and may
to determine the penile/brachial arterial fail to take appropriate preventive mearatio. If vascular and pyschogenic causes sures until neuroglycopenic symptoms
are excluded, neuropathic impotence supervene, which is often times too late
may be detected by clinical examination when coma occurs. These people may
of perianal sensation, (stroking along not be suitable candidates for intensified
side the anus and watching the anus con- insulin therapy (310,319), and caution
tract [the anal wink reflex]) or, applying in aggressive management is prudent,
pressure to the glans penis, which causes despite being contrary to the notion that

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improved diabetes control is an important component of reversing neural dysfunction. Diminished glucagon response
to hypoglycemia also may occur in affected patients (311,315,316,320-322).
Because the combination of EP1 and glucagon deficiency are potent mechanisms
for the loss of the counterregulatory response to hypoglycemia (318), these patients may experience both a steeper fall
in blood glucose and protracted hypoglycemia, as they are unable to return the
blood glucose to near-normal levels. This
may be an important and prominent
cause of erratic control of diabetes, but
not everyone concurs. It should be
noted, however, that patients with diabetes who have been intensively treated
with either pump therapy or intensive
conventional therapy also have a similar
reduction in EPI and glucagon responses
to hypoglycemia (319) and thus present
with a profile that may be difficult to
distinguish from autonomic dysfunction.
This distinction must be made, however,
because it is critical that the former patients not be overheated, and their control not be managed as strictly as patients
with intact glucose counterregulatory responses.
HAAF. Three hypoglycemia-associated
clinical syndromes in individuals with
IDDMdefective glucose counterregulation, hypoglycemia unawareness, and
elevated glycemic thresholds for symptoms, and activation of counterregulatory systems during effective intensive
therapyhave much in common. They
segregate together, are associated with an
increased frequency of severe iatrogenic
hypoglycemia, and share several pathophysiological features, including reduced
autonomic nervous system responses to a
given degree of hypoglycemia. These include reduced (elevated glycemic thresholds for) sympathochromaffin (EPI) and
parasympathetic (PP) responses. In the
setting of reduced (often absent) glucagon responses, the reduced adrenomedullary EPI responses play a key role in
the pathogenesis of iatrogenic hypoglycemia in affected patients. Thus, these

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syndromes are examples of HAAF in

IDDM, a disorder distinct from classical
diabetic autonomic neuropathy. The recent finding that short-term antecedent
hypoglycemia results in reduced symptomatic and autonomic, including adrenomedullary, responses to subsequent
hypoglycemia in nondiabetic humans
suggests that one potential pathogenetic
mechanism is recent antecedent iatrogenic hypoglycemia that reduces both
symptoms of and defenses against developing hypoglycemia, resulting in recurrent severe hypoglycemia, thus creating a
vicious cycle.
HAAF appears to be distinct
form of classical diabetic autonomic neuropathy in several ways. First, the two
disorders do not cosegregate, i.e., they
tend to occur in different patients
(311,322-332). Second, in HAAF the
deficient autonomic responses appear to
be specific for the stimulus of hypoglycemia (148,328,333), whereas reduced
sympathetic and parasympathetic responses to multiple stimuli characterize
classical diabetic autonomic neuropathy
(324,325). Third, whereas substantially
reduced adrenomedullary EPI responses
to a given degree of hypoglycemia are a
central feature of HAAF (148,301,310,
322-338), plasma EPI responses are reduced little, if at all, in classical diabetic
autonomic neuropathy. Although
Hilsted et al. (324,325) found slightly
lower EPI responses to hypoglycemia in
patients with, compared with those without, classical diabetic autonomic neuropathy, the EPI responses of the former
patients were greater than those of nondiabetic control subjects. This is consistent with evidence that classical diabetic
autonomic neuropathy is largely an axonal lesion (339,340), probably the result of nerve fiber loss. Fourth, in sharp
contrast with HAAF, clear evidence indicates that classical diabetic autonomic
neuropathy does not cause excessive iatrogenic hypoglycemia in IDDM (341344). Fifth, recent data (345-347) suggest, but do not prove, that HAAF might
be, at least in part, reversible for reasons

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1992

discussed shortly. No evidence suggests

that classical diabetic autonomic failure
is reversible.
Lowered glycemia thresholds. With recent attempts at intensification of therapy to achieve lower blood glucose levels
in people with IDDM, it appears that
blunting of the responses to hypoglycemia may occur with lowering the threshold. Indeed, a single episode of afternoon
hypoglycemia has been shown to reduce
the symptomatic and neuroendocrine response to a given degree of hypoglycemia
the following morning (255,326,335). It
has been suggested that a poor correlation exists between altered thresholds,
unawareness of hypoglycemia, and the
presence of diabetic autonomic neuropathy (324). It has thus been postulated
that the defective glucose counterregulation, hypoglycemia unawareness, and elevated glycemic thresholds during effective therapy cosegregate in the same
patient, they are associated with high frequency of iatrogenic hypoglycemia and
have reduced autonomic responses to a
given degree of hypoglycemia. These
have been grouped together by Cryer et
al. (333) as HAAF to be distinguished
from autonomic neuropathy on the following basis: They do not cosegregate.
All responses are reduced in autonomic
neuropathy, whereas only those to hypoglycemia are impaired in HAAF. EPI responses to hypoglycemia are relatively
unimpaired in autonomic neuropathy
but are uniquely impaired in HAAF. In
contrast to HAAF, little evidence indicates that autonomic neuropathy contributes to iatrogenic hypoglycemia, and
HAAF appears to be in part reversible.
Therefore, it seems that the vicious cycle
is initiated by repeated episodes of hypoglycemia that reset the threshold for
the response, thus generating further episodes of hypoglycemia and failure of the
normal counterregulatory response.
Autonomic symptoms (anxiety,
palpitations, sweating, irritability, and
tremor) began at 58 2 mg/dl, which
was significantly (P = 0.0001) lower.
Neuroglycopenic symptoms (hunger,

1945

Diabetic neuropathies

dizziness, tingling, blurred vision, difficulty thinking, and faintness) and deterioration in cognitive function tests began at 51 3 and 49 2 mg/dl.
The studies by Cryer (348) and
Gerich (337) yielded identical thresholds for symptoms (3.0 mM) and for
glucagon and EPI release (3.9 mM) in
normal subjects.
To test for the presence of these
syndromes requires elaborate and expensive equipment and is best done in a
research environment. For the sake of
completeness they are described here.
The stepped hypoglycemic clamp technique, applied to normal subjects
(337,348) and IDDM patients (330), has
been described in detail. Briefly, after an
overnight fast (and overnight i.v. insulin
infusion to achieve near euglycemia before the test in IDDM), insulin (2.0
Mu kg" 1 min" 1 ) is infused continuously and an i.v. glucose infusion is varied either to maintain euglycemia (5.0
mM) throughout (euglycemia control) or
to achieve hourly glucose clamps of 5.0,
4.4, 3.9, 3.3, and 2.8 (or even 2.2) mM.
Symptoms and hormone responses are
assessed at the end of each glycemic step.
Cognitive function also can be assessed
(337,349). The test is labor intensive requiring a minimum of two people (typically a physician and nurse); a third person is needed if cognitive function is
assessed. It also requires accurate glucose
measurements (with a Beckman or YSI
analyzer, not with a glucose monitor) at
the bedside and the analytical capacity to
perform the hormone measurements.
Cognitive assessment generally requires a
collaborating psychologist.
DIAGNOSIS OF DIABETIC
NEUROPATHIES

Clinical evaluation
A thorough clinical examination with
special attention to the feet, examining
for dryness, shiny skin, cracking of the
skin, ulceration, loss of hair, levels of loss
of sensory modalities with particular notice of vibratory sensation, reflexes, and

1946

motor power is essential in the evaluation of patients suspected of neuropathy.

It must be emphasized, however, that the
classic neurological examination is based
on the clinician's interpretation of the
patient's response to standard questions
and procedures. The clinician makes
skilled but entirely subjective judgments
concerning such aspects as motor function, sensation, and reflexes. Typically,
such judgments involve deciding
whether signs are present or not or
whether a specific function is normal or
abnormal.
Diabetic neuropathy is diagnosed
by exclusion of various other causes of
neuropathy. Systematic questioning, including family history of nondiabetic peripheral nerve disease and the presence
of toxic, metabolic, mechanical, and vascular causes of nerve disease, should be
conducted. If any other potentially neuropathic factors are present, other diagnostic methods should be used to determine the etiology of nerve disease. Some
of the disorders to be considered include
nutritional deficiencies, collagen vascular
disease, malignancies, tabes dorsalis,
toxin exposure (e.g., alcohol, occupational toxins, vitamin B6, and medications known to be associated with peripheral neuropathy [dilantin therapy for
decades, nitrofurantoin, amiodarone,
metronidazole, vincristine, cisplatinum,
taxol]), hypothyroidism, pernicious
anemia, dysproteinemias, amyloidosis,
AIDS, chronic idiopathic demyelinating neuropathy, spinal cord disease,
cauda equina syndrome, and other mechanical conditions that damage peripheral nerve tissue. Appropriate laboratory screening for these disorders
should be performed.
To aid in the assessment of neuropathy during a clinical exam, coded
examinations of neurological function
have been developed that allow assignment of broad categories of functional
abnormalities based on the clinical examination (1 = normal; 2 = mild abnormality; 3 = moderate abnormality;
4 = severe abnormality; and 5 = total

loss of function). Both signs and symptoms may be scored. Such ordinal ratings
may be invaluable as evaluation tools in
clinical studies of neuropathy, but, unfortunately, these are all that are available in a typical examination situation.
In addition, in many instances, these
sorts of nominal or ordinal ratings are
often too restrictive to detect reliably
small but clinically relevant changes in
function.
The quantification of symptoms
is probably best accomplished by using
some version of the Lekert scale, where
intensities of the sensation may be rated
on a numerical scale by the patient. Such
a scale typically would have as its end
points 0 intensity (not present) and some
representation of a maximum possible
value. This maximum value often presents a difficulty, as patients may have
difficulty relating any verbal description
of maximum intensity of a sensation to
the sensation that they experience. Such
a scoring system should allow the patient
to rate the pain present over a period of
time without recourse to comparison
with previous records. Otherwise the
evaluation of minimal changes may again
be fraught with difficulty in interpretation, as the patient's expectancy effects
will begin to play a crucial role.
Equally important and neglected
in the routine physical examination are
the functional correlates of nerve impairment. An activity instrument to measure
the functional impact of neuropathy has
been developed by us, which measures
the degree of restriction associated with a
number of daily tasks, including the ability to put on a shirt, button a shirt,
squeeze toothpaste, use a fork, turn the
pages of a book. These timed tests have
not been widely applied in the evaluation
of diabetic neuropathy and offer a means
of evaluating restriction of activities that
are of vital importance to the patient.
The broad battery of neurological tests
that has now evolved for the assessment
of neural impairment in diabetes will
lead to a better understanding of the nat-

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ural history and epidemiology of neuropathy.

Electrophysiological testing in
diabetic neuropathy
Electrophysiological testing plays an important role in detecting, characterizing,
and measuring progress of the different
forms of diabetic neuropathies. Neuropathy in diabetes may preferentially affect
different types of nerve fibers such as
either the small unmyelinated or thinly
myelinated fibers or the larger, more
heavily myelinated fibers (350). Nerve
conduction studies involve stimulation
of either motor or sensory nerves with
subsequent recording of either a sensory
or a compound motor action potential.
Evaluation of several parameters, including latency, conduction velocity, and
amplitude, is helpful in determining the
type of fiber involvement. The amplitude
of the evoked response is a function of
the number and size of nerve and muscle
fibers and may be decreased in axonopathies. Amplitude reduction, however,
also may be seen when the range of conduction velocities is greater than normal,
causing temporal dispersion of the recorded response. In these cases, measurement of the area under the curve
may be a more accurate reflection of axonal number and size (351).
Conduction velocity provides a
measure of transmission time in the largest myelinated fibers. Transmission time
may be influenced by numerous factors,
including fiber size, degree of myelination, nodal and internodal length, axonal
resistance, and temperature (352). In diffuse neuropathies, slowing of conduction
velocity may become more apparent if
measurement is obtained over long nerve
segments. F-response latency measurement, which includes conduction over
the entire motor nerve, is thus a sensitive
method/or detecting neuropathy (353).
F-wave latencies also provide a means of
assessing proximal motor nerve function,
which may be useful in conditions such
as diabetic amyotrophy (354). Conduction studies also may help identify and

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localize focal lesions within a nerve by

demonstrating localized slowing or conduction block, both of which may occur
in diabetic neuropathy. This is helpful,
especially when coincident entrapment is
apparent, as in the carpal tunnel or tarsal
tunnel, to which diabetic individuals are
susceptible.
Needle electromyography should
be used in conjunction with nerve conduction studies in the evaluation of diabetic neuropathy. Although quantification of abnormalities of motor units may
be difficult and less reliable than measurements of nerve conduction, recognition of fibrillation potentials in muscles
at rest is often straightforward and less
subject to individual interpretation. Fibrillation may be the most sensitive indicator of axonal degeneration and may
be present in asymptomatic patients,
preceding other clinical or electrophysiological evidence of neuropathy (355).
The needle examination is also
helpful in determining the distribution of
nerve involvement in various diabetic
conditions. EMG, for instance, is the
electrodiagnostic study of choice in the
evaluation of diabetic polyradiculopathy
(356,357) and provides important information in the assessment of proximal
motor neuropathy (354,358) and plexopathy.
Additional quantitative testing
can be done with single fiber electromyography, which allows measurement
of muscle fiber density and evaluation of
neuromuscular transmission (352). Muscle fiber density is increased in cases of
axonal loss with subsequent reinnervation by collateral sprouting. Ongoing
collateral sprouting also may be assessed
quantitatively by the jitter, which reflects
neuromuscular transmission.
Other modalities that are useful
in the evaluation of diabetic neuropathy,
but which may not be available at all
centers, include near-nerve recording,
somatosensory evoked potentials, or repetitive stimulation with measurement of
refractory periods.
The utility of electrophysiological

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1992

testing lies in its reliability and reproducibility. Furthermore, these are measurements that are largely independent of
patient cooperation and are reproducible
among different examiners in different
centers. They also have been shown to
play an important role in studies evaluating disease progression or regression
and the response to medical treatment
(359,360). Data are available to support
the notion that electrophysiological tests
correlate well with nerve biopsy data on
histology.
It is, however, important when
performing these tests to control for
sources of error (9). One factor of particular importance is that of limb temperature. Amplitude, latency, and conduction velocity all vary with limb
temperature (351). As the limb cools,
less dispersion of the evoked response
occurs, and the amplitude subsequently
increases. At the same time, decreases in
conduction velocity and increases in distal latencies are seen. It is generally recommended, therefore, that limb temperatures should be kept at 32-36C (355),
with warming of limbs occasionally necessary to maintain them in the ideal
range. It may be difficult in some patients
to maintain proper temperature secondary to ischemia or denervation, in which
case corrections may be made as outlined
in other texts (355).

Electrophysiological findings in
diabetic neuropathy
A brief discussion of the electrophysiological abnormalities in the various neuropathic states will be given.
Subclinical neuropathy. It has been
well-demonstrated that abnormalities of
both nerve conduction studies and EMG
occur in many neurologically asymptomatic diabetic patients. In fact, these findings may be found before the diagnosis
of diabetes (361). NCVs in this group
have mean values 10-30% below the
normal (352). Reduction of amplitude
also is found, particularly in sensory
nerves. Sensory action potentials and somatosensory evoked responses have

1947

Diabetic neuropathies

been shown to be more sensitive than

motor studies in detecting early nerve
involvement (362,363).
Lower extremity distal nerves, in
particular, the peroneal and sural nerves,
frequently show the most significant abnormalities (77,364). Studies of proximal nerve function such as somatosensory evoked responses and F-wave
testing may show changes as well, sometimes exceeding abnormalities in more
distal segments (353).
The presence of fibrillations potentials on EMG, especially in the intrinsic foot muscles, also may be found in
the asymptomatic diabetic patient, reflecting axonal loss.
Painful neuropathies. Painful neuropathy may develop in the diabetic patient
in which the symptoms predominantly
consist of pain and dysesthesias. Neurological deficit may be minimal or absent
consistent with small fiber involvement.
It is not surprising, therefore, that nerve
conduction studies show either mild or
no abnormalities, similar to findings in
asymptomatic diabetic patients (57).
These tests, therefore, are useful to identify a subset of patients destined to below
symptomatic and who would benefit
from treatment.
Symptomatic diffuse symmetrical peripheral neuropathy. Once symptoms
develop, electrophysiological testing reveals even more significant abnormalities
of both sensory and motor nerves than is
found in asymptomatic patients. Decreased amplitudes of sensory nerve action potentials are the most frequently
seen disturbances. Evoked responses
may be so small that signal averaging
techniques are needed to record the potentials. Plantar nerve responses tend to
be lost first (364), followed by the sural
and superficial peroneal nerve responses.
Mild to moderate reduction in
conduction velocities in motor and sensory nerves and mild prolongations of
distal latencies frequently are observed
(352). F-wave latencies typically are
slightly prolonged, and fibrillation potentials are frequently noted in the in-

1948

trinsic foot muscles and occasionally

elsewhere, such as the paraspinal muscles.
Diabetic amyotrophy. Diabetic amyotrophy, the electrodiagnostic abnormalities characteristic of amyotrophy generally are superimposed on a diffuse
symmetrical peripheral neuropathy
(365). The typical findings include disturbances of proximal motor function.
F-wave latencies are frequently absent or
significantly slowed out of proportion to
more distal peripheral nerve abnormalities (354,358). EMG changes are also
prominent with fibrillations recorded in
most proximal lower extremity muscles,
especially those innervated by the L2
through the L4 nerve roots (358). Widespread fibrillations also are noted in the
paraspinal muscles at many levels, differentiating diabetic amyotrophy from lumbar monoradiculopathy. Reduction in recruitment of motor units also is
frequently noted, consistent with a neuropathic process.
Focal neuropathies. Identification of a
mononeuropathy can be difficult when a
diffuse peripheral neuropathy is also
present. This matter is simplified if a
conduction block is present, however,
usually the examiner must make the diagnosis based on focal slowing of conduction, which is out of proportion to
the slowing seen in other parts of the
nerve or in other nerves either in the
same or opposite extremity.
Mononeuropathy, which also occurs in the peroneal nerve with axonal
loss (92), leads to reduction or loss of
compound muscle action potentials and
sensory nerve action potentials. Conduction velocity, when measurable, is less
severely affected. Fibrillations typically
appear 10-14 days after the onset and
may be followed by the appearance of
polyphasic potentials as regeneration and
sprouting occur (351).
Focal radiculopathies may also
present in the thoracic region of diabetic
individuals, causing pain in the back,
abdomen, or chest (356). For these patients, electromyography is the only way

of identifying this condition, by detecting fibrillations in the involved paraspinal muscles. These abnormalities are unilateral and localized, differentiating this
disorder from diabetic amyotrophy in
which the clinical and electromyographic
findings are more widespread and often
asymmetric.
In conclusion, nerve conduction
studies and electromyography play an
important role in the detection and characterization of many of the diabetic neuropathies. Studies should be individualized to the patient's clinical diagnosis
and examination to provide meaningful
information regarding the underlying
process.

