Downloaded from http://pmj.bmj.com/ on December 2, 2015 - Published by group.bmj.
com
PGMJ Online First, published on November 30, 2015 as 10.1136/postgradmedj-2015-133281
1
Diabetes Research Centre,
University of Leicester,
Leicester, UK
2
NIHR Leicester-Loughborough
Diet, Lifestyle and Physical
Activity Biomedical Research
Unit, Leicester, UK
Correspondence to
Dr Francesco Zaccardi,
Diabetes Research Centre,
Leicester General Hospital,
Leicester LE5 4PW, UK;
frazac@fastwebnet.it
Received 31 March 2015
Revised 28 October 2015
Accepted 9 November 2015
To cite: Zaccardi F,
Webb DR, Yates T, et al.
Postgrad Med J Published
Online First: [ please include
Day Month Year]
doi:10.1136/postgradmedj-
2015-133281
Copyright Article author (or their employer) 2015. Produced by BMJ Publishing Group Ltd under licence.
PMJ 90th anniversary review
Pathophysiology of type 1 and type 2 diabetes
mellitus: a 90-year perspective
Francesco Zaccardi,1 David R Webb,1 Thomas Yates,1,2 Melanie J Davies1
ABSTRACT
Diabetes mellitus is a complex metabolic disorder
associated with an increased risk of microvascular and
macrovascular disease; its main clinical characteristic is
hyperglycaemia. The last century has been characterised
by remarkable advances in our understanding of the
mechanisms leading to hyperglycaemia. The central role
of insulin in glucose metabolism regulation was clearly
demonstrated during the early 1920s, when Banting,
Best, Collip and Macleod successfully reduced blood
glucose levels and glycosuria in a patient treated with a
substance puried from bovine pancreata. Later, during
the mid-1930s, clinical observations suggested a
possible distinction between insulin-sensitive and
insulin-insensitive diabetes. Only during the 1950s,
when a reliable measure of circulating insulin was
available, was it possible to translate these clinical
observations into pathophysiological and biochemical
differences, and the terms insulin-dependent (indicating
undetectable insulin levels) and non-insulin-dependent
(normal or high insulin levels) started to emerge. The
next 30 years were characterised by pivotal progress in
the eld of immunology that were instrumental in
demonstrating an immune-mediated loss of insulin-
secreting -cells in subjects with insulin-dependent
diabetes. At the same time, new experimental
techniques allowing measurement of insulin impedance
showed a reduced peripheral effect of insulin in subjects
with non-insulin-dependent diabetes (insulin
resistance). The difference between the two types of
diabetes emerging from decades of observations and
experiments was further formally recognised in 1979,
when the denitions type I and type II diabetes were
introduced to replace the former insulin-dependent and
non-insulin-dependent terms. In the following years,
many studies elucidated the natural history and temporal
contribution of insulin resistance and -cell insulin
secretion in type II diabetes. Furthermore, a central role
for insulin resistance in the development of a cluster of
cardiometabolic alterations (dyslipidaemia, inammation,
high blood pressure) was suggested. Possibly as a
consequence of the secular changes in diabetes risk
factors, in the last 10 years the limitation of a simple
distinction between type I and type II diabetes has
been increasingly recognised, with subjects showing the
coexistence of insulin resistance and immune activation
against -cells. With the advancement of our cellular
and molecular understanding of diabetes, a more
pathophysiological classication that overcomes the
historical and simple glucocentric view could result in a
better patient phenotyping and therapeutic approach.