Quantification of cutaneous
sensitivity
QST is the determination of the sensory
threshold, defined as the minimal energy
reliably detected for a particular modality. It is a logical extension of the sensory
portion of the clinical neurological examination and has the principal advantage
of assigning a numerical value. Recent
years have seen the development of a
number of relatively inexpensive devices
that allow suitable assessment of somatosensory function, including vibration,
thermal energy, and light touch.
QST can be used to document
subtle sensory loss, characterize patients
at the onset of a clinical trial, and monitor a modality known to be associated
with a specific complication of diabetic
neuropathy (366-368). The evaluation
contributes to the differentiation of the
relative deficit in small (e.g., temperature) versus large (e.g., vibration) diameter axons, and polyneuropathy versus
mononeuropathy.
Calibration and units of measure
should be expressed in standard terminology such as |xm (vibration), C (temperature), and dynes/cm2 Gight touch);
and the physical dimensions of stimulation (e.g., waveform, frequency, risetime) should be reported.
Two testing procedures are
emerging as the standards in the field: 1)

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modified up-down stimulation with two

alternative forced-choice responses; 2)
ramping of stimulus intensity (method of
limits) combined with yes-no paradigm
(369). By using the first procedure, the
most common definition of threshold is
the stimulus intensity corresponding to
the 75% correct response point. For the
second procedure, threshold is usually
defined as the stimulus intensity corresponding to 50% correct detection. To
be acceptable, the two alternative procedures must allow sufficient reversals to
converge on a true threshold. The yes-no
paradigm must include catch trials
(where stimulus is not delivered) in sufficient numbers and variable ramps to
minimize guessing. More details concerning the different psychophysical
methods, response paradigms, and their
critical evaluation can be found in Maurissen (370).
Modalities measurable.
Vibration-perception testingThis measure is the most widely studied QST procedure and is associated with the most
extensive normal and neuropathy data
bases. If frequencies of 120-200 Hz are
used, it principally assesses function in
Meissner and Pacinian corpuscles and
their associated large-diameter fibers.
Typical sites of assessment are the glabrous skin of the fingers and toes.
Thermal-perception testingThis measure assesses function in free-nerve endings and their associated unmyelinated
and thinly myelinated fibers. The value
and reliability of this measure is enhanced by separately assessing warm and
cold perception. Although thermal
thresholds have proved especially variable, they uniquely index small fiber dysfunction (371).
Light touchQuantitative esthesiometry
techniques require a relatively sophisticated stimulus delivery system. This
measure tests the integrity of Merkel
touch domes and Meissner corpuscles
and their associated large-diameter fibers. The expanded use of this technique
in assessing diabetic neuropathy will be a
function of the anticipated increased

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availability of devices specific for this

modality.
In addition to the above modalities, QST procedures are available for
pain thresholds and cutaneous current
perception (372). Pain thresholds test
nociceptors and C fibers. Although they
may be important for selected studies,
the committee felt they should not be
included in a general assessment of diabetic neuropathy because of subject discomfort and the limited experience in
multicenter trials. Current perception assesses the detection threshold for sine
wave stimuli produced by a constant
current generator and delivered to the
skin through surface electrodes. No
known receptors exist for electrical current, and this form of stimulation appears to excite directly the cutaneous axons. Multiple frequencies have been
reported to excite different neuronal subgroups, but this claim awaits validation.
Studies in diabetic individuals suggest
strong correlations with other QST measures (367,373), however, additional
studies are required to explore the specificity and sensitivity of current perception for the assessment of diabetic neuropathy.
Strong correlations between
nerve conduction indexes and QST, and
between sensory symptom status and
QST, have been reported (374-376). By
using electrophysiology and symptoms
to identify neuropathic patients, a defined elevated vibration threshold was
associated with a sensitivity of 73% and a
false positive rate of 7% (374). Asymptomatic diabetic patients have significantly higher thresholds than nondiabetic individuals, suggesting that QST
may be useful to detect subclinical neuropathy.
Average intrasubject CVs for normal subjects have been reported as low
as 7-10% for vibration perception. In
diabetic subjects, CVs for vibration
thresholds are on the order of 10-20%,
whereas levels >20% have been observed for thermal thresholds.
To thoroughly assess the neuro-

DECEMBER

1992

logical state of patients presenting with

clinical signs or symptoms of a peripheral sensory neuropathy, the level of afferent neural function of the peripheral
skin is an essential concern. Recent technological advancements have provided
more sophisticated measures of some dimensions of sensory function. Various
instrumented equipment is now available for the detection of impairment in
thermal sensitivity and vibration perception, as well as electrical current, pressure, and pain perception. These types of
instruments allow for cutaneous sensory
functions to be assessed noninvasively,
and their measurements are by definition
correlates of specific neural fiber function. The proper application of these instruments will lead to advances in describing cutaneous sensitivity with the
level of detail necessary to make information concerning the magnitude of impairment of different cutaneous sensory
modalities useful to both the researcher
and the clinician. Information concerning fiber specificity and progression of
sensory neuropathies cannot be fully assessed until advances in the quantification of cutaneous sensory function are
put to use in both research and clinical
assessments of sensory neuropathies.
The use of standardizable equipment to
determine levels of cutaneous sensitivity
provides distinct advantages over otherwise-derived assessments, primarily
through its allowance for improvements
in scaling techniques, and more exacting
and standardized methods of stimulus
presentation and response.
Scaling techniquesThe use of standardizable, instrumented equipment allows
the assessment of sensory gradation to
achieve an interval scale, a marked improvement over the nominal or ordinal
scales possible in the typical clinical
exam. The use of proper equipment
alone is capable of accomplishing an interval scale. For example, instrumented
machinery currently allows for thermal
sensation to be described as the minimum temperature difference between
two distinct stimuli necessary to produce

1949

Diabetic neuropathies

a perceptual event of a magnitude that

allows the perceiver to correctly identify
the relative temperature of the two stimuli. In this manner, it is possible to arrive
at a difference threshold that is measured
in C, which in itself represents a substantial advancement from the skilled
but subjective clinical rating of thermal
sensation as being "normal" or "abnormal", "present" or "absent", or even a
nominal scale such as impairment levels
from 0 to 4. The units in an interval scale
advance sequentially as the amount of
stimulus increases, and they refer to an
externally identifiable scale that has precisely uniform intervals (hence the term
interval scale). The advantages of using
standardizable equipment to achieve an
interval scale are essentially fourfold
(377-379).
Initially, the use of instrumented
equipment that achieves assessments on
an interval scale almost entirely removes
the subjectivity of the examiner, because
the instrumentation of the equipment itself provides the rating that will be assigned. Secondly, it greatly enhances the
possibility of observing changes in sensitivity of the tissue under investigation
over time, primarily because of the inclusion of a much larger number of possible
scores or ratings than can be found in the
ordinal or nominal ratings of the typical
clinical exam. Thirdly, the use of a standardized interval scale can allow for a
greater level of confidence when assessing the extent of a sensory deficit. For
example, the extent of neurological damage that separates "mildly impaired" tissue from "severely impaired" tissue is
difficult to define, particularly if these
ratings come from different raters. However, if the sensitivity of some particular
tissue allows a subject to consistently
identify a minimum difference of 3C
between two stimuli, that is quantifiably
different from the ability of some tissue
to allow the subject to identify a minimum difference of 15C. This sort of
quantification allows for a description of
the sensitivity of the tissue to thermal
stimuli in which the extent of apparent

1950

neurological deficit of the less sensitive

tissue is reflected as a decrement of function equal to 12C. Lastly, this sort of
scaled quantification also allows for the
definition of normal tissue sensitivity
with its levels of variability between subjects using descriptive statistics; and
given this definition of normal sensitivity, it becomes feasible to determine a
sensitivity level beyond which the tissue
can be confidently classified as being abnormal to a specific extent. These aspects
of interval scaling are necessarily of crucial importance in research, but eventually, they also will allow for the clinician
to assess particular treatment needs and
efficacies more easily and accurately.
Methods of stimulus presentation and re-

sponseFor many years, perceptual theorists from many disciplines have been
attempting to explain an all too common
phenomenon that has plagued perceptual research: perceptual thresholds almost never appear to be completely consistent, even when interfering stimuli are
thought to be well controlled (380,381).
As long ago as 1888, Joseph Jastrow
(382) acknowledged that a number of
psychological variables are likely to affect
the measurement of perceptual thresholds. Attention, fatigue, and practice
with identification of a stimulus are the
most obvious psychological state variables that may account for some of these
fluctuations within individuals. Numerous relevant personality variables may be
of even greater concern when making
inferences concerning differences between individuals or groups of individuals, as these differences can exist in even
greater intensities as state and trait variables intrinsic to individuals or groups of
individuals. When coupled with the demands of an experimental or diagnostic
task, these personality variables may
cause unacceptable variance in perceptual measures (383-385).
The variance that may be derived
from any of these nonphysiological
sources must be held to an absolute minimum to make valid inferences about the
physiology of individuals or groups

based on their perceptual performance.

The inferences made by researchers generally are concerned with group performance, whereas the clinician is typically
more concerned with describing individual performance in an effort to diagnose
and treat the individuals. For either to
adequately achieve sensory results that
are of meaning, the adoption of a method
of stimulus presentation and response
that will accomplish sensory threshold
determination with optimum precision
and accuracy becomes a necessity. Numerous methods are available from past
and current research in perception, and
each has fairly distinct advantages and
disadvantages (378,379).
In discussing the various methods available, the manner in which the
stimulus intensity is varied or adjusted
from trial to trial is a primary concern.
Variations of the method of limits (ascending, descending, single, and multiple passes) tend to give quick but often
crudely rough estimates of absolute and
difference thresholds (378,379). The
method of constant stimuli tends to yield
more accurate estimates of sensory
thresholds; however, arguments concerning its efficiency in terms of accuracy
per number of stimulus presentations remain unresolved (386,387). Arguably, to
assure appropriate administration, algorithms that use the method of constant
stimuli will typically require a rather
large number of stimulus presentations
to achieve optimum accuracy, and,
thereby, may become exorbitantly time
consuming for the clinician and may
even impinge on fatigue and attentional
variables (382). Signal detection theory
(377,388) offers the ability to observe
and quantify both the ability of a subject
to detect a stimulus and guessing behavior of the subject on dichotomous
forced-choice trials. However, it also typically requires a large number of trials,
and it assumes an advanced level of
knowledge of the mathematical techniques involved in the quantification
process of both of the constructs that it

DIABETES CARE, VOLUME 15, NUMBER 12,

DECEMBER

1992

Vinik and Associates

measures for interpretations of results to

be valid (389).
Various other methods have been
described. Magnitude estimation
(378,390) may indeed be the most effective method for analyzing suprathreshold
sensitivities, such as difference thresholds necessary in the assessment of thermal sensation (391). Various matching
techniques within and across modalities
also show promise for suprathreshold assessments of differential sensitivity (390,
392,393).
An adaptive model commonly
known as the staircase method was first
described by Bekesy (394) for use in auditory assessment. It is essentially an alteration of the method of limits, with
stimulus intensities tracking the threshold, and it may be considered as a clinically appropriate compromise. It incorporates some of the aspects of both the
method of limits and method of constant
stimuli, and if a forced-choice model of
stimulus response is incorporated into it,
some of the principles of signal detection
theory may remain applicable to the results obtained. Additionally, staircase
methods allow for the observer to assess
adaptation that may occur within a modality over a single testing session,
whereas none of the other methods easily
allow for this type of assessment to occur
directly.
To reduce the variance that may
stem from intersubject differences in reluctance to report a mild perceptual
event, it is highly desirable to incorporate a forced-choice method of responses
to stimuli into any method of stimulus
adjustment that may be used (378,379).
When attempting to identify absolute
(perceptibility) thresholds, a forcedchoice method is made possible through
trials that include the presentation of
null (n > 1) and positive (usually n = 1)
stimuli, and the subject is required to
identify the positive stimulus. With difference thresholds, which are particularly necessary with thermal perception,
a forced-choice method is made possible
by the use of two or more separate stim-

DIABETES CARE, VOLUME 15,

NUMBER 12,

uli of differing temperatures, and the

subject is required to identify the relative
temperature of stimuli (i.e., report which
are warmer or colder than others). When
using a forced-choice paradigm, levels of
stimulus intensity that are near or at
100% correct performance are clearly suprathreshold, whereas intensities at
which performance falls to near or below
n (positive stimuli)/n(all stimuli) accuracy
are inter- or subthreshold.
A proposed algorithmThe blending of

forced-choice responses into a staircase

method of stimulus adjustment for determination of an absolute detectability
threshold will result in an algorithm that
has many of the following characteristics.
To establish an initial range of
stimulus intensities within which to begin forced-choice adaptive staircasing,
multiple passes that use both ascending
and descending method of limits may
first be used in an effort to locate a range
of stimulus intensities that appears to
include the threshold. The upper limit of
this range should represent the lowest
stimulus that is clearly suprathreshold.
The lower limit of this initial range
should represent the highest stimulus intensity that is clearly subthreshold. This
range would correspond to the interval
of uncertainty in the typical method of
limits algorithm (379).
To more accurately assess the
threshold intensity and to achieve a single number as a threshold estimate, the
initial interval of uncertainty may be divided into a serially incremented set of
stimulus intensities, any of which may be
used as intensity levels for future staircased stimulus presentations. The simplest sorts of rules for this incrementing
would be to merely divide the initial interval of uncertainty by a set number, or
to use a predetermined increment within
the interval of uncertainty. Note that the
magnitude of these increments may
limit, in part, the accuracy of the threshold determination or force an unnecessarily large number of stimulus presentations. In addition, if inferences are to
be made concerning the interval of un-

DECEMBER

1992

certainty itself, then the stimulus increments should be similar across all testing
sessions about which inferences are to be
made.
The starting point for staircasing
may be at any point within, above, or
below the initial interval of uncertainty,
with a number of concerns affecting that
decision. Chief among those concerns is
the allowance for practice effects and
concerns over the number of trials that
one is willing to present before reaching
a change in the direction of stimulus
adjustments. The staircased, forcedchoice trials then may be presented, with
stimulus intensities being lowered after n
trials, where n = number of correct responses achieving or surpassing a target
level of probability that a subject could
have randomly achieved success at a
level. Stimulus intensities are conversely
raised as a result of incorrect responses
by a set unit, depending on the target
level of correct performance. Note that
particularly low target levels of correct
performance may result in psychological
fatigue and even antagonistic effects, as
subjects may tend to resent what can
amount to multiple unsolvable problems
(395).
The trials continue, with intensities being adjusted according to the subject's performance and any applied rules
for attaining some desired level of performance. The session may be terminated according to any of the following
requirements: ]) the subject has completed a set number of trials that should
include some minimum number of
changes in the direction of stimulus intensity adjustments; 2) the stimulus intensity adjustments have changed direction some minimum number of times; or
3) the subject has achieved some desired
level of performance which, by definition, includes a minimum number of trials; or 4) any of a number of additive
combinations of 1, 2, or 3.
The threshold is often definable
as the arithmetic mean of stimulus intensities at all or certain types of changes in
the staircase direction of travel. For in-

1951

Diabetic

neuropathies

Table 6Performance characteristics of the forced-choice staircase algorithm

PERCEPTUAL MODALITY
WARM
COLD
VIBRATION
PRESSURE
5 Hz NEUROMETRY
250 Hz NEUROMETRY

2000 Hz NEUROMETRY

PRECISION

CLINICAL

(TEST-RETEST)

CUTOFF

SENSITIVITY

LEVEL

0.710
0.761
0.615
0.786
0.423
0.327
0.770

1.7C

l.rc
3.1*
3.9t
163 MA
289MA
5 4 5 MA

PREDICTIVE VALUES
P (HIT)

SPECIFICITY P
(CORRECT REJECT)

POSITIVE

NEGATIVE

0.833
0.833
0.944
0.789
0.529
0.431
0.588

0.933
0.933
0.933
0.933
0.933
1.000
1.000

0.925
0.925
0.934
0.922
0.888
1.000
1.000

0.845
0.845
0.944
0.816
0.665
0.638
0.708

"Vibration stimulus intensity is expressed here as peak to peak amplitude in microns.

tPressure intensity is the loglO (force), where force is grams pressure [see Semmes-Weinstein apparatus for details]. Sampling parameters consisted of 8 normal
control subjects and 29 diabetic neuropathic patients (by clinical diagnosis, all of whom retained measurable cutaneous perceptual function).

stance, it may be calculated in any of the

following ways: I) the mean of transitions in staircase direction from decreasing to increasing (typically the initial
points at which errors are made); 2) the
mean of transitions from increasing to
decreasing (typically the points at which
targeted levels of probability that a subject could have randomly achieved success are re- established); or 3) the means
of all of the directional changes. Each of
these yields a number that represents
somewhat particular aspects of the
threshold. From the first option, directly
above, a threshold is derived that will
allow more confidence that its result is
the transition to subthreshold. The transition to suprathreshold is probably best
represented by option two above, and
option three is a somewhat more general
estimate of both types of transitions. The
resulting interval of uncertainty will typically be much reduced from that which
the initial method of limits supplied, and
may be calculated as the range of minimum to maximum of the intensities used
in the above calculations. It also may be
appropriate to use the variance or SD of
those intensities to represent the remaining interval of uncertainty in certain situations (378,379).
The above described model
merely represents one of many standardizable methods for attaining estimates of
cutaneous thresholds that are easily ap-

1952

plied by the clinician and researcher

alike. Any of the vast number of available
models may be more accurate or more
time efficient, but most that attain
equally acceptable accuracy levels should
be difficult to apply in either the research
or clinical physician's practice. Perceptual research is continuously evaluating
and re-evaluating the many methods
available, and offering new solutions to
presently observed difficulties by establishing more sophisticated models. Given
the current status of psychophysical scaling methods, algorithms, such as that
presented herein, provide a substantial
first step towards clinic estimation of cutaneous sensitivity in the necessary detail
adequate to provide more accurate and
usable information about physiological
functions and the effects of neuropathies
on them.
In preliminary research with a
version of the above algorithm, the performance characteristics of the thresholds obtained were calculated (summarized in Table 6). Precision, the tendency
of a test to consistently yield the same
result in the same situation, is probably
the most important characteristic. If a
test yields vastly different scores under
similar testing situations (for example,
testing the same subject on repeated occasions) , then the results from any single
testing session may be meaningless. Note

that the precision varies for each modality tested.

The sensitivity of a test refers to
its ability to detect a clinically important
level of sensory impairment consistent
with the diagnosis of,in this case, a neuropathy. It often is expressed as the
probability of a hit or identification of an
impairment. Specificity refers to the likelihood that a test will correctly reject
normal control subjects by identifying
them as having normal scores. By using
ROC curves from signal detection theory, the most efficient clinical cutoff level
(threshold level above which the diagnosis of neuropathic impairment is suggested) was determined for each modality. At this most efficient level, the
sensitivity and specificity of each modality were calculated (Table 5). Prediction
values indicate the probability of a correct identification of impairment or nonimpairment when the subject's status is
unknown. Differences between modalities indicate to some extent the variability of the modality itself, as the measurement technique involved herein was held
constant.
Biopsy
Biopsy of nerve tissue may be helpful for
excluding other causes of neuropathy,
such as the familial hypertrophic
formsamyloid, sarcoid, and other
granulomatabut the pathology of dia-

DIABETES CARE, VOLUME 15, NUMBER 12, DECEMBER 1992

Vinik and Associates

betic neuropathy is not unique. The pathology of the early sensorimotor neuropathy is not known. In established
neuropathy, the characteristic picture is
that of distal fiber loss and degeneration.
Histological data recently have been reexamined in light of the subtle asymmetries and focal nature of the clinical presentation, with the evidence lending
favor to the hypothesis that differences
exist in the types of neuropathies occurring in IDDM and NIDDM. In NIDDM,
the major observation is that of Wallerian degeneration, which may be patchy
and irregular, supporting the notion of a
vascular origin of the disease (87,88,94,
101,396-398). Although these findings
cannot clearly be distinguished from
other causes of neuropathy, a microvascular occlusive picture in the absence of
known vasculitides may, however, be
pathognomonic of diabetes. In contrast,
the pathological findings in IDDM may
differ from those in NIDDM with the
axoglial dysjunction and widening of the
intemodal distance, findings interpreted
as supporting a metabolic rather than
vascular etiology and similar to those
found in animal models of diabetic neuropathy (399).

diac autonomic reflexes are complex and

may involve both sympathetic and parasympathetic innervation, for all intents
and purposes, blood pressure responses
may be taken to reflect sympathetic and
variations in pulse rate parasympathetic
nerve disease. In evaluating the severity
of the neuropathy, we have developed an
index that is simply a sum of the number
of abnormal tests. This index has been
shown to correlate well with the measured indexes of cardiac dysfunction
(256-260). The following is a list of the
measures and the normal values.

longest RR/
shortest RR. The normal value is
1.21.
Heart-rate response to standing

The subject stands with continuous

ECG monitoring, and one measures
the RR interval at beats 15 and 30. The
30/15 ratio is normally >1.03. Normal is tachycardia at beat 15, bradycardia at beat 30.
Systolic blood pressure response to standing The response is abnormal if blood
pressure falls >30 mmHg within 2 min
of standing.

Cardiovascular. A series of simple noninvasive tests are capable of detecting

cardiovascular autonomic neuropathy.
These were developed by Ewing et al.
(70) and have been applied sucessfully
by others (269,399) including ourselves
(256-260,282). These measures of cardiac integrity can be done at the bedside
very simply and provide an index of the
neuropathy that correlates well with
other measures of somatic and gut neuropathy (70,400,401). Beat-to-beat variability in the heart rate is among the
earliest and most sensitive test of cardiac
neuropathy, and although this is most
sensitively evaluated with the Hokanson
monitor, the tried and tested expirationinspiration ratio of the heart rate during
deep breathing at 6 breaths/min, also
gives reliable results. Although the car-

Photoplethysmographic beat-to - beat

Resting heart rate >100 beats per
blood
pressure recording may have
minute is considered abnormal (normal
significant
advantages and can be used
<100 beats/min).
to
evaluate
the components of the ValBeat-to- beat heart-rate variation
salva
maneuver
(403).
With the patient at rest and supine,
Diastolic
blood
pressure
rise with susbreathing 6 breaths/min with heart
tained exercise
rate monitored by EKG, a difference
A hand grip dynamometer is squeezed
(maximal-minimal) in heart rate of
to 30% of maximum (predetermined
>15 beats/min is normal, 10 beats/
in
the subject) for 5 min. The normal
min is abnormal. RR variation was
response
is a rise of diastolic blood
considered to be exclusively under the
pressure >16 mmHg.
control of the parasympathetic nerExamination of the EKG may reveal a
vous system. However, subsequent
prolonged QT interval in patients with
studies demonstrate that both fi-adcardiac autonomic neuropathy
renergic stimulation (isoproternol)
The QT interval corrected for the car(402) and (3-adrenergic blockade
diac cycle length (QTc is = QT/square
(propranolol)(43) decrease RR variaroot of longest-shortest R-R interval).
tion. Both parasympathetic, cholinNormal is a QTc < 440 ms.
ergic, blockade (atropine), and (3-adGastrointestinal.
renergic stimulation can nearly abolish
Technetium resin and chicken liver gasRR variation (402). Thus, a small detric emptying studies (281).
crease in RR variation results from,
A positive test is retention of > 50% of
sympathetic neuropathy, or stress,
the radioacivity in the stomach for
whereas a large decrease in RR varialonger than 100 min.
tion can result from either parasympaPressure/motility studies of intestinal
thetic neuropathy or stress (P-adrenfunction (281)
ergic stimulation).
Insulin hypoglycemia test of PP and catValsalva maneuver
echolamine responses (299,300,307,310,
The subject blows into mouthpiece of
317)
manometer to 40 mmHg for 15 s with Special tests of bladder function.
continuous EKG monitoring before,
In suspect cases of a vesical dysfuncduring, and after the procedure. Healthy
tion, a need may arise to do special
subjects normally develop tachycardia
tests.
and peripheral vasoconstriction during
Cystometry
strain; and an overshoot rise in blood
Sphincter electromyography
pressure and bradycardia on release.
Uroflometry
The valsalva ratio is:
Urethral pressure profile

DIABETES CASE,

1992

Special tests of autonomic function.