BACKGROUND: THE BURDEN OF DIABETES
MELLITUS
Diabetes mellitus is a complex metabolic disorder
whose main clinical and diagnostic feature is
Zaccardi F, et al. Postgrad Med J 2015;0:17. doi:10.1136/postgradmedj-2015-133281
hyperglycaemia.1 Diabetes has reached epidemic
proportions, affecting around 387 million people
worldwide. Over the next 20 years, its prevalence
is predicted to double, and more than half-a billion
people will be affected.2 Estimated regional dia-
betes prevalence ranges from 5.1% in Africa to
11.4% in North America and the Caribbean, with
more than 75% of subjects living in low- and
middle-income countries.2 Moreover, the increase
in prevalence is estimated to be greater in develop-
ing areas,3 as many countries adopt Western life-
style habits (sedentary behaviour, lack of physical
activity and energy-dense diet) which are well-
recognised risk factors for type 2 diabetes mellitus
(T2DM).4
Although much progress has been made in the
identication of risk factors associated with dia-
betes, in particular T2DM, its health and socio-
economic impact is increasing, mainly because of
its associated complications.5 Diabetes ( particularly
T2DM) approximately doubles the risk of a wide
range of cardiovascular diseases, including coronary
heart disease and stroke.6 Moreover, T2DM is also
associated with a wide range of non-vascular dis-
eases, including cancer, mental and nervous system
disorders, infections and liver disease.7 Similarly,
type 1 diabetes mellitus (T1DM; 10% of all dia-
betes cases) is associated with an increased risk of
both vascular and non-vascular complications.8 9
Therefore, a better understanding of the mechan-
isms that result in hyperglycaemia could help to
identify potential therapeutic targets to curb dia-
betes and its related complications.
The aim of this review is to summarise historical
developments in our understanding of the patho-
physiology of T1DM and T2DM from epidemio-
logical, clinical and biological studies, describing
the extraordinary progress made in the last century.
PATHOPHYSIOLOGY OF DIABETES MELLITUS
Initial discoveries
Initial discoveries in the pathophysiology of dia-
betes mellitus are intrinsically linked to polyuria,
historically considered to be its main (and diagnos-
tic) characteristic. The term diabetes is derived
from the ancient Greek word diabainen, meaning
go through, to indicate the excessive passing of
urine through the kidney.10 It was not until the
1600s, however, that Willis added the term melli-
tus (sweet) to distinguish this condition from an
excessive production of non-sweet urine (diabetes
insipidus).10 Almost 200 years later (1776),
Dobson demonstrated that the sweet taste of urine
was due to an excess of sugar in the urine and
blood.11
1
 Downloaded from http://pmj.bmj.com/ on December 2, 2015 - Published by group.bmj.com
PMJ 90th anniversary review
Another 100 years were necessary to clarify the pathogenesis
of diabetes mellitus. In 1889, Minkowski and von Mering
found that pancreatectomised dogs developed symptoms of dia-
betes, thus linking diabetes for the rst time to a specic
organ.12 In 1910, Sharpey-Schafer suggested that people with
diabetes were decient in a substance produced in the pancreatic
islets (discovered in 1869 by Langerhans) and called it insulin;
therefore, a link between the pancreas, insulin and diabetes was
starting to emerge and form the basis of the modern under-
standing of the disease. It was only in 1921, however, that a
more precise picture emerged: Banting, Best and Macleod
showed that diabetes in pancreatectomised dogs could be
reversed after the intravenous administration of the islet extrac-
tion from normal canine pancreata.13 Subsequently, Banting,
Best and Collip puried this substance from bovine pancreata,
and the rst patient was successfully treated in 1922, resulting
in a reduction in blood glucose and glycosuria.
The possibility that diabetes may exist in different forms was
hypothesised during the 1920s and 1930s. In 1926, MacLean
suggested a distinction between hepatic glycosuria (uncommon
in the young and characterised by mild glycosuria and low con-
centration of urinary ketone bodies) and true diabetes (a condi-
tion affecting young subjects, with signicant ketonuria and
fatal unless treated with insulin).14 Ten years later, Himsworth,
summarising his previous research, distinguished between
insulin-sensitive and insulin-insensitive diabetes mellitus,15
with the latter more insidious condition characterised by less
severe hyperglycaemia. During the 1950s, a reliable measure-
ment of circulating insulin with a radioimmunoassay technique
allowed a clear distinction between insulin-dependent and
non-insulin-dependent diabetes mellitus,16 and the paradigm
of two pathophysiologically distinct diseases became more and
more evident in the following years.
Type 1 diabetes mellitus
It is now well-recognised that T1DM is an autoimmune disorder
characterised by the destruction of insulin-producing pancreatic
-cells.17 Like many other immune-mediated diseases, T1DM
shows heterogeneity in terms of age of onset, severity of auto-
immune response, and efcacy of therapy. A common distinc-
tion is made between type A (accounting for up to 90% of
overall cases), with a detectable serological autoimmune
Table 1 Key selected events related to diabetes pathophysiology (chronological order)
T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus.
2 Zaccardi F, et al. Postgrad Med J 2015;0:17. doi:10.1136/postgradmedj-2015-133281
response, and type B (or idiopathic), where apparently no
humoral autoimmunity is present.18 This distinction has,
however, not been widely adopted.
Historically, the denition of T1DM as a nosological entity
dates back to 1979,19 when the National Diabetes Data Group
divided diabetes into two major subtypes (table 1). By the
1960s and 1970s, however, a comprehensive picture had
already emerged, following the discovery of inammation
within the pancreatic Langerhans islets (insulitis), the identica-
tion of an association with human leucocyte antigen (HLA)
genes,20 the detection of autoantibodies against islets cells, and
a better method for measuring insulin.16 HLA genes are critical
in regulating the immune response, as they encode cell surface
proteins involved in the antigen presentation and self-tolerance.
Genetically determined variations in the amino acid sequence of
these proteins can therefore alter the repertoire of presented
peptides and result in the loss of self-tolerance.21 These observa-
tions, along with the contemporary knowledge of an association
between HLA and other autoimmune disorders and evidence of
the efcacy of immunosuppressive therapies on T1DM disease
progression,22 23 strongly supported the idea that insulin-
dependent diabetes was an immune-mediated disease involving
the pancreatic islets of Langerhans.
Progress in understanding the pathophysiology of T1DM
cannot be separated from advances in the eld of immunology.
Like the vast majority of autoimmune disorders, the primary
cause of T1DM is still unknown. T1DM is characterised by a
selective, specic involvement of -cells without apparent patho-
logical alterations of other Langerhans cells, such as - (secret-
ing glucagon), - (somatostatin) and PP- ( pancreatic
polypeptide) cells.24 In recently diagnosed T1DM, generally
more than two-thirds of pancreata have no evidence of insulin
at all, around one-fth display insulin to some extent, and some
have no detectable alterations.17 The reason for this heterogen-
eity remains unknown, possibly being related to a true differ-
ence (different pathophysiological entities) or representative of
different stages (or severity) of the same disease.
Both humoral and cellular immunity is involved in T1DM
pathogenesis. T lymphocytes (which mature in the thymus and
play a central role in cell-mediated immunity) are predominant
in islet lesions, with lower concentrations of other immuno-
logical cells, such as macrophages, B lymphocytes and plasma
 Downloaded from http://pmj.bmj.com/ on December 2, 2015 - Published by group.bmj.com

PMJ 90th anniversary review

cells.24 The presence of humoral immunity, on the other hand,

was recognised over 40 years ago, when autoantibodies against
pancreatic islets were detected in subjects with T1DM.25 From
the 1980s, targets of autoantibodies have been discovered, and
several autoantigens are currently widely used in clinical prac-
tice, such as insulin, proinsulin, glutamic acid decarboxylase
(GAD65), glucose 6-phosphatase catalytic subunit-related
protein (G6PC2, also known as IGRP), islet cell antibody (ICA)
and zinc transporter 8 (ZnT8A).26 In genetically predisposed
individuals (eg, rst-degree relatives), autoantibodies can also be
detected months to years before the clinical diagnosis is made.27
A landmark description of the natural history of T1DM was
published in 1986 by Eisenbarth, after reported discoveries in
the 1970s and 1980s (gure 1).28 Although subsequent ndings
have helped to clarify in more detail the role of immunity in
T1DM pathogenesis,17 29 30 these earlier concepts remain
applicable. In predisposed individuals, early-life environmental
triggering factors (infections, nutrition, chemicals) are able to Figure 2 Schematic diagram of type 2 diabetes pathophysiology.