VOLUME 15,

NUMBER 12,

DECEMBER

1953

Diabetic neuropathies

Electrophysiological test of bladder innervation

Special tests of penile function.

Severe dysfunction among males is
common in diabetes. Pain with compression of the testis is normal and is
lost with autonomic neuropathy. Various tests have been developed to
quantitate erectile impotence. These
are in essence designed to exclude
psychogenic from organic and vascular from neuropathic and include:
Doppler ultrasound measurement ofbrachial and penile systolic blood pressure
Penile tumescence measurement
by
strain gauge
Penile tumescence measured by postage
stamp
Bulbocavernosus reflex response latency

Sudomotor sympathetic function.

Sudomotor function may be evaluated
with the TST, QSART, skin potentials,
or sweat imprint quantitation. The
TST is a sensitive test of sweat distribution (404). The subject is dusted
with an indicator powder that turns
purple when moist. This quantitative
test can be rendered semiquantitative
by charting the percentage of anterior
body surface that is anhidrotic.
The skin potential can be recorded
with standard EMG equipment, from
the palm and sole (401). The stimulus
is an electric shock, an inspiratory
gasp, or other stimuli that activate
type II and III mechanoreceptor afferents. The skin potential is readily
evoked but habituates.
The silastic skin imprint is obtained
after the application of silastic material
to stimulated skin (385). The sweat
droplet indents the imprint, and the
count and diameter distribution can
be determined. The usual stimulus is
pilocarpine administered by iontrophoresis.
In QSART (405,406), the stimulus
consists of the iontrophoresis of acetylcholine via the stimulus compartment of a multicompartmental sweat
cell. Postganglionic sympathetic nerve
terminals are activated, and the nerve

1954

impulse travels retrogradely, reaches a

branch point, then travels orthogradely to activate a second population of sweat glands. The sweat response from this second population of
sweat glands is recorded by a sudorometer. The stimulus compartment
surrounds the central recording compartment, separated by an air gap and
two ridges (to block diffusion). This
test evaluates the integrity of the distal
postganglionic sympathetic sudomotor axon. Four recording sites (distal
forearm and three lower extremity
sites) are used. The test has high sensitivity, a CV of 20% and, when used
in conjunction with the thermoregulatory sweat test, defines the pre- or
postganglionic site of the lesion. The
test requires specialized equipment,
trained technicians, and 20-30 min to
complete.
Peripheral skin blood flow reactions.
Microvascular skin blood flow may be
accurately measured noninvasively by
using laser Doppler flowmetry (407).
Smooth-muscled microvasculature in
the periphery reacts sympathetically
and parasympathetically to numerous
stressor tasks.
Orienting response

Typically, an orienting response can

be observed as a microvascular constriction and resulting drop in peripheral (index finger, pulpar surface) skin
blood flow when a healthy subject attenuates to speech after several minutes of relaxation with music.
Mental arithmetic

Mental arithmetic as a serial subtraction task typically results in a 30%

reduction in peripheral (index finger,
pulpar surface) skin blood flow from a
resting baseline.
Hand grip

Peripheral contralateral (index finger,

pulpar surface) response to sustained
40% maximum grip on a dynamometer is biphasic over 60 s. The initial
response is a 40-50% reduction of
flow from basal during the initial
20-30 s, followed by a dilation result-

ing in a return to typically superbasal

levels.
Cold pressor

Immersion of the contralateral hand in

cold (ice) water typically results in an
intense (50-60%) reduction in peripheral skin blood flow at the pulpar
index surface. In some individuals,
this response becomes biphasic after
prolonged exposure (30 s) to such intense cold, because it is extremely uncomfortable.
Laser flowmetry measure erythrocyte velocity (although not linearly)
and volume. In healthy individuals,
the most distinct changes that occur in
relation to these tasks are associated
primarily with changes in volume of
blood. Blood velocity is slightly increased during most stressors, while
blood volume accounts for the dramatic reductions in overall flow to the
region being measured from.

Hypoglycemia unawareness/
unresponsiveness
To test for the presence of these syndromes requires elaborate and expensive
equipment and is best done in a research
environment. For the sake of completeness, they are described herein. The
stepped hypoglycemic clamp technique,
applied to normal subjects (337,349)
and IDDM patients (330) has been described in detail. Briefly, after an overnight fast (and overnight i.v. insulin infusion to achieve near euglycemia before
the test in IDDM), insulin (2.0
Mu kg" 1 min" 1 ) is infused continuously and an intravenous glucose infusion is varied either to maintain euglycemia (5.0 mM) throughout (euglycemia
control) or to achieve hourly glucose
clamps of 5.0, 4.4, 3.9, 3.3, and 2.8 (or
even 2.2) mM. Symptoms and hormone
responses are assessed at the end of each
glycemic step. Cognitive function also
can be assessed (337,349). The test is
labor intensive, requiring a minimum of
two people (typically a physician and
nurse); a third person is needed if cognitive function is assessed. It also re-

DIABETES CARE, VOLUME 15,

NUMBER 12,

DECEMBER

1992

Vinik and Associates

diabetes control (408-413). Some neuropathic patients who experience tremendous pain may benefit from a period
of intravenous insulin administration irrespective of the degree of improvement
in glycemic control or HbAx. Prospective
studies that have compared conventional
therapy with that of an intensified regime
either by continuous subcutaneous insulin infusion or multiple injections each
day have shown improvement in motor
NCV velocity (412-416) with resistance
of improvement in sensory function; although in studies where treatment has
been prolonged for 8 mo to 2 yr
(412,413,415), improvement in all modalities of nerve function has been found.
One problem with the evaluation of
these studies, however, is the lack of data
pertinent to the relationship between
nerve conduction studies and the symptom complex. In neuropathies involving
the small nerve fibers, which are slow
conductors and thus contribute little to
the overall measurement of nerve conduction, little or no change in the EMG
may be detected, even in the face of dramatic clinical effects of normalization of
the blood glucose. It is not apparent from
these studies whether the improvement
is related to a reduction in the endoneural edema, improvement of the vascular
supply to the nerves, or regrowth of
damaged neurons. Until the outcome of
the multicenter DCCT (417) is known in
7 yr, the prudent advice is to normalize
MANAGEMENT Management may diabetes control as much as possible, esbe divided into general and specific mea- pecially in those individuals who have
sures. The general measures include di- evidence of early neuropathy.
abetes control, and the specific measures
Nutritional factors.Several different facinclude symptomatic, palliative, and
tors have been implicated in the pathosupportive treatment directed at the
genesis of neuropathy, including vitamin
symptom complex present.
B12 deficiency, vitamin A deficiency,
General measures
pyridoxine (B6) deficiency, and a host of
Diabetes control.Although some retromacro- and micronutrients. Although
spective studies suggest that the prevalence of diabetic neuropathy increases in the beneficial effects of some of these
direct proportion to worsening control of nutritional factors have been suggested,
diabetes (13-15), data indicate that this studies have not been controlled, and the
complication, more than retinopathy and present recommendation is to maintain
nephropathy, may improve with better adequate and healthy nutrition.

quires accurate glucose measurements

(with a Beckman or YSI analyzer, not
with a glucose monitor) at the bedside
and the analytical capacity to perform
the hormone measurements. Cognitive
assessment generally requires a collaborating psychologist.
The insulin infusion test, applied
to normal subjects and IDDM patients,
also has been described in detail (301).
Briefly, after an overnight fast (and overnight i.v. insulin infusion to achieve near
euglycemia prior to the test in IDDM),
insulin (67 mU kg" 1 min" 1 ) is infused continuously and glucose is not
infused because the plasma glucose concentration is the primary end point. The
test is continued until the plasma glucose
plateaus at 2.0 mM, neuroglycopenia develops, or both (defective glucose counterregulation). Hormone levels and
symptoms are preferably measured serially (assessment of cognitive function is
more problematic given the time required to perform cognitive tests). However, serial measurements of the plasma
glucose concentration and assessments
of mental status are sufficient for clinical
interpretation of the test. The test requires two individuals, one of which
must be a physician (because a medical
judgment must be made as to whether or
not an end point is reached, and insulin
infusion should be stopped). It also requires accurate glucose measurements at
the bedside.

DIABETES CASE,

VOLUME 15, NUMBER 12,

DECEMBER

1992

Trials of specific therapy

ARIs.The trials of ARIs are still in the
research arena, and although some
promising reports have been issued on
improvement in symptoms and in some
objective measures of neuropathy, the
degree of benefit obtained has not been
by any means outstanding. Currently, it
is too early to evaluate the place of ARIs
in the management of diabetic neuropathy.
In recent years, numerous studies
have been reported in which ARIs have
been used to treat diabetic neuropathy
(117,360,418-428). Enthusiasm for this
form of treatment has been based on the
observation that the excessive accumulation of the sugar alcohol sorbitol and
fructose within the major target tissues is
relevant to the diabetic complications,
namely the retina, the kidney, and the
peripheral nerves.
Alrestatin, the first available AR1
to be used, generated conflicting results
(360,418-420), probably because of a
poor selection of cases with fairly advanced neuropathy so that reversal of the
condition was unlikely.
Sorbinil, a spirol hydantoin, has
been shown in human diabetic neuropathy to be effective in producing both a
significant improvement in the symptoms of pain and paresthesia and also in
motor NCV (117), where the increase
was small but statistically significant. The
response may be limited, however, because longer duration of treatment or
treatment with smaller doses has not
achieved any significantly greater effect
than that found with short-term treatment (360). The major problem relating
to the use of the hydantoin is the development of significant toxicity in ~16%
of cases (421,422), which is characterized by lymphadenopathy and a macular
papular erythematous rash associated
with fever and pancytopenia. These
symptoms usually appear within the first
1-2 wk of starting therapy, but disappear with cessation of the drug. As a
result, further studies involving the use
of this ARI for the treatment of diabetic

1955

Diabetic neuropathies

neuropathy have been suspended. It

should be noted that a significant improvement in the autonomic measures of
cardiac function also has been shown
after treatment with sorbinil (421; M.A.
Pfeiffer, unpublished observations). If
these data indicate reversibility of autonomic dysfunction, then the clinical
ramifications are considerable in light of
the high mortality associated with diabetic autonomic neuropathy. Tolrestat, a
compound that has no hydantoinlike
structure, was shown after 1 yr of treatment to generate significant but modest
improvement in nerve conduction when
used in a dose of 200 mg/day (426).
After longer term treatment, the improvement continues but even more
modestly (427). This drug is relatively
free of side effects, with only 4% of patients developing abnormalities in liver
enzymes.
None of the ARIs are currently
approved for clinical use in the U.S.; all
patients currently receiving treatment are
participants of trials conducted by the
various centers. A major problem related
to the interpretation of the data generated in the early studies has been the lack
of standardization of the approaches
used to determine: I) clinical symptomatic responsiveness; 2) electrophysiological means of monitoring thermal and
vibratory changes; 3) the optimum electrophysiological measurement used to
quantitate neuropathic change or improvement; and 4) use of surrogate histological data to support the notion of
nerve regeneration. Furthermore, variability in the measurements conducted
by different centers in control studies has
been considerable, thus highlighting the
need for minimizing both inter- and intracenter variability. Thus, for trials of
this nature to be successful and for
meaningful results to be achieved, it will
be necessary to standardize carefully the
clinical measurements of symptoms and
physical findings as well as those for
quantitative physiological testing and to
prospectively identify the histological
end points to be used as primary goals of

1956

therapy. We believe such a study is now one research group has treated diabetic
being conducted at various centers in the subjects for 1 yr and longer with 7-linoU.S. with tolrestat.
lenic acid and has documented improved
As alluded to earlier, patient se- nerve function compared with a placebolection is also an important consider- treated group (439). The results generation, with ideal candidates afflicted with ated by this small trial are exciting beonly mild or very modest neuropathy. cause 7-linolenic acid also has an
But because many of these patients will important lipid-lowering effect and thus
experience predominantly small fiber could be useful in the general manageneuropathy, which is not detected on ment of diabetes. Further exploration of
electrophysiological measurements, this area is needed.
quantitation of nerve defects are based Aminoguanidine.New studies in rats
predominantly on subjective responses. has shown that aminoguanidine may be
Thus, these studies need to be blinded
of value in reversing the glycation of proand placebo controlled.
teins implicated in the pathogenesis of
Myo-inositol.Myo-inositol deficiency
the complications of diabetes. Studies are
has been reported in animal models and
being conducted on a research basis, and
intolerance to myo-inositol in diabetes in
the product is not yet available for huhumans. Results from several studies
man use.
suggest that myo-inositol supplements of
the normal diet will improve neuropathy Pain control
(55,430-432), but the treatment may Control of pain in diabetic neuropathy
have to be prolonged for at least 6 mo for may present one of the most trying proba significant effect to be achieved (55). In lems for both physician and patient. Ofdesperate situations, however, individu- ten patients are depressed, and the deals with a normal myo-inositol intake of pression does not appear to be a function
800 mg/day may have this increased to of the extent or severity of the neuropa1600 mg/day. This is easily obtainable by thy but rather a sense of uselessness. An
purchasing Brewer's yeast from a phar- accompanying sense of weakness also
macy where it comes in two forms, one may be present, and this often is not
containing 400 mg and one containing because of a muscle deficit, but rather a
800 mg of inositol with the appropriate feeling of hopelessness. Enrollment of
some patients to various drug trials has
number of tablets prescribed per day.
Gangliosides.Gangliosides are sialogly- yielded improvement in ~50% of subcolipids found in nerve cell membranes jects, even before institution of drug
and nerve growth cones. A series of stud- therapy or the administration of placebo.
ies reported from Europe (359,433- This trial effect highlights the need for
437) and one from the U.S. (438) in physicians to treat these patients with
small groups of patients have shown compassion, sympathy, understanding,
some improvement in lower extremity and a sense of hope. Simple maneuvers,
sensation but without changes in the such as wearing body stockings to deelectrophysiological measures of nerve crease movement of hair follicles, can be
function. Although these studies hold helpful.
promise, they need to be conducted in a
Generally, two types of pain are
controlled manner in larger series of pa- exhibited in neuropathy. In one variety,
tients.
the pain consists of marked hyperaestheEvening primrose oil.On the basis that sia and a burning, laminating dysesthestc
diabetic subjects have a deficiency in the component. This subgroup may respond
ability to generate arachidoninc acid to topical application of capsaicin (440).
from their membrane phospholipids and In the second type, the pain is akin to a
thus a deficient substrate for the synthe- deep-seated, gnawing toothache; it gensis of certain prostaglandin derivatives, erally does not do well with topical ther-

DIABETES CARE, VOLUME 15,

NUMBER 12,

DECEMBER

1992

Vinik and Associates

SIMPLE PHYSICAL MEASURES

Warm baths, body stockings, TENS

SIMPLE ANALGESICS
Aspirin, paracetamol, NSAIDS

(sensitivity to gentle stimulation)

PROTOPATHIC
Deep-seated, gnawing,
"toothache" poorly localized

TRIAL OF TROPICAL AGENT

TRIAL OF "BENIGN" DRUGS

EPICRITIC
Burning, Dysesthesia

Insulin infusion

Capsaicin

Clonidine 100-500 ^ H S
1

Metoclopramide 10 mg/tid
Mexilitene<10mg/Kd/d
Pentoxifylline 400 mg/tid

TRIAL OF ANTIDEPRESSANTS PHENOTHIAZINES

Amitriptyline 50 -150 mg nocte
fluphenazine 1 6 mg/d
Clonazepam 0.5 - 3.0 mg/d
Figure 3Suggested sequence for treatment of painful diabetic neuropathy.

apy and should therefore follow the following path (Fig. 3).
Analgesics.Various analgesic drugs
have been used for the management of
pain in diabetic neuropathy, including
aspirin, paracetomol, the non-steroidal
anti-inflammatory drugs, and demerol.
Care must be exercised in the use of
more potent analgesics for fear of addiction.
Dilantin.Dilantin, long advocated in
the treatment of pain, is generally not
thought to be of value in diabetic neuropathy (441,442). One problem is that
it tends to yield toxicity with macrocytic
anemia, hypertrophic gums, and ataxia
before a therapeutic effect is observed.

DIABETES CASE,

VOLUME 15,

NUMBER 12,

Carbamazepine.Carbamazepine
is
highly useful in the management of epilepsy in children and has been shown to
be effective for certain individuals in
double-blind placebo-controlled studies
(443-445). In general, however, this
drug is too toxic to be considered as the
first line drug.
Clonidine.Interest in clonidine in the
management of painful diabetic neuropathy has been motivated by the considerable success achieved by this drug in
the management of patients who have
been withdrawn from alcohol and other
drugs. It also seems to work reasonably
well in many causalgic situations. One
should start with a small dose of 75-100

DECEMBER

1992

|xg given at night to avoid hypotension

and sleepiness, and the dose then should
be increased gradually until a desired
effect is achieved. About 33% of the patients will respond in this manner.
Amitriptyline.Several studies have examined the effects of various tricyclic
drugs in combination with phenothiazines and have reported a beneficial effect
that is unrelated to the relief of depression (446-448). The usual doses are
50-150 mg amitryptyline in divided
doses plus 1-2 mg fluphenazine orally at
night. Unfortunately, however, dysautonomia, dry mouth, and visual disturbances caused by the tricyclics may be
limiting; and the tardive dyskinesia with
the phenothiazines is troublesome. Recently reported is the benefit of treatment with the tricyclics alone in doublemasked placebo-controlled studies
indicating greater effectiveness of the
drug compared with placebo alone
(449,450). As mentioned earlier, many
of these patients are extremely depressed, and a trial of imipramine alone
or amitriptyline given together with fluphenazine may be of benefit in many
patients.
Transcutaneous nerve stimulation.Transcutaneous nerve stimulation must be
considered, if only for the reason that it
represents one of the most benign approaches to management. Often this approach is abandoned prematurely when
the practitioner fails to move the electrodes around sufficiently to identify sensitive areas. When the approach is effective, salutary results are usually obtained
only after the electrodes are moved to
multiple areas, including those not in the
distribution of the nerves involved.
Nerve blocking.The administration of
lidocaine by slow infusion of 5 mg/kg
over 30 min has been shown to provide
relief of intractable pain for a period of
3-21 days (451). When the pain is localized to a nerve root distribution, the
temporary pain relief provided by the
local nerve blockers may constitute sufficient management, because such pain is
self-limiting.

1957

Diabetic neuropathies

Rheological agents.Pentoxyfylline is a
rheological agent that increases the deformability of erythrocytes and increases
blood flow with enhanced oxygenation of tissues. Use of this agent has
been reported sporadically in diabetic
neuropathy, and it merits the current
six center clinical investigation of the
safety and efficacy in painful diabetic
neuropathy.
Neuropathic ulcers
It must be stressed that neuropathic ulcers constitute the greatest hazard to loss
of limbs in patients with diabetes, and it
is the responsibility of the physician to
insure that the patient understands the
importance of foot care.
Meticulous foot care.Drying between
the toes after bathing, application of drying powder such as Johnson's baby powder and application of softening creams
such as lanolin are critical measures for
the prevention of foot ulcers. Daily inspection of the feet is tantamount, and
patients must be taught nail-cutting
skills.
Orthotic devices.If one finds marked
loss of sensation with the development of
ulcers in the pressure areas indicated
above, then the purchase of a shoe one
size larger than regular with an insert of
plastozet or alzet, which will mold to the
foot and distribute the pressure, can result in healing of ulcers within several
months.
Ulcer care.Ulcer care requires debridement of necrotic tissue, repeated sterile
dressings, removal from further pressure
with supportive devices, or even bed rest
or a plaster cast. Infection must be aggressively treated, with appropriate antibiotics often for at least 3 wk and the
underlying osteomyelitis excluded by
x-ray. Trials of topical platelet-derived
growth factor as a means of accelerating
wound healing are being undertaken in
several cities in the U.S. This area probably constitutes the single greatest cause
of mismanagement of diabetic patients,
which often gives rise to medico/legal
suits.