activate self-targeting immune cascades. The initial event,
however, is still unclear. Of note, the presence of detectable auto-
antibodies is not sufcient for the clinical development of Several pivotal pathophysiological studies underpin our
T1DM, as some subjects with serological positivity will never understanding of insulin resistance and secretion in the course
develop T1DM.18 These observations underline the importance of disease onset and progression.3746 Subjects at risk of T2DM
of -cell function and -cell turnover (mass) in the pathogenesis (obese subjects and rst-degree relatives) display an initial state
of insulin deciency.31 In the initial phases, the progressive of insulin resistance compensated by -cell hypersecretion of
destruction of -cells and serological positivity are not associated insulin (hyperinsulinaemia). Such pancreatic functional reserve,
with changes in blood glucose, as a functional pancreatic reserve however, is eventually unable to cope with the required insulin
is sufcient to maintain euglycaemia (gure 1). In the following secretion. Compared with lean euglycaemic subjects, obese
stages, there is further -cell destruction, with a consequent loss euglycaemic people have 30% reduced insulin sensitivity46
of insulin production and a parallel increase in blood glucose and therefore show increased insulin secretion to maintain
concentration. When the majority of -cells are destroyed, overt normal glucose tolerance (euglycaemic hyperinsulinaemia).
diabetes develops. Tight glycaemic control after diagnosis is of Over time, obese euglycaemic subjects experience a further
paramount importance, as near-to-normal glucose has been reduction in insulin sensitivity that is no longer associated with
shown not only to reduce the risk of diabetic complications,32 compensatory hyperinsulinaemia, resulting in an increased
but also to preserve any remaining -cell mass/function.33 blood glucose concentration (hyperglycaemic hyperinsulinae-
mia). By the time diabetes is diagnosed, -cells are no longer
able to secrete enough insulin, with consequent manifestation of
Type 2 diabetes mellitus
overt hyperglycaemia (hyperglycaemic hypoinsulinaemia).46
While in recent years many major risk factors for the emergent
Although the relative contribution of -cell dysfunction and
T2DM epidemic have been identied, the mechanisms linking
insulin resistance can vary, it is generally accepted that abnor-
them to the clinical manifestations of T2DM and its complica-
mal insulin sensitivity precedes the clinical diagnosis of diabetes
tions are intensively investigated (gure 2). The availability of
by up to 15 years.47 The results of these pathophysiological
radioimmunoassays in the 1950s helped differentiate insulin-
studies illustrate the failure of compensatory hyperinsulinaemia
dependent from non-insulin-dependent diabetes, and such dif-
as the hallmark of frank hyperglycaemia. Therefore, along
ferences were formally recognised in the 1979 classication of
with mechanistic studies investigating mechanisms forming the
diabetes by the National Diabetes Data Group in type I (former
basis of insulin resistance, more recent research has also focused
insulin-dependent) and type II (non-insulin-dependent) dia-
on the pathways leading to -cell failure.
betes mellitus.19 It was not until the 1980s and 1990s, with the
Liver and muscles have long been recognised as major contri-
standardisation and evolution of techniques to measure glucose
butors of systemic insulin resistance.37 To ensure constant avail-
disposal by insulin,34 35 that researchers performed independent
ability of a carbohydrate energy source during fasting, the liver
experiments conrming the presence of insulin resistance in
produces glucose from non-glucose substrates (gluconeogen-
maturity-onset diabetes.35 36
esis).48 Several studies have shown increased gluconeogenesis in
subjects with T2DM, which occurs despite a state of hyperinsu-
linaemia, suggesting hepatic insulin resistance as a main deter-
minant of fasting hyperglycaemia.49 50 The reasons behind
reduced hepatic insulin sensitivity are poorly dened, but accu-
mulation of fat within the liver (steatosis) is considered a major
determinant.51 Interestingly, liver steatosis precedes overt
T2DM and is commonly associated with obesity,52 particularly
visceral (android or abdominal) obesity.53 It is now well
accepted that a continuous positive energy balance due to excess
calories and a lack of physical activity leads initially to fat accu-
mulation in the subcutaneous tissue. When this storage capacity
Figure 1 Natural history of type 1 diabetes (adapted from ref 28). is exceeded, fat is diverted to ectopic compartments such as
Zaccardi F, et al. Postgrad Med J 2015;0:17. doi:10.1136/postgradmedj-2015-133281 3
 Downloaded from http://pmj.bmj.com/ on December 2, 2015 - Published by group.bmj.com

PMJ 90th anniversary review

the liver, pancreas, muscles, perivascular, pericardium and values seem to be higher in T2DM subjects, further exacerbating
omentum (spill-over or adipose tissue overow hypothesis).53 hyperglycaemia in a vicious cycle.65 The mechanism possibly
Hepatic and muscle fat accumulation results in impaired insulin- associated with the change in Tm could be the upregulation of
mediated glucose uptake due to intracellular impairment of SGLT2 secondary to hyperglycaemia.66
insulin signalling.37 Of note, muscle insulin resistance has been
shown in lean T2DM,35 suggesting that mechanisms independ-
Maturity-onset diabetes of the young, latent autoimmune
ent of body fat may also be involved in its pathogenesis. Fat
diabetes of adults, and double diabetes
accumulation within the pancreatic islets, on the other hand,
With a better understanding of diabetes pathophysiology, it has
determines -cell dysfunction and increases in plasma glucose
also become clearer that some forms of diabetes do not entirely
which, in turn, reduce insulin response to ingested glucose
fall into type 1 or type 2 categories. The term maturity-onset
(twin cycle hypothesis52).
diabetes of the young (MODY) describes single-gene disorders
As highlighted, defects in pancreatic -cell function are essen-
causing type 2 diabetes-like conditions in younger age groups.67
tial for the manifestation of hyperglycaemia.54 Research per-
These monogenic forms, possibly representing 2% of all dia-
formed in the last few years has attempted to clarify the
betic cases in the UK,68 display an autosomal dominant pattern
mechanisms of -cell failure. In genetically predisposed indivi-
of inheritance of diabetes and are usually diagnosed around
duals,55 56 the increased demand of insulin synthesis and secre-
childhood or adolescence. While there is variability in the
tion eventually results in -cell dysfunction. Yet, among the
natural history, the progression from normal to mild hypergly-
proposed potential mechanisms causing -cell dysfunction
caemia and frank diabetes is generally slow.67 Initial genetic
(including direct effects of glucose and free fatty acids), their
studies on MODY started in the mid 1980s, and several genetic
comparative and chronological role is unknown. It has been sug-
defects have been discovered since then. The two most common
gested that the stressed -cell may stimulate local inammation
conditions are MODY2 (mutation of a glucokinase (GCK) gene)
and modify the balance between - and -cell mass and function
and MODY3 (hepatocyte nuclear factor (HNF)), with the latter
within the Langerhans islets. Of note, insulin exerts negative
characterised by a remarkable response to sulfonylureas (drugs
paracrine (a signal inducing changes in nearby cells) action on
stimulating insulin secretion). Of note, recognised forms of
-cells, thus limiting the secretion of glucagon;57 therefore, lack
MODY are characterised by ineffective insulin production and/
of insulin results in higher levels of glucagon, which further
or release by pancreatic -cells.69
increase blood glucose concentration via hepatic
Latent autoimmune diabetes of adults (LADA), also known as
gluconeogenesis.