1958

Charcot jointsorthotic devices

mg/tid) will be helpful. In the event that
Once destruction of a charcot joint is P-receptors are increased in number, as
complete and total loss of joint pain and occurs in a small portion of cases, inderal
perception has occurred, the only means (propranolol) (456) 10 mg/qid or pindolol may be of more value. If, however,
of treatment is orthotic devices.
there is an a-receptor deficiency
Mononeuropathies
Physiotherapy is important to prevent (256,257), then the use of clonidine may
contractures, and the joints should be paradoxically raise blood pressure rather
protected until spontaneous recovery oc- than decrease it. One needs, of course, to
start with a small dose and then increase
curs.
the dose to 400 u.g/day. In the event that
Postural hypotension
The management of postural hypoten- all of these measures fail, then the direct
sion in the individual with diabetic au- a - a d r e n e r g i c agonist midodrine
tonomic neuropathy can be complex. (Gutron) 2.5-40 mg q 6 h or dihydroOne has to tread a narrow path between ergotamine 2.5-40 |xg q 6 h given in
elevating the blood pressure in the stand- combination with caffeine (457) may be
ing position and ensuring that supine of value. Of particular note is the poshypertension does not occur. The situa- tural hypotension that occurs in some
tion is further complicated by the com- individuals soon after meal ingestion
plex nature of the pathogenesis of the which may prove particularly refractory
to treatment. Hoeldtke (458) has shown
neuropathy.
Supportive garments.The first step in the that a small dose of the analogue of sotreatment of postural hypotension should matostatin, sandostatin, 0.1-0.5 |xg/kg
always be to attempt to increase venous given as a single s.c. injection in the
return from the periphery with supportive mornings may allow these subjects to
elements, such as total body stockings. live normally and remain normotensive
These stockings should be applied while throughout the day. The mechanism of
the individual is lying in bed and should action has not yet been resolved but does
not be taken off until the individual returns not appear to be related to effects on the
to the supine position. Unfortunately, adrenergic nervous system. Care must be
some patients find them uncomfortable, exercised, because slightly higher doses
particularly during the summer months. In may result in hypertension which could
severe cases, an Air Force antigraviry suit be dangerous in these individuals.
Gastropathy
may be required (452).
Drug therapy.The treatment with 9-a- The initial management of gastropathy
fluohydrocortisone (0.5 mg gd) (453, should include multiple small feedings
454) and supplementary salt (2-6 g) with a reduction in the fat content which
may relieve individuals of symptoms, but tends to delay gastric emptying. If this is
the inherent danger of developing not helpful, metoclopramide given 10
edema, congestive cardiac failure, and mg by mouth up to 4 times a day may be
supine hypertension is always present. In of value (459-462). If marked gastrofact, one does not see relief of the symp- paresis is present with a large gastric retoms of postural hypotension until sidual volume filled with fluid, however,
edema occurs. In the event that these then the drug is poorly absorbed, and
measures fail, if the a- and (3-adrenergic one needs to commence therapy with
receptor status is known, one can make a intravenous administration of fuels and
reasonable guess as to which drug the gastric suction until it has been shown
individual is likely to respond. If there is that the stomach is beginning to empty
a dopamine excess, metoclopramide or and only then to switch to the oral form.
Reglan 10 mg rid may be useful (455). If Other agents such as cholinergic agonists
there is an a-adreno receptor excess, (bethanechol chloride: 10 mg/qid (462)
then the a-2-antagonist yohimbine (10 and cholinesterase inhibitors (pyridostig-

DIABETES CARE, VOLUME 15,

NUMBER 12,

DECEMBER

1992

Vinik and Associates

mine bromide: 1-2 mg/day) may produce marked drying of secretions in the
mouth, blurring of vision, and colic
without enhancing gastric emptying.
Two investigational drugs, 10-40 mg
domperidone 30 min before meals and
10-40 mg cisapride 30 min before meals
have proved to be useful in some patients
but probably is of no greater value than
metoclopramide (463). Erythromycin
given as liquid or suppository stimulates
IMMC and may be helpful. In the event
that all else fails, we have resorted to
placing a jejunostomy tube transabdominally and feeding by this route into an
area of bowel that has normal function.
Nutrients are given during the night,
thus freeing the patient for their daily
activities during the day. This approach
simplifies matters because it allows the
insulin requirements to be tailored to the
nocturnal feeding (464).
Enteropathy

Pancreatic exocrine insufficiency. Viokase

should be added to the treatment regimen in doses that are large (e.g., 10-18
tabs/day) if it is to be effective. Many of
these patients have evidence of pancreatic exocrine insufficiency and replacement of the exocrine secretions with 18
tablets/day of viokase may be helpful.
Clonidine may prove useful in the
management of some of these patients
(290,291), but unfortunately only a single small trial involving few patients has
evaluated its efficacy.
In resistant cases, we have used a combination of SRIF analogue together with
lithium and have been successful in
treating cases refractory to all other
forms of intervention (292,293).
Withdrawal from narcotics should be
avoided at all costs, because this can lead
to a cycle of chronic constipation followed by explosive episodes of diarrhea,
sometimes with toxic megacolon.
Cystopathy
Diabetic enteropathy can be the most
Probably the first step in the managetrying and difficult of all diabetes comment of patients who are insensitive to a
plications to treat.
full bladder is to educate the individual
Antibiotics. A broad spectrum antibiotic
to do repeated palpations of their lower
is usually the treatment of choice. This
abdomen to determine whether or not
may be tetracycline (465), bactrim, or
the bladder is full. Such patients often
what appears to work best of all, metronwill be able to initiate micturition simply
idazole (Flagyl), in a dose of 750 mg/ted. by applying pressure to the bladder, a
It is important, however, to continue procedure known as Crede's maneuver.
treatment for a minimum of 3 wk and, if When this procedure fails, the use of
possible, to check that the breath hydro- parasympathomimetics such as bethanegen test has returned to normal, which chol chloride (10 |xg/qid) may be conindicates that bacterial overgrowth is sidered, although this may produce colic
controlled.
without allowing adequate bladder empCholestyramine. Retention of bile some- tying. A most useful and simple aptimes occurs, which may be highly irri- proach that we have used is repeated
tant to the gut (287), and chelation of bladder self-catherizations (466), with
bile salts with 4 g/tid cholestyramine infection resulting only infrequently. In
mixed in fluid and given orally (288) male patients, bladder neck surgery can
may be of considerable help.
be done to relieve the spasm of the inDiphenoxylate HC1 plus atropine: lomotil 2 ternal sphincter. Continence is preserved
mg/qid (PO). The use of diphenoxylate is because of the somatic supply of the exa last resort measure, and extreme care ternal sphincter.
should be exercised because toxic mega- Erectile failure
colon can occur.
As mentioned earlier (467-469), this abGluten-free diet may be of value normality is probably one of the most
in those patients who have the added significant, at least to the patient, presentations of autonomic dysfunction as it
insult of poor digestion.

DIABETES CASE, VOLUME 15,

NUMBER 12,

DECEMBER

1992

may result in matrimonial and other disharmony. Counseling and management

of behavioral problems is cardinal to the
care of these patients. Today, numerous
treatment modalities are available, including use of inflatable devices (470).
These devices operate on the principal of
obstruction of venous outflow aided by
negative pressure to increase inflow and
have been used with some degree of success. In addition, the a-adrenergic antagonist yohimbine given as 10 mg/tid
may help in 33% of cases, and lastly,
the direct intrapenile injection of regitine
and papaverine has met with some success. This latter regimen, however, invariably is associated with a small proportion of patients developing infections,
priapism, and ultimately fibrosis. It does,
however, provide the patient with relief
of symptoms for a period of time ranging
from months to years, and this may be a
godsend. Finally, in the event of failure
of these therapies, rigid and semirigid
protheses are available, and this option
should be discussed with the patient and
the significant other.
Retrograde ejaculation may be
treated with 8 mg twice a day brompheniramine, an anticholinergic (471), 25
mg/tid imipramine (472), or 60 mg phenylephrine i.v., an a-adrenergic agonist
(473).
Gustatory sweating

Gustatory sweating and sudomotor disturbance appear to respond to some

degree to propantheline hydrobromide
15 mg/tid (PO) and to scopolamine
patches.
Hypoglycemia unawareness/unresponsiveness/HAAF
Patients with this complication pose a
genuine dilemma for the physician. If
one believes that autonomic neuropathy
may reverse with intensive therapy and
subsequent normalization of blood glucose and HbAj, then the objective is to
try and normalize these measures. On
the other hand, considerable risk is
posed to these patients who are not
aware of the hypoglycemia and lack the
counterregulatory response to mount a

1959

Diabetic neuropathies

and perhaps for other diabetic complications.

Peripheral and possibly autonomic neuropathy is also an important
contribution to the development of neuropathic foot ulceration, which can be a
devastating complication for some unfortunate patients. It has been estimated
that > 50% of all nontraumatic amputations in this country occur in diabetic
patients and that 50% of these are potentially preventable (476). These statistics highlight the need for careful attention to foot care in diabetic patients.

Patient with diabetes

NIDDM
Evaluate AN function
after 5 years then
yearly thereafter

Evaluate AN function
at diagnosis then
yearly thereafter

yearly evaluations
control diabetes
consider preventive
therapy eg. Aldose
reductase inhibitors

supervise exercise
regulate BP
- nocturnal
- exercise
perioperative
- preparation
foot care
relax - intensity of diabetes
control (hypoglycemia
unawareness &
unresponsiveness
thermoregulation - hydration in
hot environment
specific Rx.
- system dependent

Figure 4Suggested paradigm for management ofautonomic neuropathy.

means of combating their fall in blood

glucose concentration. Thus, it is our
contention that if pump therapy is to be
used, one should avoid boluses; and if
intensive conventional therapy is to be
used, one should elect to use long-acting
insulins with very small boluses. In general, one should not aim for normal
HbAx and normal blood glucose levels
when this complication supervenes.
Scrupulous avoidance of hypoglycemia is
mandatory.
The following is paradigm for the
management of autonomic neuropathy.

SUGGESTED MANAGEMENT OF
AUTONOMIC NEUROPATHY
1. General measures
a. Improve diabetes control and general nutrition

1960

2. Trials of specific therapy

a. ARIs(in Research Arena)
b. Myo-inositol: diet containing 1650
-3200 mg/day (normal < 800 mg/
day)
3. A paradigm (Fig. 4)

PROGNOSIS The tendency for

neuropathy, nephropathy, and retinopathy to cluster together in the same patient has long been recognized (474) and
is now referred to as a tripoathy with this
clustering appearing independently of
age and duration of diabetes (13-15).
Neuropathy is often the first of these
complications to become manifest and
thus may serve as a marker for those at
high risk for future development of retinopathy, as suggested by Knowler (475)

The presence of autonomic neuropathy also may lead to accelerated development of other morbid conditions.
Among women with diabetes, for example, it is reported that those with cardiovascular autonomic neuropathy have a
higher prevalence rate of bacteriuria than
women of similar age, duration of diabetes, and GHb but without cardiovascular
autonomic neuropathy (477). Hypothesizing that cardiovascular autonomic abnormalities might be an indicator of autonomic bladder dysfunction, these
researchers suggested that a causal association between autonomic neuropathy
and bladder involvement could explain
previously reported associations between
diabetes and urinary tract infections
(477-481).
The increased mortality risk associated with diabetic autonomic neuropathy has been well publicized, primarily
by the work of Ewing et al. (72,482,
483). Among 73 clinic patients with
symptoms of autonomic neuropathy followed for up to 5 yr, these researchers
observed an overall mortality rate of
35%. Among subjects with abnormal autonomic function tests at baseline, the.
mortality rate was 44% at 2.5 yr and
56% at 5 yr as compared with 15% at 2.5
yr and 21% at 5 yr for the group testing
normal at baseline (482). The poorer
survival of the abnormal group could not
easily be explained by selection factors,
because no significant differences were
observed in age, duration of diabetes,
and duration of autonomic neuropathy

DIABETES CARE, VOLUME 15,

NUMBER 12,

DECEMBER

1992

Vinik and Associates

11. Orchard TJ, Dorman JS, LaPorte RE,

Ferrell RE, Drash AL: Host and environmental interactions in diabetes mellitus. J Chronic Dis 39:979-99, 1986
12. Bruyn GW, Garland H: Neuropathies of
endocrine origin. In Handbook of Clinical Neurology, Vinkin PJ, Bruyn GW,
Eds. Amsterdam, North-Holland, 1970,
p. 29-71
13. PirartJ: Diabetes mellitus and its degenerative complications: a prospective
References
study of 4,400 patients observed between 1947 and 1973. Diabete Metab
1. Deckert T: Late diabetic manifestations
3:97-107, 1977
in "pancreatogenic" diabetes mellitus.
Ada Med Scand 168:439-46, 1960
14. PirartJ: Diabetes mellitus and its degen2. Galton DJ: Diabetic retinopathy and
erative complications: a prospective
haemochromatosis. Br Med J 1:1169,
study of 4,400 patients observed be1965
tween 1947 and 1973. Part 2. Diabete
3. Bank S, Marks IN, Vinik Al: Clinical
Metab 3:173-82, 1977
and hormonal aspects of pancreatic di15. PirartJ: Diabetes mellitus and its degenabetes. Am J Gastroenterol 64:13-22,
erative complications: a prospective
1975
study of 4,400 patients observed be4. Thomas PK, Eliasson SG: Diabetic neutween 1947 and 1973. Part 3. Diabete
ropathy. In Peripheral neuropathy. Dyck
Metab 3:245-56, 1977
PJ, Thomas PK, Lambert EH, Bunge R,
16. Franklin G, Kahn L, Bacter J: An epideEds. Philadelphia, Saunders, 1984, p.
miologic study of neuropathy in the San
1773-1810
Luis Valley, SET Meetings, Amherst, MA,
5. Sullivan JF: The neuropathies of diabe1987
tes. Neurology 8: 243-49, 1958
17. Goodman Jl, Baumoel S, Frankel L: The
6. Ellenberg M: Diabetic neuropathy. In
Diabetic Neuropathies. Springfield, 1L,
Diabetes Mellitus: Theory and Practice.
Thomas, 1953
Ellenberg M, Rifkin H, Eds. New York,
18. Boulton AJ, Knight G, Drury J, Ward
McGraw-Hill, 1982, p. 777-801
JD: The prevalence of symptomatic, di7. Greene DA, Pfeifer MA: Diabetic neuabetic neuropathy in an insulin-treated
ropathy. In Diabetes Mellitus: Managepopulation. Diabetes Care 8:125-28,
ment and Complications. Olefsky JM,
1985
Sherwin RS, Eds. New York, Churchill
19. Fry IK, Hardwick C, Scot GW: Diabetic
Livingston, 1985, p. 223-54
neuropathy: a survey and follow-up of
8. Brown MJ, Asbury AK: Diabetic neu66 cases. Guy's Hosp Report 111:113
ropathy. Ann Neurol 15:2-12, 1984
29, 1962
9. American Diabetes Association Ameri20. Nilsson SV, Nilsson JE, Frostberg N,
can, Academy of Neurology: Consensus
Emilsson T: The Kristianstad survey: II.
statement: report and recommendaStudies in a representative adult diations of the San Antonio conference on
betic population with special reference
diabetic neuropathy. Diabetes Care 11:
to comparison with an adequate control
592-97, 1988
group. Ada Med Scand Suppl 469:1-42,
10. Dyck PJ, Kratz KM, Lehman KA,
1967
Karnes JL, Melton LJ, O'Brien PC, Li21. Paisey RB, Arredondo G, Villalobos A,
chty WJ, Windebank AJ, Low PA: The
Lozano O, Guevara L, Kelly S: AssociaRochester Diabetic Neuropathy Study:
tion of differing dietary, metabolic, and
design, criteria for types of neuropathy,
clinical risk factors with microvascular
selection bias, and reproducibility of
complications of diabetes: a prevalence
neuropathic tests. Neurology 41:799study of 503 Mexican type II diabetic
807, 1991
subjects. Diabetes Care 7:428-33, 1984

symptoms between the two groups at

baseline. Patients who died were, however, more likely to present with postural
hypotension, gastric symptoms, and hypoglycemic unawareness at baseline examination. Possible mechanisms for the
increased risk associated with diabetic
autonomic neuropathy have been discussed earlier.

DIABETES CARE, VOLUME 15,

NUMBER 12,

DECEMBER

1992

22. Haimanot RT, Abdulkadir J: Neuropathy in Ethiopian diabetics: a correlation

of clinical and nerve conduction studies. Trop Geogr Med 37:62-68, 1985
23. Factors in development of diabetic neuropathy. Baseline analysis of neuropathy in feasibility phase of Diabetes Control and Complications Trial (DCCT).
The DCCT Research Group. Diabetes
37:476-81, 1988
24. Marcus J, Ehrlich R, Kelly M, Murphy
EG: Nerve conduction in childhood diabetes. Can MedAssocJ 108: 1116-19,
1973
25. Kruger M, Brunko E, Dorchy H, Noel P:
Femoral versus peroneal neuropathy in
diabetic children and adolescents
relationships to clinical status, metabolic control and retinopathy. Diabete
Metab 13:110-15, 1987
26. Sosenko JM, Boulton AJ, Kubrusly DB,
Weintraub JK, SkylerJS: The vibratory
perception threshold in young diabetic
patients: associations with glycemia and
puberty. Diabetes Care 8:605-607,
1985
27. Osuntokun BO, Akinkugbe FM, Francis TI, Reddy S, Osuntokun O, Taylor
GO: Diabetes mellitus in Nigerians: a
study of 832 patients. West Afr Med J
Niger Pract 20:295-312, 1971
29. Jeyarajah R, Samarawickrama P, Jameel
MM: Autonomic function tests in noninsulin dependent diabetic patients and
apparently healthy volunteers. J Chronic
Dis 39:479-84, 1986
30. Sharpey-Schafer EP, Taylor PJ: Absent
circulatory reflexes in diabetic neuritis.
Lancet 1:559-62, 1960
31. Ewing DJ; Irving JB, Kerr F, Wildsmith
JA, Clarke BF: Cardiovascular responses to sustained handgrip in normal subjects and in patients with diabetes mellitus: a test of autonomic
function. Clin Sci Mol Med 46:295-306,
1974
32. Drybert T, Benn J, Christiansen JS,
Hilsted J, Nerup J: Prevalence of diabetic autonomic neuropathy measured
by simple bedside tests. Diabetologia 20:
190-94, 1981
33. Burke CM, O'Doherty A, Flanagan A,
O'Connel BM, Devlin JG: Autonomic
neuropathy in a diabetic clinic. Ir Med]

1961

Diabetic neuropathies

77:202-205, 1984
34. Veglio MP, Carpano-Maglioli P, Tonda
L, Quadri R, Giannella R, Rosa C,
Fonzo D: Autonomic neuropathy in
non-insulin-dependent diabetic patients: correlation with age, sex, duration and metabolic control of diabetes.
Diabete Metab 16:200-206, 1990
35. Maser RE, Pfeifer MA, Dorman JS,
Kuller LH, Becker DJ, Orchard TJ: Diabetic autonomic neuropathy and cardiovascular risk. Pittsburgh Epidemiology of Diabetes Complications Study
III. Arch Intern Med 150:1218-22,
1990
36. Bergstrom B, Lilja B, Osterlin S, Sundkvist G: Autonomic neuropathy in noninsulin dependent (type II) diabetes
mellitus. Possible influence of obesity J
Intern Med 227:57-63, 1990.
37. Boulton AJ, Worth RC, Drury J, Hardisty CA, Wolf E, Cudworth AG, Ward
JD: Genetic and metabolic studies in
diabetic neuropathy. Diabetologia 26:
15-19, 1984
38. Shenfield GM, McCann VJ, Tjokresetio
R: Acetylator status and diabetic neuropathy. Diabetologia 22:441-44, 1982
39. Chochinov RH, Ullyot GL, Moorhouse
JA: Sensory perception thresholds in
patients with juvenile diabetes and their
close relatives. N EnglJ Med 286:123337, 1972
40. Gadia MT, Ayyar DR, Ramos LB, Natori
N, SkylerJS, Sosenko JM: The association between neurologic dysfunction
and body stature (Abstract). Diabetes 35
(Suppl l):103A, 1986
41. Greene DA, Brown M, Gilbert P,
Nielsen VK, Pfieffer EA: Age and gender
are factors in the development of diabetic neuropathy: baseline neurologic
assessment in the Diabetes Control and
Complications Trial (DCCT) (Abstract). Diabetes 35 (Suppl 1):12A, 1986
42. Grenfell A, Migdalis I, Leslie DG: Short
stature and diabetic complications.
Transplant Proc 18(6): 1500, 1986
43. Weinberg CR, Pfeifer MA: Development of a predictive model for symptomatic neuropathy in diabetes. Diabetes 35:873-80, 1986
44. Rudy A, Epstein SH: Review of 100
cases of "diabetic neuropathy" followed

1962

from 1-10 years. J Clin Endocrinol Metab

5:92-109, 1945
45. Bhatt HR, Linnell JC, Matthews DM:
Can faulty vitamin B-12 (cobalamin)
metabolism produce diabetic neuropathy? (Letter). Lancet 2:572, 1983
46. Chuttani PN, Chawla LS: Diabetic neuropathy in India. Indian] Med Res 62:
99-109, 1974
47. Fraser DM, Campbell IW, Ewing DJ,
Murray A, Neilson JM, Clarke BF: Peripheral and autonomic nerve function
in newly diagnosed diabetes mellitus.
Diabetes 26:546-50, 1977
48. WardJD, Barnes CG, Fisher DJ, Jessop
JD, Baker RW: Improvement in nerve
conduction following treatment in
newly diagnosed diabetics. Lancet
1:428-30, 1971
49. Christensen NJ: Diabetic macroangiopathy blood flow and radiological studies. In Vascular and Neurological Changes
in Early Diabetes. Camerini-Davalos RA,
Cole HS, Eds. New York, Academic,
1973, p. 129-34
50. Ziegler D, Cicmir I, Wiefels K, Mayer P:
Peripheral and autonomic nerve dysfunction in newly diagnosed insulindependent diabetics (IDDM) (Abstract).
Diabetes 35 (Suppl l):102A, 1986
51. Gregersen G: Diabetic neuropathy: influence of age, sex, metabolic control,
and duration of diabetes on motor conduction velocity. Neurology 17:972-80,
1967
52. Lamontagne A, Buchthal F: Electrophysiological studies in diabetic neuropathy. J Neurol Neurosurg Psychiatry
33:442-52, 1970
53. Mulder DW, Lambert EH, Bastron JA,
Sprague RG: The neuropathies associated with diabetes mellitus: a clinical
and electromyographic study of 103
unselected diabetic patients. Neurology
ll(4):275-84, 1961
54. Skillman TG, Johnson EW, Hamwi GJ,
Driskill HJ: Motor nerve conduction velocity in diabetes mellitus. Diabetes
10(l):46-51, 1961
55. Greene DA, Brown MJ, Braunstein SN,
Schwartz SS, Asbury AK, Winegrad AI:
Comparison of clinical course and sequential electrophysiological tests in diabetics with symptomatic polyneuropa-

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.
70.

thy and its implications for clinical

trials. Diabetes 30:139-47, 1981
Archer AG, Watkins PJ, Thomas PK,
Sharma AK, Payan J: The natural history of acute painful neuropathy in diabetes mellitus. J Neurol Neurosurg Psychiatry 46:491-99, 1983
Bischoff A: The natural course of diabetic neuropathy: a follow-up. Horm
Metab Res 9 (Suppl l):98-100, 1980
Mayne N: The short-term prognosis in
diabetic neuropathy. Diabetes 17:27073, 1968
Edmonds ME, Nicolaides K, Watkins
PJ: The importance of autonomic neuropathy in the etiology of diabetic neuropathic foot ulceration (Abstract). Diabetologia 21:506-507, 1981
Deanfield JE, Daggett PR, Harrison MJ:
The role of autonomic neuropathy in
diabetic foot ulceration. J Neurol Sci 47:
203-10, 1980
Barkowshi M: An experimental study
on the role of arteriovenous anastomoses in the pathogenesis of the trophic
ulcer. Arch Immunol Ther Exp (Warsz)
21:363-75, 1973
Edmonds ME: The diabetic foot: pathophysiology and treatment. Clin Endocrinol Metab 15:889-916, 1986
Stevens MJ, Roberts VC, Watkins PJ:
Selective neuropathy and preserved
vascular responses in the diabetic Charcot foot. Diabetologia 1992. In press
Edmonds ME, Roberts, Watkins PJ:
Blood flow in the diabetic neuropathic
foot. Diabetologia 22:9-15, 1982
Ewing DJ, Clarke BF: Diagnosis and
management of diabetic autonomic
neuropathy. Br Med J 285:916-18,
1982
Bellavere F, Bosello G, Cardone C, Girardello L, Ferri M, Fedele D: Evidence
of early impairment of parasympathetic
reflexes in insulin dependent diabetics
without autonomic symptoms. Diabete
Metab 11:152-56, 1985
Watkins PJ, Edmonds ME: Sympathetic
nerve failure in diabetes. Diabetologia
25:73-77, 1983
Hilsted J: Testing for autonomic neuropathy. Ann Clin Res 16:128-35, 1984
Ewing DJ, Martyn CN, Young RJ,
Clarke BF: The value of cardiovascular

DIABETES CARE, VOLUME 15,

NUMBER 12,

DECEMBER

1992

Vinik and Associates

autonomic function tests: 10 years experience in diabetes. Diabetes Care 8:49198, 1985
71. MacKay JD, Page MM, Cambridge J,
Watkins PJ: Diabetic autonomic neuropathy. The diagnostic value of heart
rate monitoring Diabetologia 18:47178, 1980
72. Ewing DJ, Campbell IW, Clarke BF:
Mortality in diabetic autonomic neuropathy. Lancet 1:601-603, 1976
73. Thomas PK, Ward JD, Watkins PJ: Diabetic neuropathy. In Complications of
Diabetes. Keen H, Jarrett J, Eds. London, Edward Arnold, 1982, p. 109-36
74. Sundkvist G: Autonomic nervous function in asymptomatic diabetic patients
with signs of peripheral neuropathy.
Diabetes Care 4:529-34, 1981
74a.Hasslacher C, Bassler G: Prognosis of
cardiac autonomic neuropathy in diabetics. MMW Munch Med Wochenschr
125:375-77, 1983
75. O'Brien 1A, Lewin 1G, O'Hare JP,
Arendt J, Corrall RJ: Abnormal circadian rhythm of melatonin in diabetic
autonomic neuropathy. Clin Endocrinol
(Oxf) 24:359-64, 1986
76. Chopra JS, Fannin T: Pathology of diabetic neuropathy. J Pathol 104:175-84,
1971
77. Kimura J, Yamada T, Stevland NP: Distal slowing of motor nerve conduction
velocity in diabetic polyneuropathy. J
Neurol Sci 42:291-302, 1979
78. Thomas PK, Lascelles RG: The pathology of diabetic neuropathy. QJ Med 35
(140):489-509, 1966
79. Said G, Slama G, Selva J: Progressive
centripetal degeneration of axons in
small fibre diabetic polyneuropathy.
Brain 106:791-807, 1983
80. Sima A A, Nathaniel V, Bril V, McEwen
TA, Greene DA: Histopathological heterogeneity of neuropathy in insulindependent and non-insulin-dependent
diabetes, and demonstration of axoglial
dysjunction in human diabetic neuropathy. J Clin Invest 81:349-64, 1988
81. Sima A A, Brismar T: Reversible diabetic
nerve dysfunction:structural correlates
to electrophysiological abnormalities.
Ann Neurol 18:21-29, 1985
82. Behse F, Buchthal F, Carlsen F: Nerve

DIABETES CARE, VOLUME 15,

NUMBER 12,

DECEMBER

83.

84.

85.

86.

87.

88.

89.

90.

91.

92.

93.

94.

95.

biopsy and conduction studies in diabetic neuropathy. J Neurol Neurosurg

Psychiatry 40:1072-82, 1977
SladkyJT, Tschoepe RL, GreenbergJH,
Brown MJ: Peripheral neuropathy after
chronic endoneurial ischemia. Ann
Neurol 29:272-78, 1991
Xu Y, Sladky JT, Brown MJ: Dosedependent expression of neuronopathy
after experimental pyridoxine intoxication. Neurology 39:1077-83, 1989
Fagerberg SE: Diabetic neuropathy, a
clinical and histological study on the
significance of vascular affections. Acta
Med Scand 345:1-97, 1959
Powell HC, Rosoff J, Myers RR: Microangiopathy in human diabetic neuropathy. Acta Neuropathol (Berl) 68:
295-305, 1985
Yasuda H, Dyck PJ: Abnormalities of
endoneurial microvessels and sural
nerve pathology in diabetic neuropathy.
Neurology 37:20-28, 1987
Johnson PC, Doll SC, Cromey DW:
Pathogenesis of diabetic neuropathy.
Ann Neurol 19:450-57, 1986
Sugimura K, Dyck PJ: Multifocal fiber
loss in proximal sciatic nerve in symmetric distal diabetic neuropathy. J
Neurol Sci 53:501-509, 1982
Sladky JT, Greenberg JH, Brown MJ:
Enhanced 2-deoxyglucose incorporation in peripheral nerve during ischemia. Brain Res 414:323-29, 1987
Waxman SG: Pathophysiology of nerve
conduction: relation to diabetic neuropathy. Ann Intern Med 92:297-301,
1980
Raff MC, Asbury AK: Ischemic mononeuropathy and mononeuropathy multiplex in diabetes mellitus. N EngI J Med
279:17-21, 1968
Dyck PJ: Hypoxic neuropathy: does hypoxia play a role in diabetic neuropathy? The 1988 Robert Wallenberg lecture. Neurology 39:111-18, 1989
Timperley WR, Ward JD, Preston FE,
Duckworth T, O'Malley BC: A reassessment of vascular factors in relation to
intravascular coagulation. Diabetologia
12:237-43, 1976
Mitchell BD, Vinik AI: Macrovascular
disease, microvascular disease, and
polyneuropathy in diabetes. 1992. Sub-

1992

mitted
96. Siperstein MD, Unger RH, Madison LL:
Studies of muscle capillary basement
membranes in normal subjects, diabetic, and prediabetic patients. J Clin
Invest 47:1973-99, 1968
97. Nukada H, Dyck PJ: Acute ischemia
causes axonal stasis, swelling, attenuation, and secondary demyelination. Ann
Neurol 22:311-18, 1987
98. Tuck RR, Schmelzer JD, Low PA: Endoneurial blood flow and oxygen tension in the sciatic nerves of rats with
experimental diabetic neuropathy.
Brain 107:935-50, 1984
99. Low PA, Tuck RR, Dyck PJ, Schmelzer
JD, Yao JK Prevention of some electrophysiologic and biochemical abnormalities with oxygen supplementation in
experimental diabetic neuropathy. Proc
Natl Acad SciUSA 81:6894-98, 1984
100. Niakan E, Harati Y, Rolak LA, Cornstock JP, Rokey R: Silent myocardial
infarction and diabetic cardiovascular
autonomic neuropathy. Arch Intern Med
146:2229-30, 1986
101. Dyck PJ, Hansen S, KamesJ, O'Brien P,
Yasuda H, Windebank A, Zimmerman:
Capillary number and percentage
closed in human diabetic sural nerve.
Proc Natl Acad Sci U S A 82:2513-17,
1985
102. Mitchell BD, Hawthorne VM, Vinik AI:
Cigarette smoking and neuropathy in
diabetic patients. Diabetes Care 13:
434-37, 1990
103. Pfeiffer EA: Electrical stimulation of
sensory nerves with skin electrodes for
research, diagnosis, communication
and behavioral conditioning: a survey.
Med Biol Eng 6:637-51, 1968
104. Waff LJ, Kemoff L, Vinik AI, Jackson
WP, Jacobs P: Sulfonylureas and platelet function. Am J Med 70:627-30,
1981
105. Bastyr EJ, Kadrofske MM, Dershimer
RC, Vinik AI: Decreased platelet phosphoinositide turnover and enhanced
platelet activation in IDDM. Diabetes
38:1097-102, 1989
106. Brownlee MA, Cerami A, Vlassara H:
Advanced glycosylation end products
in tissue and the biochemical basis of
diabetic complications. N EngI J Med

1963

Diabetic neuropathies

318:1315-21, 1988
107. Cagliero E, Maiello M, Boeri D, Roy S,
Lorenzi M: Increased expression of
basement membrane components in
human endothelial cells cultured in
high glucose. J Clin Invest 82:735-38,
1988
108. Greene DA, Lattimer SA, Sima A A: Sorbitol, phosphoinositides, and sodiumpotassium-ATPase in the pathogenesis
of diabetic complications. N EnglJ Med
316:599-606, 1987
109. Winegrad AI: Banting lecture 1986:
Does a common mechanism induce the
diverse complications of diabetes? Diabetes 36:396-406, 1987
110. Gabbay KH: Role of sorbitol pathway in
neuropathy. Adv Metab Disord 2 (Suppl.
2):417-32, 1973
111. Dvornik D: Aldose Reductase InhibitionAn Approach to the Prevention of
Diabetic Complications. New York, McGraw-Hill, 1987
112. Greene DA, Lattimer SA, Sima A A: Are
disturbances of sorbitol, phosphoinositide, and Na+-K+-ATPase regulation involved in pathogenesis of diabetic neuropathy? Diabetes 37:688-93, 1988
113. Dyck PJ, Zimmerman BR, Vilen TH,
Minnerath SR, Karnes JL, Yao JK, Poduslo JF: Nerve glucose, fructose, sorbitol, myo-inositol, and fiber degeneration and regeneration in diabetic
neuropathy. N EnglJ Med 319:542-48,
1988
114. MayhewJA, Gillon KR, Hawthorn JN:
Free and lipid inositol, sorbitol and
sugars in sciatic nerve obtained postmortem from diabetic patients and control subjects. Diabetologia 24:13-15,
1983
115. Sima A A, Bril V, Nathaniel V, McEwen
TA, Brown MB, Lattimer SA, Greene
DA: Regeneration and repair of myelinated fibers in sural-nerve biopsy specimens from patients with diabetic neuropathy treated with sorbinil. N Engl J
Med 319:548-55, 1988
116. Ward JD: The polyol pathway in the
neuropathy of early diabetes. In Vascular and Neurological Changes in Early
Diabetes. Camerini-Davalos RA, Cole
HS, Eds. New York, Academic, 1973, p.
425

1964

117. Judzewitsch RG, Jaspan JB, Polonsky

KS, Weinberg CR, Halter JB, Halar E,
Pfeifer MA, Vukadinovic C, Bernstein
L, Schneider M, Liang KY, Gabbay KH,
Rubenstein AH, Porte D Jr: Aldose reductase inhibition improves nerve conduction velocity in diabetic patients. N
EnglJ Med 308:119-25, 1983
118. Greene DA, Lattimer-Greene S, Sima
AA: Pathogenesis of diabetic neuropathy: role of altered phosphoinositide
metabolism. Crit Rev Neurobiol 5:143219, 1989
119. Brismar T, Sima A A: Changes in nodal
function in nerve fibres of the spontaneously diabetic BB-Wistar rat: potential clamp analysis. Acta Physiol Scand
113:499-506, 1981
120. Brismar T, Sima A A, Greene DA: Reversible and irreversible nodal dysfunction in diabetic neuropathy. Ann Neurol
21:504-507, 1987
121. Berridge MJ: The Albert Lasker Medical
Awards. Inositol trisphosphate, calcium, lithium, and cell signaling. JAMA
262:1834-41, 1989
122. Kowluru R, Bitensky MW, Kowluru A,
Dembo M, Keaton PA, Buican T: Reversible sodium pump defect and swelling in the diabetic rat erythrocyte: effects on filterabiliry and implications for
microangiopathy. Proc Natl Acad Sci U S
A 86:3327-31, 1989
123. WardJD, Baker RW, Davis BH: Effect of
blood sugar control on the accumulation of sorbitol and fructose in nervous
tissues. Diabetes 21:1173-78, 1972
124. Dyck PJ, Sherman WR, Hallcher LM,
Service FJ, O'Brien PC, Grina LA,
Palumbo PJ, Swanson CJ: Human diabetic endoneurial sorbitol, fructose, and
myo-inositol related to sural nerve morphometry. Ann Neurol 8:590-96, 1980
125. Greene DA, Bril V, Lattimer SA, Sima
AA: Correction of myo-inositol depletion in diabetic human sural nerve by
treatment with an aldose reductase inhibitor (Abstract). Diabetes 36 (Suppl.
1):86A, 1987
126. Dyck PJ, Karnes J, Lais A, Lofgren EP,
Stevens JC: Pathologic alterations of the
peripheral nervous system of humans.
In Peripheral Neuropathy. Dyck PJ, Thomas PK, Lambert EH, Bunge R, Eds.

Philadelphia, Saunders, 1984, p. 760870

127. Dyck PJ, Kames J, O'Brien P, Nukada
H, Lais A, Low P: Spatial pattern of
nerve fiber abnormality indicative of
pathologic mechanism. Am J Pathol
117:225-38, 1984
128. Jaspan JB, Wollman RL, Bernstein L,
Rubenstein AH: Hypoglycemic peripheral neuropathy in association with insulinoma: implication of glucopenia
rather than hyperinsulinism. Case report and literature review. Medicine
(Baltimore) 61:33-44, 1982
129. Frier BM, Hilsted J: Does hypoglycaemia aggravate the complications of diabetes? Lancet 2:1175-77, 1985
130. McCulloch DK, Campbell IW, Prescott
RJ, Clarke BF: Effect of alcohol intake
on symptomatic peripheral neuropathy
in diabetic men. Diabetes Care 3:24547, 1980
131. Mitchell BD, Vinik AI: Alcohol consumption: a risk factor for diabetic neuropathy (Abstract)? Diabetes 36 (Suppl.
1):71A, 1987
132. Rabinowe SL, Brown FM, Watts M,
Kadrofske MM, Vinik AI: Anti-sympathetic ganglia antibodies and postural
blood pressure in IDDM subjects of
varying duration and patients at high
risk of developing IDDM. Diabetes Care
12:1-6, 1989
133. Sinha AA, Lopez MT, McDevitt HO:
Autoimmune diseases: the failure of self
tolerance. Science 248:1380-88, 1990
134. Bottazzo GF, Pujol-Borrell R, Hanafusa
T, Feldmann M: Role of aberrant
HLA-DR expression and antigen presentation in induction of endocrine autoimmunity. Lancet 2:1115-19, 1983
135. MacLaren N, Schatz D, Drash A, Grave
G: Initial pathogenic events in IDDM.
Diabetes 38:534-38, 1989
136. Todd JA, Acha-Orbea H, Bell JI, Chao
N, Fronek Z, Jacob CO, McDermott M,
Sinha AA, Timmerman L, Steinman L:
A molecular basis for MHC class II
associated autoimmunity. Science 240:
1003-1009, 1988
137. ToddJA: Genetic control of autoimmunity in type I diabetes. Immunol Today
11:122-29, 1990
138. Baekkskov S, Neilsen JH, Mamer B,

DIABETES CARE, VOLUME 15,

NUMBER 12,

DECEMBER

1992

Vinik and Associates

Bilde T, LudvigssonJ, Lemmark A: Autoantibodies in newly diagnosed diabetic children immunoprecipitate human pancreatic islet cell proteins.
Nature 298:167-69, 1982
139. Baekkeskov S, Landin M, Kristensen JK,
Srikanta S, Bruining GJ, MandrupPoulsen T, De Beaufort C, Soeldner JS,
Eisenbarth G, Lindgren F: Antibodies to
a 64,000 Mr human islet cell antigen
precede the clinical onset of insulindependent diabetes. J Clin Invest 79:
926-34, 1987
140. Atkinson MA, MacLaren NK, Scharp
DW, Lacy PE, Riley WJ: 64,000 Mr
autoantibodies as predictors of insulindependent diabetes. Lancet 335:135760, 1990
141. Solimena M, Folli F, Denis-Donini S,
Comi GC, Pozza G, De Camilli P, Vicari
AM: Autoantibodies to glutamic acid
decarboxylase in a patient with stiffman syndrome, epilepsy, and type 1 diabetes mellitus. N Engl J Med 318:
1012-20, 1988
142. Baekkskov S, Aanstoot HJ, Christgau S,
Reetz A, Solimena M, Cascalho M, Folli
F, Richter-Olesen H, De Camilli P:
Identification of the 64K autoantigen in
insulin-dependent diabetes as the
GABA-synthesizing enzyme glutamic
acid decarboxylase Nature 347:151-56,
1990
143. Erdo SL, Wolff JR: -y-Aminobutyric acid
outside the mammalian brain. J Neurochem 54:363-72, 1990
144. Erlander MG, Tillakaratne NJK, Feldblum S, Patel N, Tobin AJ: Two genes
encode distinct glutamate decarboxylases with different responses to pyridocal phosphate. Neuron 7:91-100,
1991
145. Kaufman DL, McGinnis JF, Krieger NR,
Tobin AJ: Brain glutamate decarboxylase cloned in lambda gt-11: fusion
protein produces gamma-aminobutyric
acid. Science 232:1138-40, 1986
146. Kobayashi Y, Kaufman DL, Tobin AJ:
Glutamic acid decarboxylase cDNA:
nucleotide sequence encoding an enzymatically active fusion protein. J Neurosci 7:2768-72, 1987
147. Kaufman DL, Houser CR, Tobin AJ:
Two forms of the gamma-aminobutyric

DIABETES CARE, VOLUME 15,

NUMBER 12,

acid synthetic enzyme glutamate decarboxylase have distinct intraneuronal

distributions and cofactor interactions.
J Neurochem 56:720-23, 1991
148. Hirsch BR, Shamoon H: Defective epinephrine and growth hormone responses in type I diabetes are stimulus
specific. Diabetes 36:20-26, 1987
149. Brown FM, Vinik Al, Ganda OP, Adri
MN, Rabinowe SL: Different effects of
duration on prevalence of anti- adrenal
medullary and pancreatic islet cell antibodies in type I diabetes mellitus. Horm
Metab Res 21:434-37, 1989
150. Brown FM, Brink SJ, Freeman R, Rabinowe SL: Anti-sympathetic nervous
system autoantibodies. Diminished catecholamines with orthostasis. Diabetes
38:938-41, 1989
151. Dyck PJ, Low PA, Windebank AJ, Jaradeh SS, Gosselin S, Bourque P, Smith
BE, Kratz KM, Kames JL, Evans BA:
Plasma exchange in polyneuropathy associated with monoclonal gammopathy
of undetermined significance. N Engl J
Med 325:1482-86, 1991
152. Levi-Montalcini R, Booker B: Destruction of the sympathetic ganglia in mammals by an antiserum to the nervegrowth promoting factor. Proc Natl
Acad SciUSA 42:384-90, 1960
153. Levi-Montalcini R, Calissano P: The
nerve-growth factor. Sci Am 240:6877, 1979
154. Levi-Montalcini R: The nerve growth
factor 35 years later. Science 237:115462, 1987
155 .Matheson SF, Gold B, Mobley WC: Somatofugal axonal atrophy in intact adult
sensory neurons following injection of
nerve growth factor (NGF) antiserum.
Soc Neurosci Abstr 15:707, 1989
156. Rich KM, Luszczynski JR, Osbome PA,
Johnson EM Jr: Nerve growth factor
protects adult sensory neurons from
cell death and atrophy caused by nerve
injury. J Neurocytol 16:261-68, 1987
157. Faradji V, Sotelo J: Low serum levels of
nerve growth factor in diabetic neuropathy. Acta Neurol Scand 81:402-406,
1990
158. Hellweg R, Hartung HD: Endogenous
levels of nerve growth factor (NGF) are
altered in experimental diabetes melli-

DECEMBER

1992

tus: a possible role for NGF in the

pathogenesis of diabetic neuropathy. J
Neurosci Res 26:258-67, 1990
159. Hellweg R, Hartung HD, Hock C, Whohrle, Raivich G: Nerve growth factor
(NGF) changes in rat diabetic neuropathy. Soc Neurosci Abstr 17:1497, 1991
160. Schmidt RE, Plurad SB, SaffitzJE, Grabau G, Yip HK: Retrograde axonal
transport of 1251-nerve growth factor in
rat ileal mesenteric nerves: effect of
streptozocin diabetes. Diabetes 34:
1230-40, 1985
161. Himes BT, Tessler A: Death of some
dorsal root ganglion neurons and plasticity of others following sciatic nerve
section in adult and neonatal rats. J
Comp Neurol 284:215-30, 1989
162. Melville S, Sherburn TE, Coggeshall RE:
Preservation of sensory cells by placing
stumps of transected nerve in an impermeable tube. Exp Neurol 105:311-15,
1989
163. Verge VM, Tetzlaff W, Bisby MA, Richardson PM: Influence of nerve growth
factor on neurofilament gene expression in mature primary sensory neurons. J Neurosci 10:2018-25, 1990
164. Hoffman PN, GriffinJW, Price DL: Control of axonal caliber by neurofilament
transport. J Cell Biol 99:705-14, 1984
165. Hoffman PN, Griffin JW, Koo EH,
Muma NA, Price DL: Neurofilaments,
axonal caliber and perikaryal size. In
Aging and the Brain. Terry RD, Ed. New

166.