slowly progressing insulin-dependent diabetes,70 denes a form
Among the regulators of -cells, a central role for gut hor-
of diabetes characterised by three features: adult age at diagno-
mones has also been discovered over the last two to three
sis, presence of diabetes-associated autoantibodies, and no need
decades. Insulin secretion is greater after glucose ingestion than
for insulin therapy at diagnosis.71 From a pathophysiological
after an intravenous glucose infusion with superimposable
perspective, this form of diabetes can indeed be considered a
glucose excursion (isoglycaemic infusion). This observation sug-
slowly progressive T1DM. Moreover, given the increased preva-
gests the existence of factors that stimulate insulin secretion
lence of obesity and insulin resistance, cases of combined type 1
after glucose ingestion. These factors have been shown to be
diabetes and insulin resistance are increasing, giving rise to the
gut messengers (termed incretins) able to stimulate insulin
denitions of type 1.572 or double diabetes.73 These patients
secretion.58 Two incretins, glucagon-like peptide-1 (GLP-1,
often represent a diagnostic challenge, particularly if some -cell
secreted by L cells located predominantly in the ileum and
insulin is initially preserved.
colon) and gastric inhibitory polypeptide (GIP, secreted by
Diabetes mellitus can also be present in a range of rare
enteroendocrine K cells concentrated in the duodenum and
genetic (eg, Alstrm syndrome, Friedrichs ataxia, Huntingtons
proximal jejunum, also interpreted as glucose-dependent insuli-
disease, congenital lipodystrophy, mitochondrial DNA) and
notropic polypeptide), have been identied as the main hor-
chromosomal (eg, Downs syndrome, Turners syndrome,
mones responsible for this phenomenon. These polypeptides
Klinefelters syndrome) disorders involving multiple organs.74
are secreted after food ingestion and are able to increase
insulin (GLP-1 and GIP) and reduce glucagon (GLP-1) secre-
tion.58 While a major secretory defect in GIP secretion does CURRENT RESEARCH: ROLE OF BROWN ADIPOSE TISSUE
not seem to exist in T2DM, signicantly decreased secretion of AND GUT
GLP-1 has been consistently found in T2DM,59 insulin resist- A great deal of research into the pathophysiology of diabetes and
ance60 and obesity.61 Therefore, after food ingestion, subjects its complications now centres on the biological role of fat tissue.
with T2DM have a blunted GLP-1 response, resulting in lower Compared with white adipose tissue (the main role of which is
postprandial GLP-1 and insulin concentrations and relative energy storage), brown adipose tissue (BAT) is a biologically dis-
hyperglucagonaemia. Further to this, T2DM subjects also show tinct form involved in adaptive thermogenesis to maintain
reduced responsiveness to both GIP and GLP-1, a condition normal body temperature.75 Animal studies have demonstrated
that can be improved by restoring euglycaemia,62 suggesting the importance of BAT in regulating energy and glucose homeo-
that the loss of incretin is secondary to the development of stasis. BAT activation increases energy expenditure and is asso-
hyperglycaemia and not a direct cause of it. ciated with peripheral insulin resistance and glucose levels.76 77
The role of the kidney in blood glucose regulation has long Although further research on BAT is essential, preliminary data
been known.14 About 180 g of glucose is ltered by the glom- suggest BAT to be an attractive therapeutic target.
erulus every day: about 90% is reabsorbed in the proximal The role of the gut in the pathophysiology of diabetes can be
tubule through the sodiumglucose cotransporter 2 (SGLT2) viewed from two different perspectives. Beyond malabsorption
membrane transporter and 10% in the descending tubule and/or anatomical restriction, studies have suggested that several
(SGLT1).63 Reabsorption of ltered glucose increases linearly mechanisms may be involved in weight loss and diabetes control
until the maximal reabsorptive capacity (Tm) is exceeded, which after bariatric surgery.78 Indeed, complex changes in multiple
is 11.0 mmol/L (200 mg/dL) in healthy adults.64 Notably, Tm gut hormones have been shown after bariatric procedures and
4 Zaccardi F, et al. Postgrad Med J 2015;0:17. doi:10.1136/postgradmedj-2015-133281
 Downloaded from http://pmj.bmj.com/ on December 2, 2015 - Published by group.bmj.com

PMJ 90th anniversary review

have been proposed as adjunctive (weight-loss-independent)

mechanisms for short- and long-term positive metabolic Current research questions
effects.79 A better understanding of these physiological adapta-
tions would help to clarify the role of gut hormones in the patho-
Can a better pathophysiological denition of type 2 diabetes
genesis of diabetes, as well as offer novel therapeutic approaches
phenotypes result in a personalised therapy and better
to obesity and insulin resistance.80 Further to this, in the last few
outcomes?