167.

168.
169.

York, Raven, 1988, p. 205-17

Sidenius P, Jakobsen J: Reduced
perikaryal volume of lower motor and
primary sensory neurons in early experimental diabetes. Diabetes 29:182-86,
1980
Moore SA, Peterson RG, Felten DL,
O'Connor BL: A quantitative comparison of motor and sensory conduction
velocities in short- and long-term streptozotocin- and alloxan-diabetic rats. J
Neurol Sci 48:133-52, 1980
Sidenius P: The axonopathy of diabetic
neuropathy. Diabetes 31:356-63, 1982
Valmier J, Tafti M, Baldy-Moulinier M:
Skeletal muscle extracts promote the
survival of neurofilament- positive
mammalian sensory neurons. Neurosci
Lett 114:39-44, 1990

1965

Diabetic neuropathies

170. Larsen JR, Sidenius: Slow axonal transport of structural polypeptides in rat,
early changes in streptozocin diabetes,
and effect of insulin treatment. J Neurochem 52:390-401, 1989
171. Schwartz JP, Pearson J, Johnson EM:
Effect of exposure to anti-NGF on sensory neurons of adult rats and guinea
pigs. Brain Res 1982
172. Lindsay RM, Harmar AJ: Nerve growth
factor regulates expression of neuropeptide genes in adult sensory neurons. Nature 337:362-64, 1989
173. Pernow B: Substance P. Pharmacol Rev
35:85-141, 1983
174. Calcutt NA, Tomlinson DR, Willars GB,
Keen P: Axonal transport of substance
P-like immunoreactivity in gangliosidetreated diabetic rats. J Neurol Sci 96:
283-91, 1990
175. Robinson JP, Willars GB, Tomlinson
DR, Keen P: Axonal transport and tissue
contents of substance P in rats with
long- term streptozotocin-diabetes. Effects of the aldose reductase inhibitor
'statil'. Brain Res 426:339-48, 1987
176. Tomlinson DR, Robinson JP, Willars
GB, Keen P: Deficient axonal transport
of substance P in streptozocin-induced
diabetic rats. Effects of sorbinil and insulin. Diabetes 37:488-93, 1988.
177. Recio-Pinto E, Lang FF, Ishii DN: Insulin and insulin-like growth factor II permit nerve growth factor binding and the
neurite formation response in cultured
human neuroblastoma cells. Proc Nail
Acad SciUSA 81:2562-66, 1984
178. Recio-Pinto E, Ishii SN: Effects of insulin, insulin-like growth factor-II and
nerve growth factor on neurite outgrowth in cultured human neuroblastoma cells. Brain Res 302:323-34,
1984.
179. Fellows R, Al-Hadar A, Kadle R: IGF-I
supports survival and differentiation of
fetal rat brain neurons in serum-free
hormone-free defined medium. Soc
Neurosci Abstr 13:1615, 1987.
180. SjobergJ, Kanje M: Insulin-like growth
factor (IGF-1) as a stimulator of regeneration in the freeze-injured rat sciatic
nerve. Brain Res 485:102-108, 1989.
181. Kanje M, Skottner A, SjobergJ, Lundborg G: Insulin-like growth factor I

1966

182.

183.

184.

185.

186.

187.

188.

189.

190.

191.

(IGF-I) stimulates regeneration of the

rat sciatic nerve. Brain Res 486:396-98,
1989.
Ekstrom AR, Kanje M, Skottner A:
Nerve regeneration and serum levels of
insulin-like growth factor-I in rats with
streptozotocin-induced insulin deficiency. Brain Res 496:141-47, 1989.
Longo FM, Powell HC, Le Beau J, Gerrero MR, Heckman H, Myers RR: Delayed nerve regeneration in streptozotocin diabetic rats. Muscle. Nerve.
9:385-393, 1986.
Longo FM, Hayman EG, Davis GE, Ruoslahti E, Engvall E, Manthorpe M,
Varon S: Neurite-promoting factors
and extracellular matrix components
accumulating in vivo within nerve regeneration chambers. Brain Res 309:
105-17, 1984.
Le Beau JM, Lacorbiere M, Powell HC,
Ellisman MH, Schubert D: Extracellular
fluid conditioned during peripheral
nerve regeneration stimulates Schwann
cell adhesion, migration and proliferation. Brain Res 459:93-104, 1988
Kaplan DR, Hempstead BL, MartinZanca D, Chao MV, Parada LF: The trk
proto-oncogene product: a signal
transducing receptor for nerve growth
factor. Science 252:554-58, 1991
Berkemeier LR, Winslow JW, Kaplan
DR, Nikolics K, Goeddel DV, Rosenthal
A: Neurotrophin-5: a novel neurotrophic factor that activates trk and trkB.
Neuron 7:857-66, 1991
Arakawa Y, Sendtner M, Thoenen H:
Survival effect of ciliary neurotrophic
factor (CNTF) on chick embryonic motoneurons in culture: comparison with
other neurotrophic factors and cytokines. J Neurosci 10:3507-15, 1990
Ishii DN: Relationship of insulin-like
growth factor II gene expression in
muscle to synaptogenesis. Proc Natl
Acad SciU SA 86:2898-2902, 1989
Sendtner M, Kreutzberg GW, Thoenen
H: Ciliary neurotrophic factor prevents
the degeneration of motor neurons after
axotomy. Nature 345: 440-41, 1990
Barbin G, Manthorpe M, Varon S: Purification of the chick eye ciliary neuronotrophic factor. J Neurochem 43:
1468-78, 1984

192. Oppenheim RW, Prevette D, Yin QW,

Collins F, MacDonaldJ: Control of embryonic motoneuron survival in vivo by
ciliary neurotrophic factor. Science 251:
1616-18, 1991
193. Hefti F, Schneider LS: Rationale for the
planned clinical trials with nerve
growth factor in Alzheimer's disease.
PsychiatrDev 7:297-315, 1989
194. Koliatsos VE, Clatterbuck RE, Nauta
HJ, Knusel B, Burton LE, Hefti FF,
Mobley WC, Price DL: Human nerve
growth factor prevents degeneration of
basal forebrain cholinergic neurons in
primates. Ann Neurol 30:831-40, 1991
195. Tuszynski MH, Sang H, Yoshida K,
Gage FH: Recombinant human nerve
growth factor infusions prevent cholinergic neuronal degeneration in the
adult primate brain. Ann Neurol 30:
625-36, 1991
196. Anderson KJ, Dam D, Lee S, Cotman
CW: Basic fibroblast growth factor prevents death of lesioned cholinergic neurons in vivo. Nature 332:360-61, 1988
197. Schwaber JS, Due BR, Rogers WT,
Junard EO, Hefti F: Use of a digital
brain atlas to compare the distribution
of NGF- and bFGF-protected cholinergic neurons. J Comp Neurol 309:2739, 1991
198. Alderson RF, Alterman AL, Barde YA,
Lindsay RM: Brain-derived neurotrophic factor increases survival and differentiated functions of rat septal cholinergic neurons in culture. Neuron 5:297306, 1990
199. Ferrari G, Toffano G, Skaper SD: Epidermal growth factor exerts neuronotrophic effects on dopaminergic
and GABAergic CNS neurons: comparison with basic fibroblast growth factor.
J Neurosci Res 30:493-97, 1991
200. Knusel B, Winslow JW, Rosenthal A,
Burton LE, Seid DP, Nikolics K, Hefti F:
Promotion of central cholinergic and
dopaminergic neuron differentiation by
brain-derived neurotrophic factor but
not neurotrophin 3. Proc Natl Acad Sci
USA 88:961-65, 1991
201. Hyman C, Hofer M, Barde YA, Juhasz
M, Yancopoulos GD, Squinto SP, Lindsay RM: BDNF is a neurotrophic factor
for dopaminergic neurons of the sub-

DIABETES CARE, VOLUME 15,

NUMBER 12,

DECEMBER

1992

Vinik and Associates

202.

203.

204.

205.

206.

207.

208.

209.

210.

211.

212.

stantia nigra. Nature 350:230-32,

1991
Apfel SC, Lipton RB, Arezzo JC, Kessler
JA: Nerve growth factor prevents toxic
neuropathy in mice. Ann Neurol 29:8790, 1991
Mollman JE: Cisplatin neurotoxicity
[editorial; comment]. N EnglJ Med 322:
126-27, 1990
Apfel SC, Arezzo JC, Lipson L, Kessler
JA: Nerve growth factor prevents experimental cisplatin neuropathy. Ann Neurol 31:76-80, 1992
Rosenberg MB, Friedmann T, Robertson RC, Tuszynski M, Wolff JA, Breakefield XO, Gage FH: Grafting genetically
modified cells to the damaged brain:
restorative effects of NGF expression.
Science 242:1575-78, 1988
Whittemore SR, Holets VR, Keane RW,
Levy DJ, McKay RD: Transplantation of
a temperature-sensitive, nerve growth
factor-secreting, neuroblastoma cell line
into adult rats with fimbria-fornix lesions rescues cholinergic septal neurons. J Neurosd Res 28:156-70, 1991
Berg MM, Sternberg DW, Parada LF,
Chao MV: K-252a inhibits nerve
growth factor-induced trk proto-oncogene tyrosine phosphorylation and kinase activity. J Biol Chem 267:13-16,
1992
Knusel B, Hefti F: K-252b is a selective
and nontoxic inhibitor of nerve growth
factor action on cultured brain neurons.
J Neurochem 57:955-62, 1991
Evans RW, Harati Y: What's new: review of clinical presentations, pathophysiology, and treatment of diabetic
neuropathies. Tex Med 79:50-54, 1983
Dyck PJ, Karnes J, O'Brien PC: Diagnosis.staging, and classification of diabetic
neuropathy and association with other
complications. In Diabetic Neuropathy.
Dyck PJ, Thomas PK, Asbury AK, Winegard AI, Porte D, Eds. Philadelphia,
PA, Saunders, 1987, p. 36-44
Dyck PJ, Bushek W, Spring EM, Karnes
JL, Llchty WJ, O'Brien PC, Service FJ:
Vibratory and cooling detection thresholds compared with other tests in diagnosing and staging diabetic neuropathy.
Diabetes Care 10:432-40, 1987
Guy RJ, Clark CA, Malcolm PN, Wat-

DIABETES CARE, VOLUME 15,

NUMBER 12,

213.

214.

215.

216.

217.

218.
219.

220.

221.

222.

223.

DECEMBER

kins PJ: Evaluation of thermal and vibration sensation in diabetic neuropathy. Diabetologia 28:131-37, 1985
Wilkins RW, Kolb LC: Vasomotor disturbance in peripheral neuritis. Am J
Med Sci 202:216-21, 1982
Stevens MJ, Edmonds ME, Douglas SL,
Watkins PJ: Influence of neuropathy on
the microvascular response to local
heating in the human diabetic foot. Clin
Sci 80:249-56, 1991
Llewelyn JG, Thomas PK, Fonseca V,
King RH, Dandona P: Acute painful diabetic neuropathy precipitated by strict
glycaemic control. Acta Neuropathol
(Berl) 72:157-63, 1986
Boulton AJ, DruryJ, Clarke B, WardJD:
Continuous subcutaneous insulin infusion in the management of painful diabetic neuropathy. Diabetes Care 5:38690, 1982
Ellenberg M: Diabetic neuropathy precipitating after institution of diabetic
control. Am] Med Sci 236 (4):466-71,
1958
Ellenberg M: Diabetic neuropathic cachexia. Diabetes 23:418-23, 1974
Morley GK, Mooradian AD, Levine AS,
Morley JE: Mechanism of pain in diabetic peripheral neuropathy. Effect of
glucose on pain perception in humans.
Am] Med 77:79-82, 1984
Burchiel KJ, Russell LC, Lee RP, SIma
AA: Spontaneous activity of primary afferent neurons in diabetic BB/Wistar
rats: a possible mechanism of chronic
diabetic neuropathic pain. Diabetes 34:
1210-13, 1985
Young RJ, Maclntyre CC, Martyn CN,
Prescott RJ, Ewing DJ, Smith AF, Viberti G, Clarke BF: Progression of subclinical polyneuropathy in young patients with type I (insulin-dependent)
diabetes: associations with glycaemic
control and microangiopathy (micro vascular complications). Diabetologia
29:156-61, 1986.
Edmonds ME, Blundell MP, Morris ME,
Thomas EM, Cotton LT, Watkins PJ:
Improved survival of the diabetic foot:
the role of a specialized foot clinic. Q J
Med 60:763-71, 1986
Ahmed ME, Le Quesne PM: Quantitative sweat test in diabetics with neuro-

1992

224.

225.

226.

227.

228.
229.

230.

231.

232.

233.

234.

235.

236.

237.

pathic foot lesions. J Neurol Neurosurg

Psychiatry 49:1059-62, 1986
Archer AG, Roberts VC, Watkins PJ:
Blood flow patterns in painful diabetic
neuropathy. Diabetologia. 27:563-67,
1984
Edmonds ME, Clarke MB, Newton S,
Barrett J, Watkins PJ: Increased uptake
of bone radiopharmaceutical in diabetic
neuropathy. QJ Med 57:843-55, 1985
Raff MC, Sangalang V, Asbury AK: Ischemic mononeuropathy multiplex associated with diabetes mellitus. Arch Neurol 18:487-99, 1968
Chokroverty S, Reyes MG, Rubino FA,
Tonaki H: The syndrome of diabetic
amyotrophy. Ann Neurol 2:181-94,
1977
Asbury AK Proximal diabetic neuropathy. Ann Neurol 2:179-80, 1977
Ellenberg M: Diabetic truncal mononeuropathya new clinical syndrome.
Diabetes Care 1:10-13, 1978
Longstreth GF, Newcomer AD: Abdominal pain caused by diabetic radiculopathy. Ann Intern Med 86:166-68,
1977
Boulton AJ, Angus E, Ayyar DR, Weiss
DR: Diabetic thoracic polyradiculopathy presenting as abdominal swelling.
Br Med J (Clin Res Ed) 289:798-99,
1984
Streib EW, Sun SF, Paustian FF, Gallagher TF, Shipp JC, Ecklund RE: Diabetic thoracic radiculopathy: electrodiagnostic study. Muscle Nerve 9:548-53,
1986
Harati Y, Niakan E: Diabetic thoracoabdominal neuropathy. A cause for chest
and abdominal pain (Editorial). Arch
Intern Med 146:1493-94, 1986
Edvinsson L, Ekman R, Jansen I, Ottosson A, Uddman R: Peptide-containing
nerve fibers in human cerebral arteries:
immunocytochemistry, radioimmunoassay, and in vitro pharmacology. Ann
Neurol 21:431-37, 1987
Zorrilla E, Kozak GP: Opthalmophegia
in diabetes mellitus. Ann Intern Med 67
(5):968-76, 1967
Fraser DM, Campbell IW, Ewing DJ,
Clarke BF: Mononeuropathy in diabetes
mellitus. Diabetes 28:96-101, 1979
Calverley JR, Mulder DW: Femoral

1967

Diabetic neuropathies

neuropathy. Neurology 10:963-67,

1960
238. Ewing DJ, Bellavere F, Espi F, McKibben BM, Buchanan KD, Riemersma
RA, Clarke BF: Correlation of cardiovascular and neuroendocrine tests of
autonomic function in diabetes. Metabolism 35:349-53, 1986
239. Feldman M, Schiller LR: Disorders of
gastrointestinal motility associated with
diabetes mellitus. Ann Intern Med 98:
378-84, 1983
240. Young RJ, Ewing DJ, Clarke BF: Nerve
function and metabolic control in teenage diabetics. Diabetes 32:142-47,
1983
241. Niakan E, Harati Y, Comstock JP: Diabetic autonomic neuropathy. Metabolism 35:224-34, 1986
242. McLeod JG, Tuck RR: Disorders of the
autonomic nervous system: Part 1.
Pathophysiology and clinical features.
Ann Neurol 21:419-30, 1987
243. McLeod JG, Tuck RR: Disorders of the
autonomic nervous system: Part 2. Investigation and treatment. Ann Neurol
21:519-29, 1987
244. Ewing DJ, Clarke BF: Diabetic autonomic neuropathy: present insights and
future prospects. Diabetes Care 9:64865, 1986
245. Kahn JK, Sisson JC, Vinik AI: QT interval prolongation and sudden cardiac
death in diabetic autonomic neuropathy. J Clin Endocrinol Metab 64:751-54,
1987
246. Sampson MJ, Wilson S, Karagiannis P,
Edmonds M, Watkins PJ: Progression of
diabetic autonomic neuropathy over a
decade in insulin-dependent diabetics.
QJMed 75:635-46, 1990
247. Zola BE, Vinik AI: Effect of diabetic
autonomic neuropathy on heart rate.
Current Science 3:33-41, 1992. In press
248. Hosking DJ, Bennett T, Hamptom JR:
Diabetic autonomic neuropathy. Diabetes 1043:1055, 22
249. Faerman I, Faccio E, Milei J, Nunez R,
Jadzinsky M, Fox D, Rapaport M: autonomic neuropathy and painless myocardial infarction in diabetic patients.
Histologic evidence of their relationship. Diabetes 26:1147-58, 1977
250. Campbell IW, Ewing DJ, Clarke BF:

1968

251.

252.

253.

254.

255.

256.

257.

258.

259.

260.

261.

Painful myocardial infarction in severe

diabetic autonomic neuropathy. Ada
Diabetol hat 15:201-204, 1978
Hreidarsson AB, Gundersen HJ: The
pupillary response to light in type I
(insulin-dependent) diabetes. Diabetologia 28:815-21, 1985
Grover-Johnson NM, Baumann FG, Imparato AM, Kim GE, Thomas PK: Abnormal innervation of lower limb
epineurial arterioles in human diabetes.
Diabetologia 20:31-38, 1981
Low PA, Walsh JC, Huang CY, McLeod
JG: The sympathetic nervous system in
diabetic neuropathy. A clinical and
pathological study. Brain 98:341-56,
1975
Hoeldtke RD, Cilmi KM: Norepinephrine secretion and production in diabetic autonomic neuropathy. J Clin Endocrinol Metab 59:246-52, 1984
Cryer PE: Physiology and pathophysiology of the human sympathoadrenal
neuroendocrine system. N Engl J Med
303:436-44, 1980
Abrahm DR, Hollingsworth PJ, Smith
CB, Jim L, Zucker LB, Sobotka PA,
Vinik AI: Decreased a-2-adrenergic receptors on platelet membranes from diabetic patients with autonomic neuropathy and orthostatic hypotension. J Clin
Endocrinol Metab 63:906-12, 1986
Vinik AI, Abrahams D, Jim L, Smith CB:
Platelet a 2 receptors and in vivo blood
pressure (BP) regulation (Abstract). Diabetes 34 (Suppl. 1):12A, 1985
Zola BE, Kahn JK, Juni JE, Vinik AI:
Abnormal cardiac function in diabetic
patients with autonomic neuropathy in
the absence of ischemic heart disease. J
Clin Endocrinol Metab 63:208-14, 1986
Kahn JK, Zola BE, Juni JE, Vinik AI:
Radionuclide assessment of left ventricular diastolic filling in diabetes mellitus
with and without cardiac autonomic
neuropathy. J Am Coll Cardiol 7:1303309, 1986
Kahn JK, Zola BE, Juni JE, Vinik AI:
Decreased exercise heart rate and blood
pressure response in diabetic subjects
with cardiac autonomic neuropathy.
Diabetes Care 9:389-94, 1986
Page MM, Watkins PJ: Provocation of
postural hypotension by insulin in dia-

262.

263.

264.

265.

266.

267.

268.

269.

270.

271.

272.

273.

274.

betic autonomic neuropathy. Diabetes

25:90-95, 1976
Takata S, Yamamoto M, Yagi S, NOto Y,
Ikeda T, Hattori N: Peripheral circulatory effects of insulin in diabetes. Angiology 36:110-15, 1985
Boulton AJ, Scarpello JH, Ward JD: Venous oxygenation in the diabetic neuropathic foot: evidence of arteriovenous
shunting? Diabetologia 22:6-8, 1982
Guilleminault C, Mondini S, Hayes B:
Diabetic autonomic dysfunction, blood
pressure, and sleep. Ann Neurol 18:
670-75, 1985
Edmonds ME, Archer AG, Watkins PJ:
Ephedrine: a new treatment for diabetic
neuropathic oedema. Lancet 1:548-51,
1983
Ewing DJ, Borsey DQ, Travis P, Bellavere F, NeilsonJM, Clarke BF: Abnormalities of ambulatory 24-hour heart
rate in diabetes mellitus. Diabetes 32:
101-105, 1983
Ewing DJ, Campbell IW, Clarke BF:
Heart rate changes in diabetes mellitus.
Lancet 1:183-86, 1981
Bradley RF, Shonefeld A: Diminished
pain in diabetic pain in diabetic patients
with acute myocardial infarction. Geriatrics 17:322-26, 1962
Nesto RW, Phillips RT: Asymptomatic
myocardial ischemia in diabetic patients. Am] Med 80:40-47, 1986
Soler NG, Bennett MA, Pentecost BL,
Fitzgerald MG, Malins JM: Myocardial
infarction in diabetics. QJ Med 44:12532, 1975
Sobotka PA, Iiss HP, Vinik AI: Impaired hypoxic ventilatory drive in diabetic patients with autonomic neuropathy. J Clin Endocrinol Metab 62:65863, 1986
Kassander P: Asymptomatic gastric retention in diabetics (gastroparesis diabeticorum). Ann Intern Med 48:797812, 1958
Campbell IW, Heading RC, Tothill P,
Buist TA, Ewing DJ, Clarke BF: Gastric
emptying in diabetic autonomic neuropathy. Gut 18:462-67, 1977
Loo FD, Palmer DW, Soergel KH, Kalbfleisch JH, Wood CM: Gastric emptying
in patients with diabetes mellitus. Gastroenterology 86:485-94, 1984

DIABETES CARE, VOLUME 15,

NUMBER 12,

DECEMBER

1992

Vinik and Associates

275. Wright RA, Clemente R, Wathen R: Diabetic gastroparesis: an abnormality of

gastric emptying of solids. Am] Med Sci
289:240-42, 1985
276. Feldman M, Corbett DB, Ramsey EJ,
Walsh JH, Richardson CT: Abnormal
gastric function in long standing, insulin-dependent diabetic patients. Gastroenterology 77:12-17, 1979
277. Hosking DJ, Moody F, Stewart 1M, Atkinson M: Vagal impairment of gastric
secretion in diabetic autonomic neuropathy. BrMedJ 2:588-90, 1975
278. Buysschaert M, Donckier J, Dive A, Ketelslegers JM, Lambert AE: Gastric acid
and pancreatic polypeptide responses
to sham feeding are impaired in diabetic subjects with autonomic neuropathy. Diabetes 34:1181-85, 1985
279. Kanatsuka A, Osegawa M, An T, Suzuki
T, Hashimoto N, Makino H: Augmented gastrin responses in diabetic
patients with vagal neuropathy. Diabetologia 26:449-52, 1984
280. Vinik Al, Achem-Karam S, Owyang C:
Gastrointestinal hormones in clinical

285. Camilleri M, Malagelada JR: Abnormal

intestinal motility in diabetics with the
gastroparesis syndrome. Eur J Clin Invest 14:420-27, 1984.
286. Scarpello JH, Hague RV, Cullen DR,
Sladen GE: The 14C-glycocholate test
in diabetic diarrhoea. Br Med] 2:67375, 1976
287. Molloy AM, Tomkin GH: Altered bile
in diabetic diarrhoea. Br Med] 2:146263, 1978
288. Condon JR, Suleman Ml, Fan YS, McKeown MD: Cholestyramine and diabetic
post-vagotomy diarrhoea (Letter). Br
Med] 4:423, 1973
289. Vinik Al, Jackson WPU: Endocrine secretions in chronic pancreatitis. In The

290.

291.

medicine. In Special Topics in Endocrinology and Metabolism. Cohen MP, Foa

281.

282.

283.

284.

PP, Eds. New York, Liss, 1983, p. 9 4 138

Achem-Karam SR, Funakoshi A, Vinik
Al, Owyang C: Plasma motilin concentration and interdigestive migrating
motor complex in diabetic gastroparesis: effect of metoclopramide. Gastroenterology 88:492-99, 1985
Levitt NS, Vinik Al, Slve AA, Child PT,
Jackson WP: The effect of dietary fiber
on glucose and hormone responses to a
mixed meal in normal subjects and in
diabetic subjects with and without autonomic neuropathy. Diabetes Care
3:515-19, 1980
Read NW, Harford WV, Schmulen AC,
Read MG, Santa Ana CA, FordtranJS: A
clinical study of patients with fecal incontinence and diarrhea. Gastroenterology 76:747-56, 1979
Schiller LR, Santa Ana CA, Schmulen
AC, Hendler RS, Harford WV, Fordtran
JS: Pathogenesis of fecal incontinence in
diabetes mellitus: evidence for intemalanal-sphincter dysfunction. N Engl J
Med 307:1666-71, 1982

DIABETES CARE, VOLUME

15,

NUMBER 12,

292.

293.

294.

295.

296.

297.

DECEMBER

mechanism. Metabolism 32:57-61,

1983
298. Glaser B, Vinik Al, Slve AA, Floyd JC
Jr: Plasma human pancreatic polypeptide responses to administered secretin:
effects of surgical vagotomy, cholinergic
blockade, and chronic pancreatitis. J
Clin Endocrinol Metab 50:1094-99,
1980
299. Levitt NS, Vinik Al, Sive AA, van
Tonder S, Lund A: Impaired pancreatic
polypeptide responses to insulin-induced hypoglycemia in diabetic autonomic neuropathy. ] Clin Endocrinol
Metab 50:445-49, 1980

300. Krarup T, Schwartz TW, Hilsted J,

Madsbad S, Overlaege O, Sestoft L: ImSpectrum of the Diabetic Syndromes. Podpaired response of pancreatic polypepolsky S, Viswanathan M, Eds. New
tide to hypoglycaemia: an early sign of
York, Raven Press, 1980, p. 165-189
autonomic neuropathy in diabetics. Br
Med J 2:1544-46, 1979
Chang EB, Bergenstal RM, Field M: Diabetic diarrhea: loss of adrenergic reg- 301. White NH, Skor DA, Cryer PE, Levanulation of intestinal fluid and electrolyte
doski LA, Bier DM, Santiago JV:Identitransport (Abstract). Gastroenterology
fication of type 1 diabetic patients at
84:1121, 1983
increased risk for hypoglycemia during
intensive therapy. N Engl ] Med 308:
Fedorak RN, Field M, Chang EB: Treat485-91, 1983
ment of diabetic diarrhea with clonidine. Ann Intern Med 102:197-99, 302. Hilsted J, Galbo H, Tronier B, Chris1985
tensen NJ, Schwartz TW: Hormonal
Tsai ST, Vinik Al, Brunner JF:Diabetic
and metabolic responses to exercise in
diarrhea and somatostatin (Letter). Ann
insulin-dependent diabetics with and
Intern Med 104:894, 1986
without autonomic neuropathy and in
Vinik Al, Tsai ST, Moattari AR, Cheung
normal subjects, lnt ] Sports Med
P, Eckhauser FE, Cho K: Somatostatin
2:216-19, 1981
analogue (SMS 201-995) in the man- 303. Bloom SR, Vaghan NJ, Russell RC: Vaagement of gastroenteropancreatic tugal control of glucagon release in man.
mors and diarrhea syndromes. Am ]
Lancet 2:546-49, 1974
Med 81:23-40, 1986
304. Gerich JE, Langlois M, Noacco C,
Smith PH, Madson KL: Interactions beSchneider V, Forsham PH: Adrenergic
tween autonomic nerves and endocrine
modulation of pancreatic glucagon secells of the gastroenteropancreatic syscretion in man. J Clin Invest 53:1441tem. Diabetologia 20 (Suppl. 1):31446, 1974
24, 1981
305. Maher TD, Tanenberg RJ, Greenberg
Vinik Al, Glowniak JV: Hormonal seBZ, Hoffman JE, Doe RP, Goetz FC:
cretion in diabetic autonomic neuropaLack of glucagon response to hypoglythy. N Y State] Med 82:871-86, 1982
cemia in diabetic autonomic neuropathy. Diabetes 26:196-200, 1977
Sive AA, Vinik Al, Levitt N: Adrenergic
modulation of human pancreatic 306. Levitt NS, Vinik Al, Sive AA, Child P,
polypeptide (hPP) release. GastroenterJackson WP: Studies on plasma glucaology 79:665-72, 1980
gon concentration in maturity-onset diGlaser B, Floyd JC Jr, Vinik Al: Secreabetics with autonomic neuropathy. Dition of pancreatic polypeptide in man
abetes 28:1015-21, 1979
in response to beef ingestion is medi- 307. Hilsted J, Madsbad S, Krarup T, Tronier
ated in part by an extravagal cholinergic
B, Galbo H, Sestoft L, Schwartz TW: No

1992

1969

Diabetic neuropathies

308.

309.

310.

311.

312.

313.

314.

315.

316.

1970

response of pancreatic hormones to hypoglycemia in diabetic autonomic neuropathy. J Clin Endocrinol Metab 54:
815-19, 1982
Horie H, Hanafusa T, Matsuyama T,
Namba M, Nonaka K, Tarui S, Yamatodani A, Wada H: Decreased response
of epinephrine and norepinephrine to
insulin-induced hypoglycemia in diabetic autonomic neuropathy. Horm
Metab Res 16:398-401, 1984
Femandez-Castaner M, Webb S, Levy I,
Rios M, Casamitjana R, Bergua M,
Figuerola D, Rivera F: Somatostatin and
counterregulatory hormone responses
to hypoglycaemia in diabetics with and
without autonomic neuropathy. Diabete
Metab 11:81-86, 1985
White NH, Gingerich RL, Levandoski
LA, Cryer PE, Santiago JV: Plasma pancreatic polypeptide response to insulininduced hypoglycemia as a marker for
defective glucose counterregulation in
insulin-dependent diabetes mellitus.
Diabetes 34:870-75, 1985
Levitt NS, Vinik AI, Child PT: Glucosedependent insulin-releasing peptide in
noninsulin- dependent maturity- onset
diabetes: effects of autonomic neuropathy. J Clin Endocrinol Metab 51:254-58,
1980
Glaser B, Vinik AI, Valtysson G, Zoghlin
G: Truncal vagotomy abolishes the somatostatin response to insulin-induced
hypoglycemia in man. J Clin Endocrinol
Metab 52:823-25, 1981
Sasaki H, Nagulesparan M, Dubois A,
Straus E, Samloff IM, Lawrence WH,
Johnson GC, Sievers ML, Unger RH:
Hypergastrinemia in obese noninsulindependent diabetes: a possible reflection of high prevalence of vagal dysfunction. J Clin Endocrinol Metab 56:
744-50, 1983
Cryer PE: The metabolic impact of autonomic neuropathy in insulin-dependent diabetes mellitus. Arch Intern Med
146:2127-29, 1986
Funakoshi A, Ho LT, Jen KL, Knopf R,
Vinik AI: Diumal profile of plasma raotilin concentrations during fasting and
feeding in man. Gastroenterol Jpn 20:
447-56, 1985
Sussman KE, Crout JR, Marble A: Fail-

317.

318.
319.

320.

321.

322.

323.

324.

325.

ure of warning in insulin-induced hypoglycemic reaction. Diabetes 12

(Suppl. l):38-45, 1963
Hoeldtke RD, Boden G, Shuman CR,
Owen OE: Reduced epinephrine secretion and hypoglycemia unawareness in
diabetic autonomic neuropathy. Ann Intern Med 96:459-62, 1982
Cryer PE: Glucose counterregulation in
man. Diabetes 30:261-64, 1981
Bolli GB, de Feo P, Compagnucci P,
Cartechini MG, Angeletti G, Santeusanio F, Brunetti P, Gerich JE: Abnormal glucose counterregulation in insulin-dependent diabetes mellitus.
Interaction of anti-insulin antibodies
and impaired glucagon and epinephrine secretion. Diabetes 32:134-41,
1983
Gerich JE, Langlois M, Noacco C,
Karam JH, Forsham PH: Lack of glucagon response to hypoglycemia in diabetes: evidence for an intrinsic pancreatic
a-cell defect. Science 182:171-73,1973
Campbell LV, Kraegen EW, Lazarus L:
Defective blood glucose counter-regulation in diabetics is a selective form of
autonomic neuropathy. Br Med J
2:1527-29, 1977
Bolli GB, de Feo P, de Cosmo S, Perriello G, Ventura MM, Benedetti MM,
Santeusanio F, Gerich JE, Brunetti P: A
reliable and reproducible test for adequate glucose counterregulation in type
I diabetes mellitus. Diabetes 33:73237, 1984
Sjobom NC, Adamson U, Lin PE: The
prevalence of impaired glucose
counter-regulation during an insulininfusion test in insulin-treated diabetic
patients prone to severe hypoglycaemia.
Diabetologia 32:818-25, 1989
Ryder RE, Owens DR, Hayes TM,
Ghatei MA, Bloom SR: Unawareness of
hypoglycaemia and inadequate hypoglycaemic counterregulation: no causal
relation widi diabetic autonomic neuropathy. Br Med] 301:783-87, 1990
Amiel SA, Tamborlane WV, Simonson
DC, Sherwin RS: Defective glucose
counterregulation after strict glycemic
control of insulin-dependent diabetes

326.

327.

328.

329.

330.

331.

332.

333.

334.

mellitus. N Engl J Med 316:1376-83,

1987
Heller SR, MacDonald IA, Herbert M,
Tattersall RB: Influence of sympathetic
nervous system on hypoglycaemic
warning symptoms. Lancet 2:359-63,
1987
Hepburn DA, Patrick AW, Eadington
DW, Ewing DJ, Frier BM: Unawareness
of hypoglycaemia in insulin-treated diabetic patients: prevalence and relationship to autonomic neuropathy. Diabetic
Med 7:711-71, 1990
Cryer PE, Binder C, Bolli GB, Cherrington AD, Gale EA, Gerich JE, Sherwin RS: Hypoglycemia in IDDM. Diabetes 38:1193-99, 1989
Grimaldi A, Bosquet F, Davidoff P, Digy
JP, Sachon C, Landault C, Thervet F,
Zoghbi F, LeGrand JC: Unawareness of
hypoglycemia by insulin-dependent diabetics. Horm Metab Res 22:90-95,
1990
Boyle PJ, Schwartz NS, Shah SD, Clutter WE, Cryer PE: Plasma glucose concentrations at the onset of hypoglycemic symptoms in patients with poorly
controlled diabetes and in nondiabetics.
N EnglJ Med 318:1487-92, 1988
Clarke WL, Gonder-Frederick LA, Richards FE, Cryer PE: Multifactorial origin of hypoglycemic symptom unawareness in IDDM. Association with
defective glucose counterregulation and
better glycemic control. Diabetes 40:
680-85, 1991
Amiel SA, Pottinger RC, Archibald HR,
Chusney G, Cunnah DT, Prior PF, Gale
EA: Effect of antecedent glucose control
on cerebral function during hypoglycemia. Diabetes Care 14:109-18, 1991
Cryer PE, Gerich JE: Hypoglycemia in
insulin dependent diabetes mellitus: Insulin excess and defective glucose
counterregulation. In Diabetes Mellitus:
Theory and Practice. Rifkin H, Porte D,
Eds. New York, Elsevier Science Publishing, 1990, p. 526-46
Caprio S, Gerety G, Tamborlan WV,
Simonson DC, Sherwin RS: Defective
glucose counterregulation after strict
control of insulin-dependent diabetes
mellitus. N Engl J Med 316:1376-83,
1987

DIABETES CARE, VOLUME 15,

NUMBER 12,

DECEMBER

1992

Vinik and Associates

335. Amiel SA, Sherwin RS, Simonson DC,

Tamborlane WV: Effect of intensive insulin therapy on glycemic thresholds
for counterregulatory hormone release.
Diabetes 37:901-907, 1988
336. Widom B, Simonson DC: Glycemic
control and neuropsychologic function
during hypoglycemia in patients with
insulin-dependent diabetes mellitus.
Ann Intern Med 112:904-12, 1990
337. Mitrakou A, Ryan C, Veneman T, Mokan M, Jenssen T, Kiss I, Durrant I,
CryerP, GerichJ: Hierarchy of glycemic
thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. Am] Physiol 260:E6774, 1991
338. Jones TW, McCarthy G, Tamborlane
WX, Roessler E, Sherwin RS: Resistance
to neuroglycopenia: an adaptive response during intensive insulin treatment of diabetes (Abstract). Diabetes
40:557A, 1991
339. Leveston SA, Shah SD, Cryer PE: Cholinergic stimulation of norepinephrine
release in man. Evidence of a sympathetic postganglionic axonal lesion in
diabetic adrenergic neuropathy. J Clin
Invest 64:374-80, 1979
340. Matthews DM, Martyn CN, Riemersma
RA, Clarke BF, Ewing DJ: Noradrenaline response to edrophonium (Tensilon) and its relation to other autonomic
tests in diabetic subjects. Diabetes Res
6:175-80, 1987
341. Hilsted J, Madsbad S, Krarup T, Sestoft
L, Christensen NJ, Tronier B, Galbo H:
Hormonal, metabolic, and cardiovascular responses to hypoglycemia in diabetic autonomic neuropathy. Diabetes
30:626-33, 1981
342. Hilsted J: Pathophysiology in diabetic
autonomic neuropathy: cardiovascular,
hormonal, and metabolic studies. Diabetes 31:730-37, 1982
343. Epidemiology of severe hypoglycemia
in the diabetes control and complications trial. The DCCT Research Group.
Am] Med 90:450-59, 1991
344. Bjork E, Palmer M, Schvarcz E, Berne
C: Incidence of severe hypoglycaemia
in an unselected population of patients
with insulin-treated diabetes mellitus,
with special reference to autonomic

DIABETES CARE, VOLUME 15, NUMBER 12,

345.

346.

347.

348.

349.

350.

351.

352.

353.

neuropathy. Diab Nutr Metab 4:303- 357.

309, 1990
Heller SR, Cryer PE: Reduced neuroendocrine and symptomatic responses to
subsequent hypoglycemia after 1 epi- 358.
sode of hypoglycemia in nondiabetic
humans. Diabetes 40:223-26, 1991
Widom B, Simonson DC: Effect of in- 359.
termittent hypoglycaemia on counterregulatory hormone secretion. Diabetologia 33:A84, 1990 (Abstract).
Davis M, Shamoon H: Adaptive counterregulatory responses to hypoglyce- 360.
mia (hypo) in nondiabetic humans (Abstract). Diabetes 38 (Suppl. 1):5A, 1989
Schwartz NS, Clutter WE, Shah SD,
Cryer PE: Glycemic thresholds for activation of glucose counterregulatory sys- 361.
tems are higher than the threshold for
symptoms. J Clin Invest 79:777-81,
1987
Hirsch IB, Boyle PJ, Craft S, Cryer PE: 362.
Higher glycemic thresholds for symptoms during P-adrenergic blockade in
IDDM. Diabetes 40:1177-86, 1991
Vinik AI, Mitchell BD: Clinical aspects 363.
of diabetic neuropathies (Abstract). Diabetes Metab Rev 4:233-53, 1988
KimuraJ: Electrodiagnosis in diseases of364.
nerve and muscle. Philadelphia, Davis,
1989
Daube JR: Electrophysiologic testing in
diabetic neuropathy. In Diabetic Neuropathy. Dyck PJ, Thomas PK, Asbury 365.
AK, Winegrad AI, Porte D, Eds. Philadelphia, Saunders, 1987, p. 162-76
Argyropoulos CJ, Panayiotopolus CP,
Scarpalezos S, Nastas PE: F-wave and 366.
M-response conduction velocity in diabetes mellitus. Electromyogr Clin Neuro-

physiol 19:443-58, 1979

354. Chokroverty S: Proximal nerve dysfunction in diabetic proximal amyotrophy. Electrophysiology and electron
microscopy. Arch Neurol 39:403-07,
1982
355. Greene DA, Sima AA, Albers JW, Pfeifer
MA: Diabetic neuropathy. In Diabetes
Mellitus: Theory and Practice. New York,

Elsevier, 1990, p. 710-55

356. Kitka DG, Breuer AC, Wllbourn AJ:
Thoracic root pain in diabetes: the spectrum of clinical and electromyographic
findings. Ann Neurol 11:80-85, 1982

DECEMBER

1992

Sun SF, Streib WE: Diabetic thoracoabdominal neuropathy: clinical and electrodiagnostic features. Ann Neurol
9:75-79, 1981
Williams IR, Mayer RF: Subacute proximal diabetic neuropathy. Neurology 26:
108-16, 1976
Bassi S, Albizati MG, Calloni E, Frattola
L: Electromyographic study of diabetic
and alcoholic polyneuropathic patients
treated with gangliosides. Muscle Nerve
5:351-56, 1981
Fagius J, Jameson S: Effects of aldose
reductase inhibitor treatment in diabetic polyneuropathya clinical and
neurophysiological study. J Neurol Neurosurg Psychiatry 44:991-1001, 1981
Downie AW, Newell DJ: Sensory nerve
conduction in patients with diabetes
mellitus and controls. Neurology 11
(10):876-82, 1961
Cracco J, Casteels S, Mark E: Spinal
somatosensory evoked potentials in juvenile diabetes. Ann Neurol 15:55-58,
1984
Gupta PR, Dorfman LJ: Spinal somatosensory conduction in diabetes. Neurology 31:841-45, 1981
Reeves ML, Seigler DE, Ayyar DR, Skyler JS: Medial plantar sensory response.
Sensitive indicator of peripheral nerve
dysfunction in patients with diabetes
mellitus. Am] Med 76:842-46, 1984
Bastron JA, Thomas JE: Diabetic polyradiculopathy: clinical and electromyographic findings in 105 patients. Mayo
Clin Proc 56:725-32, 1981
Arrezzo J, Laudadio C, Schaumburg H:
The optacon tactile tester and the Pfizer
thermal tester: new devices for the detection of diabetic neuropathy (Abstract). Diabetes 33 (Suppl. 1):185A,
1984
367. Masson EA, Veves A, Fernando D,
Boulton AJ: Current perception thresholds: a new, quick, and reproducible
method for the assessment of peripheral
neuropathy in diabetes mellitus. Diabetologia 32:724-28, 1989
368. Sosenko JM, Kato M, Soto R, Bild DE:
Comparison of quantitative sensorythreshold measures for their association
with foot ulceration in diabetic patients.
Diabetes Care 13:1057-61, 1990

1971

Diabetic neuropathies

369. Wetherill GB, Levitt H: Sequential estimation of points on a psychometric

function. Br J Math Stat Psychol 18:1- 382.
10, 1965
370. Maurissen JP: Quantitative sensory assessment in toxicology and occupa- 383.
tional medicine: applications, theory,
and critical appraisal. Toxicol Lett 43:
321-43, 1988
371. Sosenko JM, Kato M, Soto RA, Gadia
MT, Ayyar DR: Specific assessments of 384.
warm and cool sensitivities in adult diabetic patients. Diabetes Care 11:481
83, 1988
372. Katims JJ, Naviasky EH, Rendell MS, 385.
Ng LK, Bleecker ML: Constant current
sine wave transcutaneous nerve stimulation for the evaluation of peripheral 386.
neuropathy. Arch Phys Med Rehabil 68:
210-13, 1987
373. Rendell MS, Dovgan DJ, Bergman TF, 387.
O'Donnell GP, Drobny EP, Katims JJ:
Mapping diabetic sensory neuropathy
by current perception threshold testing. 388.
Diabetes Care 12:636-40, 1989
374. Sosenko JM, Gadia MT, Natori N, Ayyar
DR, Ramos LB, Skyler JS: Neurofunc- 389.
tional testing for the detection of diabetic peripheral neuropathy. Arch Intern 390.
Med 147:1741-44, 1987
375. Rendell MS, Katims JJ, Richter R, Rowland F: A comparison of nerve conduc- 391.
tion velocities and current perception
thresholds as correlates of clinical severity of diabetic sensory neuropathy. J
Neurol Neurosurg Psychiatry 52:502- 392.
11, 1989
376. Masson EA, Boulton AJ: The neurometer: validation and comparison with
conventional tests for diabetic neurop- 393.
athy. Diabetic Med 8 Spec No.:S63-66,
1991
377. Baird JC, Noma E: Fundamentals of scal- 394.
ing and psychophysics. New York, Wiley,
1978
395.
378. Gescheider GA: Psychophysics: method,
theory, and application. New York,
Wiley, 1985
379. Laming D: Sensory analysis. London, 396.
Academic, 1986
380. Bekesy G von: Sensory inhibition. Princeton, NJ, Princeton University Press,
1967
381. Jesteadt W: An adaptive procedure for 397.