years, a potential role of the gut microbiome (1014 bacteria) in
What is the temporal involvement of the kidney and gut in
energy balance has been demonstrated.81 The gut microbiome
the pathophysiology of type 2 diabetes?
differs between obese and lean subjects,82 and a faecal micro-
Are the natural history and the risk of type 2 diabetes
biome transplantation from lean donors to insulin-resistant sub-
complications related to its different phenotypes?
jects results in benecial metabolic effects.83 These observations
suggest a causal role of gut bacteria (and possibly their products,
such as short-chain fatty acids) in metabolism, and research is
ongoing to disentangle the inter-relationship between bariatric
procedures and changes in gut hormones and microbiome.84 Key references

CONCLUSIONS Banting FG, Best CH, Collip JB, et al. Pancreatic extracts in
Over the last 50 years, many pathophysiological studies have the treatment of diabetes mellitus: preliminary report. 1922.
contributed to a better understanding of diabetes. Available CMAJ 1991;145:12816.
evidence clearly demonstrates that diabetes mellitus is a spec- Himsworth HP. Diabetes mellitus: its differentiation into
trum of disorders characterised by variable degrees of insulin insulin-sensitive and insulin-insensitive types. Lancet
resistance and -cell dysfunction. Factors modifying either or 1936;227:12730.
both lead eventually to hyperglycaemia and appear to have Yalow RS, Berson SA. Immunoassay of endogenous plasma
independent actions. It is therefore possible that, on a back- insulin in man. J Clin Invest 1960;39:115775.
ground of monogenic -cell dysfunction (ie, MODY) or National Diabetes Data Group. Classication and diagnosis
obesity-related insulin resistance, a patient may also develop an of diabetes mellitus and other categories of glucose
autoimmune response against -cells, which is particularly rele- intolerance. Diabetes 1979;28:103957.
vant in the context of the current diagnosis and treatment of the Tabak AG, Jokela M, Akbaraly TN, et al. Trajectories of
disease based on polarised denitions of type 1 and type 2. glycaemia, insulin sensitivity and insulin secretion before
Historical denitions of diabetes may become less applicable diagnosis of type 2 diabetes: an analysis from the Whitehall
in the future as classication of diabetes based on a greater II study. Lancet 2009;373:221521.
pathophysiological understanding emerges.85 Although much
discussed, a personalised treatment of hyperglycaemia has not
yet been widely implemented in clinical practice. It would be
Self assessment questions
reasonable to identify and treat patients on the basis of the
degree of -cell dysfunction and insulin resistance, as a simple
glucocentric therapeutic approach could potentially result in Please answer true (T) or false (F) to the below
no benet (and possibly harm) in some patients.86 Moreover, a
1. Type 1 diabetes mellitus is
clearer denition of diabetes phenotypes would further help us
A. A single-gene disease
to understand the comparative contribution of hyperglycaemia
B. A multifactorial disease
and insulin resistance in the development of diabetes-related
C. An autoimmune disease
vascular and non-vascular complications and help us to design
2. Type 2 diabetes mellitus is associated with an increased risk
future randomised clinical trials in pathophysiologically similar
of
subgroups of patients with T2DM.
A. Only vascular diseases
Lastly, it is worth noting that, from an historical perspective, a
B. Only non-vascular diseases
detailed picture of diabetes pathophysiology has emerged only
C. Both vascular and non-vascular diseases (eg, cancer)
after decades of research. Similarly, the role of emerging organs
3. Insulin secretion is regulated by
(ie, kidney, adipose tissue, gut) can be claried only in independ-
A. Glucose
ent, replicated studies, with the main goal being to establish their
B. GLP-1
temporal involvement in the natural history of diabetes.