1972

subjective judgments. Percept Psychophys 28:85-88, 1980

Coren S, Ward LM: Sensation and perception. New York, Harcourt Brace Jovanovich, 1989, p. 17
Coles MG, Gale A, Kline P: Personality
and habituation of the orienting reaction: tonic and response measures of
electrodermal activity. Psychophysiology
8:54-63, 1971
Witkin HA, Berry JW: Psychological
differentiation in cross-cultural perspective, journal of Cross-Cultural Psychology 6:4-87, 1975
Stelmack RM: Biological bases of extraversion: psychophysiological evidence.
JPers 58:293-311, 1990
Simpson WA: The method of constant
stimuli is efficient. Percept Psychophys
44:433-36, 1988
Watson AB, Fitzhugh A: The method of
constant stimuli is inefficient. Percept
Psychophys 47:87-91, 1990
Green DM, Swets JA: Signal detection
theory and psychophysics. New York,
Krieger, 1966
McNicol D: A primer of signal detection
theory. Sydney, Allen & Unwin, 1972
Stevens SS: Matching functions between loudness and ten other continua.
Percept Psychophys 1:5-8, 1966
Refinetti R: Magnitude estimation of
warmth: intra- and intersubject variability. Percept Psychophys 46:81-84,
1989
Luce RD: On the possible psychophysical laws revisited: remarks on crossmodal matching. Psychol Rev 97:66-77,
1990
Ward LM: Mixed-method mixed-modality psychophysical scaling. Percept
Psychophys 48:571-82, 1990
von Bekesy G: A new audiometer. Ada
Oncol 35:411-22, 1947
Stillman JA: A comparison of three
adaptive psychophysical procedures using inexperienced listeners. Percept Psychophys 46:345-50, 1989
Dyck PJ, Kames JL, O'Brien P, Okazaki
H, Lais A, Engelstad J: The spatial distribution of fiber loss in diabetic polyneuropathy suggests ischemia. Ann
Neurol 19:440-49, 1986
Dyck PJ, Lais A, Karnes JL, O'Brien P,

398.

399.

400.

401.

402.

403.

404.

405.

406.

407.

Rizza R: Fiber loss is primary and multifocal in sural nerves in diabetic polyneuropathy. Ann Neurol 19:425-39,
1986
Williams E, Timperley WR, Ward JD,
Duckworth T: Electron microscopical
studies of vessels in diabetic peripheral
neuropathy. J Clin Pathol 33:462-70,
1980
Sima AA, Lattimer SA, Yagihashi S,
Greene DA: Axo-glial dysjunction. A
novel structural lesion that accounts for
poorly reversible slowing of nerve conduction in the spontaneously diabetic
bio-breeding rat. J Clin Invest 77:47484, 1986
Pfeifer MA, Weinberg CR, Cook DL,
Reenan A, Halar E, Halter JB, Lacava
EC, Porte D Jr: Correlations among autonomic, sensory, and motor neural
function tests in untreated non-insulindependent diabetic individuals. Diabetes Care 8:576-84, 1985
Shahani BT, Halperin JJ, Boulu P, Cohen J: Sympathetic skin responsea
method of assessing unmyelinated axon
dysfunction in peripheral neuropathies.
J Neurol Neurosurg Psychiatry 47:53642, 1984
Pfeifer MA, Cook D, BrodskyJ, Tice D,
Reenan A, Swedine S, Halter JB, Porte D
Jr: Quantitative evaluation of cardiac
parasympathetic activity in normal and
diabetic man. Diabetes 31:339-45,
1982
Sandroni P, Benarroch EE, Low PA:
Pharmacological dissection of components of the Valsalva maneuver in adrenergic failure. JAppI Physiol 71:156367, 1991
Fealey RD, Low PA, Thomas JE: Thermoregulatory sweating abnormalities in
diabetes mellitus. Mayo Clin Proc 64:
617-28, 1989
Low PA, Zimmerman BR, Dyck PJ:
Comparison of distal sympathetic with
vagal function in diabetic neuropathy.
Muscle Nerve 9:592-96, 1986
Low PA, Caskey PE, Tuck RR, Fealey
RD, Dyck PJ: Quantitative sudomotor
axon reflex test in normal and neuropathic subjects. Ann Neurol 14:573-80,
1983
Rendell M, Bergman T, O'Donnell G,

DIABETES CARE, VOLUME

15,

NUMBER 12,

DECEMBER

1992

Vinik and Associates

Drobny E, Bonner RF: Microvascular

blood flow, volume, and velocity measured by laser Doppler techniques in
IDDM. Diabetes 38:819-24, 1989
408. Albers JW, Cavender GD, Levine SP,
Langolf GD: Asymptomatic sensorimotor polyneuropathy in workers exposed
to elemental mercury. Neurology 32:
1168-74, 1982
409. Horowitz SH, Ginsberg-Fellner F: Ischemia and sensory nerve conduction in
diabetes mellitus. Neurology 29:695704, 1979
410. Pietri A, Ehle AL, Raskin P: Changes in
nerve conduction velocity after six
weeks of glucoregulation with portable
insulin infusion pumps. Diabetes 29:
668-71, 1980
411. Terkildsen AB, Chris tensen NJ: Reversible nervous abnormalities in juvenile
diabetics with recently diagnosed diabetes. Diabetologia 7:113-17, 1971
412. Lauritzen T, Frost-Larsen K, Larsen
HW, Deckert T: Two-year experience
with continuous subcutaneous insulin
infusion in relation to retinopathy and
neuropathy. Diabetes 34 (Suppl 3):7479, 1985
413. Dahl-Jorgensen K, Brinchmann-Hansen
CHanssen KF, Ganes T, Kierulf P,
Smeland E, Sandvik L, Aagenaes O: Effect of near normoglycaemia for two
years on progression of early diabetic
retinopathy, nephropathy, and neuropathy: the Oslo study. Br MedJ (Clin Res
Ed) 293:1195-99, 1986
414. Service FJ, Daube JR, O'Brien PC, Dyck
PJ: Effect of artificial pancreas treatment
on peripheral nerve function in diabetes. Neurology 31:1375-80, 1981
415. Service FJ, Rizza RA, Daube JR, O'Brien
PC, Dyck PJ: Near normoglycaemia improved nerve conduction and vibration
sensation in diabetic neuropathy. Diabetologia 28:722-27, 1985
416. Graf RJ, Halter JB, Pfiefer MA, Halar E,
Brozovich F, Porte D Jr: Glycemic control and nerve conduction abnormalities in non-insulin- dependent diabetic
subjects. Ann Intern Med 94:307-11,
1981
417. The Diabetes Control and Complications Trial (DCCT). Design and methodologic considerations for the feasibil-

DIABETES CARE, VOLUME 15,

NUMBER 12,

ity phase. The DCCT Research Group.

Diabetes 35:530-45, 1986
418. Handelsman DJ, Turtle JR: Clinical trial
of an aldose reductase inhibitor in diabetic neuropathy. Diabetes 30:459-64,
1981
419. Culebras A, Alio J, Herrera JL, LopezFraile Ml: Effect of an aldose reductase
inhibitor on diabetic peripheral neuropathy. Preliminary report. Arch Neurol 38:133-34, 1981

new class of agents for the pharmacological control of certain diabetic complications. J Med Chem 28:841-49,
1985
430. SalwayJG, Whitehead L, Finnegan JA,
Karunanayaka A, Bamett D, Payne RB:
Effect of myo-inositol on peripheralnerve function in diabetes. Lancet
2:1282-84, 1978

431. Clements RS, Vourganti B, Kuba T, Oh

SJ, Darnell B: Dietary myo-inositol intake and peripheral nerve function in
420. Gabbay LJ, Spack N, Loo S, Hirsch HJ,
diabetic neuropathy. Metabolism 28:
Ackil AA: Aldose reductase inhibition:
477-83, 1979
studies with alrestatin. Metabolism 28:
471-76, 1979
432. Gregersen G, Borsting H, Theil P, Servo
421. Jaspan JB, Towle VL, Maselli R, Herold
C: myo-Inositol and function of periphK Clinical studies with an aldose reeral nerves in human diabetics. A conductase inhibitor in the autonomic and
trolled clinical trial. Acta Neurol Scand
somatic neuropathies of diabetes. Me58:241-48, 1978
tabolism 35:83-92, 1986
433. Pozza G, Saibene V, Comi G: The effect
422. Young RJ, Ewing DJ, Clarke BF: A conof ganglioside administration in human
trolled trial of sorbinil, an aldose reducdiabetic peripheral neuropathy. In:
tase inhibitor, in chronic painful diaGangliosides in neurological and neurobetic neuropathy. Diabetes 32:938-42,
muscular junction, development, and re1983
pair. Rapport MM, Gorio A, Eds. New
York, Raven, 1981, p. 253-57
423. Christensen JE, Vamek L, Gregersen G:
The effect of an aldose reductase inhib- 434. Abraham RR, Abraham RM, Wynn V: A
itor (Sorbinil) on diabetic neuropathy
double blind placebo controlled trial of
and neural function of the retina: a doumixed gangliosides in diabetic periphble-blind study. Acta Nenrol Scand 71:
eral and autonomic neuropathy. Adv
164-67, 1985
Exp Med Biol 174:607-24, 1984
424. FagiusJ, Brattberg A, Jameson S, Beme 435. Bradley WG, Tandan R, Fillyaw MJ:
C: Limited benefit of treatment of diaDouble-blind controlled trials of crobetic polyneuropathy with an aldose renassial in chronic peripheral neuropaductase inhibitor: a 24-week controlled
thies (Abstract). Neurology 37(Suppl.
trial. Diabetologia 28:323-29, 1985
l):254-55, 1987
425. Lewin 1G, O'Brien LA, Morgan MH, 436. Naarden A, Davidson J, Harris L, Moore
Corrall RJ: Clinical and neurophysioJ, Defelice S: Treatment of painful dialogical studies with the aldose reductase
betic polyneuropathy with mixed ganinhibitor, sorbinil, in symptomatic diagliosides. Adv Exp Med Biol 174:581betic neuropathy. Diabetologia 26:44592, 1984
48, 1984.
437. Crepaldi G, Fedele D, Tiengo A, Battis426. Boulton AJ: Effects of Tolrestat, a new
tin L, Negrin P, Pozza G, Canal N, Comi
aldose reductase inhibitor, on nerve
GC, Lenti G, Pagano G: Ganglioside
conduction and paresthetic symptoms
treatment in diabetic peripheral neuin diabetic neuropathy (Abstract). Diaropathy: a multicenter trial. Acta Diabebetologia 29:521A-22A, 1986
tol hat 20:265-76, 1983
427 Harati Y, Niakan E, ComstockJP, Logan 438. Horowitz SH: Ganglioside therapy in
C: Aldose reductase inhibitor (Tolrestat)
diabetic neuropathy. Muscle Nerve
therapy in patients with diabetic periph9:531-36, 1986
eral neuropathy (Abstract). Ann Neurol 439. Jamal GA, Carmichael H, Weir Al:
22:129, 1987
Gamma-linolenic acid in diabetic neu428. Kador PF, Kinoshita JH, Sharpless NE:
ropathy Getter). Lancet 1:1098, 1986
Aldose reductase inhibitors: a potential 440. Vinik AI: Management of painful syn-

DECEMBER

1992

1973

Diabetic neuropathies

441.

442.

443.

444.

445.

446.

447.

448.

449.

450.

451.

1974

dromes in diabetes mellitus. Clinical Diabetes 9:57-62, 1991

Ellenberg M: Treatment of diabetic neuropathy with diphenylhydantoin. N Y
State] Ued 68:2653-55, 1968
Saudek CD, Wems S, Reidenberg MM:
Phenytoin in the treatment of diabetic
symmetrical polyneuropathy. Clin Pharmacol Ther 22:196-99, 1977
Rull JA, Quibrera R, Gonzalez-Millan
H, Lozano-Castaneda O: Symptomatic
treatment of peripheral diabetic neuropathy with carbamazepine (Tegretol):
double blind crossover trial. Diabetologia 5:215-18, 1969
Wilton TD: Tegretol in the treatment of
diabetic neuropathy. 5 Ajr Med J 48:
869-72, 1974
Chakrabarti AK, Samantaray SK: Diabetic peripheral neuropathy: nerve conduction studies before, during and after
carbamazepine therapy. Aust N ZJ Med
6:565-68, 1976
Davis JL, Lewis SB, Gerich JE, Kaplan
RA, Schultz TA, Wallin JD: Peripheral
diabetic neuropathy treated with amitriptyline and fluphenazine. JAMA 238:
2291-92, 1977
Mendel CM, Klein RF, Chappell DA,
Dere WH, Gertz BJ, Karam JH, Lavin
TN, Grunfeld C: A trial of amitriptyline
and fluphenazine in the treatment of
painful diabetic neuropathy. JAMA
255:637-39, 1986
Gomez-Perez, FJ, Rull JA, RodriquezRivera, Gonzalez-Barranco, LozanoCastaneda O: Nortriptyline and fluphenazine in the symptomatic
treatment of diabetic neuropathy: A
double-blind cross-over study. Pain 23:
395-400, 1985
Young RJ, Clarke BF: Pain relief in diabetic neuropathy: the effectiveness of
imipramine and related drugs. Diabetic
Med 2:363-66, 1985
Max MB, Culnane M, Schafer SC,
Gracely RH, Walther DJ, Smoller B,
Dubner R: Amitriptyline relieves diabetic neuropathy pain in patients with
normal or depressed mood. Neurology
37:589-96, 1987
Kastrup J, Petersen P, Dejgard A, Angelo HR, Hilsted J: Intravenous lidocaine infusiona new treatment of

452.

453.

454.

455.

456.

457.

458.

459.

460.

461.

462.

chronic painful diabetic neuropathy?

Pain 28:69-75, 1987
Stanford W: Use of an air force antigravity suit in a case of severe postural
hypotension. Arch Intern Med 55:84345, 1961
Campbell IW, Ewing DJ, Clarke BF:
9-a-fluorohydrocortisone in the treatment of postural hypotension in diabetic autonomic neuropathy. Diabetes
24:381-84, 1975
Schmid PG, Eckstein JW, Abboud FM:
Effect of 9-a-fluorohydrocortisone on
forearm vascular responses to norepinephrine. Circulation 34:620-26, 1966
Kuchel O, Buu NT, GutkowskaJ, Genest J: Treatment of severe orthostatic
hypotension by metoclopramide. Ann
Intern Med 93:841-43, 1980
Boesen F, Andersen EB, Kanstrup IL,
Hesse B, Christensen NJ: Treatment of
diabetic orthostatic hypotension with
pindolol. Ada Neurol Scand 66:38691, 1982
Hoeldtke RD, Cavanaugh ST, Hughes
JD, Polansky M: Treatment of orthostatic hypotension with dihydroergotamine and caffeine. Ann Intern Med 105:
168-73, 1986
Hoeldtke RD, Boden G, O'Dorisio TM:
Treatment of postprandial hypotension
with a somatostatin analogue (SMS
201-995). Am] Med 81:83-87, 1986
Brownlee M, Kroopf SS: Metoclopramide for gastroparesis diabeticorum
(Letter). N Engl J Med 291:1257-58,
1974
Snape WJ Jr., Battle WM, Schwartz SS,
Braunstein SN, Goldstein HA, Alavi A:
Metoclopramide to treat gastroparesis
due to diabetes mellitus: a doubleblind, controlled trial. Ann Intern Med
96:444-46, 1982
Pinder RM, Brogden RN, Sawyer PR,
Speight TM, Avery GS: Metoclopramide: a review of its pharmacological
properties and clinical use. Drugs 12:
81-131, 1976
Malagelada JR, Rees WD, Mazzotta LJ,
Go VL: Gastric motor abnormalities in
diabetic and postvagotomy gastroparesis: effect of metoclopramide and bethanechol. Gastroenterology 78:28693, 1980

463. Maddem GJ, Horowitz M, Jamieson

GG: The effect of domperidone on oesophageal emptying in diabetic autonomic neuropathy. Br] Clin Pharmacol
19:441-44, 1985
464. Jacober SJ, Narayan A, Strodel WE,
Vinik Al: Jejunostomy feeding in the
management of gastroparesis diabeticorum [letter]. Diabetes Care 9:217-19,
1986
465. Green PA, Berge KG, Sprague RG: Control of diabetic diarrhea with antibiotic
therapy. Diabetes 17:385-87, 1968
466. Frimodt-Moller C, Mortensen S: Treatment of diabetic cystopathy. Ann Intern
Med 92:327-28, 1980
467. Jensen SB: Sexual dysfunction in insulin-treated diabetics: a six-year follow-up study of 101 patients. Arch Sex
Behav. 15:271-83, 1986
468. Tyrer G, Steel JM, Ewing DJ, Bancroft J,
Wamer P, Clarke BF: Sexual responsiveness in diabetic women. Diabetologia 24:166-71, 1983
469. Newman AS, Bertelson AD: Sexual dysfunction in diabetic women. J Behav
Med 9:261-70, 1986
470. Scott FB, Fishman 1J, Light JK: An inflatable penile prosthesis for treatment
of diabetic impotence. Ann Intern Med
92:340-42, 1980
471. Andaloro VAJR, Dube A: Treatment of
retrograde ejaculation with brompheniramine. Urology 5:520-22, 1975
472. Brooks ME, Berezin M, Braf Z: Treatment of retrograde ejaculation with imipramine. Urology 15:353-55, 1980
473. Stockamp K, Schreiter F, Altwein JE:
a-Adrenergic drugs in retrograde ejaculation. Fertil Steril 25:817-20, 1974
474. Root HF, Pote WH, Frehner H: Sequence of diabetes, retinopathy and nephropathy in one hundred and fifty-five
patients. Arch Intern Med 94:931-41,
1954
475. Knowler WC, Bennett P.H., Ballintine
EJ: Increased incidence of retinopathy
in diabetics with elevated blood pressure. A six-year follow-up study in
Pima Indians. N Engl J Med 302:64550, 1980
476. .American Diabetes Association: The
physician's guide to type II diabetes
(N1DDM): diagnosis and treatment. New

DIABETES CARE, VOLUME 15,

NUMBER 12,

DECEMBER

1992

Vinik and Associates

York, American Diabetes Association,

mellitus. Diabetes. 9:460-64, 1955
1984
479. Hansen RO: Bacteriuria in diabetic and
non-diabetic outpatients. Ada Med
477. Sawyers JS, Todd WA, Kellett HA,
Scand 176:721-30, 1964
Miles RS, Allan PL, Ewing DJ, Clarke
BF: Bacteriuria in diabetic and non- 480. Boshell BR, Hunter EO: Bacteriuria in
diabetes mellitus: a clinical study. AlaJ
diabetic outpatients. Diabetes Care 176:
Med Sci 2:404-409, 1965
721-30,1986
478. Joron GE, DeVries J, Reid G, Matthews 481. Vejlsgaard R: Studies on urinary infecWH, McKay JW: The diagnosis and
tion in diabetics. I. Bacteriuria in patreatment of pyelonephritis in diabetes
tients with diabetes mellitus and in con-

DIABETES CARE, VOLUME 15,

NUMBER 12,

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1992

trol subjects. Acta Med Scand. 179:173

82, 1966
482. Clarke BF, Campbell IW, Ewing DJ:
Prognosis in diabetic autonomic neuropathy. Horm Metab Res Suppl 9:101104, 1980
483. Ewing DJ, Campbell IW, Clarke BF:
The natural history of diabetic autonomic neuropathy. QJ Med 49:95-108,
1980

1975