C. GIP
4. Insulin resistance is present
A. Only in type 1 diabetes mellitus
Main messages B. Only in type 2 diabetes mellitus
C. Only in subjects with hyperglycaemia
Epidemiological, human and molecular studies in the last 5. HLA genes are associated with
50 years have substantially claried the pathophysiology of A. MODY 3
diabetes mellitus. B. Type 1 diabetes mellitus
The current classication of diabetes reects only in part C. Type 2 diabetes mellitus
recent progress in understanding its pathophysiology.
A more pathophysiological classication could potentially
result in a better patient phenotyping and therapeutic Acknowledgements We acknowledge the support of the following institutes in
approach. this work: the National Institute for Health Research; Collaboration for Leadership in
Applied Health Research and CareEast Midlands (NIHR CLARHC East Midlands);

Zaccardi F, et al. Postgrad Med J 2015;0:17. doi:10.1136/postgradmedj-2015-133281 5

 Downloaded from http://pmj.bmj.com/ on December 2, 2015 - Published by group.bmj.com
PMJ 90th anniversary review
the National Institute for Health Research (NIHR) Diet, Lifestyle & Physical Activity
Biomedical Research Unit based at University Hospitals of Leicester and
Loughborough University. The views expressed are those of the authors and not
necessarily those of the NHS, the NIHR or the Department of Health.
Contributors All authors planned the outline, contributed to gures and tables,
and wrote and approved the manuscript. FZ carried out the literature search.
Funding This study is funded by the National Institute for Health Research.
Competing interests FZ is a clinical research fellow funded with an educational
grant from Sano-Aventis to the University of Leicester. MJD has acted as a
consultant, advisory board member and speaker for Novo Nordisk, Sano-Aventis,
Lilly, Merck Sharp & Dohme, Boehringer Ingelheim, AstraZeneca and Janssen and as
a speaker for Mitsubishi Tanabe Pharma Corporation. She has received grants in
support of investigator and investigator-initiated trials from Novo Nordisk,
Sano-Aventis and Lilly.
Provenance and peer review Commissioned; externally peer reviewed.
REFERENCES
1 Inzucchi SE. Diagnosis of diabetes. N Engl J Med 2013;368:193.
2 IDF. http://www.idf.org/diabetesatlas (accessed 27 Mar 2015).
3 Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for
2010 and 2030. Diabetes Res Clin Pract 2010;87:414.
4 Chan JC, Malik V, Jia W, et al. Diabetes in Asia: epidemiology, risk factors, and
pathophysiology. JAMA 2009;301:212940.
5 ADA. Diagnosis and classication of diabetes mellitus. Diabetes Care 2014;37
(Suppl 1):S8190.
6 Sarwar N, Gao P, Seshasai SR, et al. Diabetes mellitus, fasting blood glucose
concentration, and risk of vascular disease: a collaborative meta-analysis of 102
prospective studies. Lancet 2010;375:221522.
7 Seshasai SR, Kaptoge S, Thompson A, et al. Diabetes mellitus, fasting glucose, and
risk of cause-specic death. N Engl J Med 2011;364:82941.
8 Lind M, Svensson AM, Kosiborod M, et al. Glycemic control and excess mortality in
type 1 diabetes. N Engl J Med 2014;371:197282.
9 Livingstone SJ, Levin D, Looker HC, et al. Estimated life expectancy in a Scottish
cohort with type 1 diabetes, 20082010. JAMA 2015;313:3744.
10 Poretsky L. Principles of diabetes mellitus. US: Springer, 2009.
11 Dobson M. Nature of the urine in diabetes. Medical Observations and Inquiries
1776;5:298310.
12 Von Mehring J, Minkowski O. Diabetes mellitus nach pankreasexstirpation. Arch Exp
Pathol Pharmakol 1890;26:37187.
13 Banting FG, Best CH, Collip JB, et al. Pancreatic extracts in the treatment of
diabetes mellitus: preliminary report. 1922. CMAJ 1991;145:12816.
14 Maclean H. Some observations on diabetes and insulin in general practice. Postgrad
Med J 1926;1:737.
15 Himsworth HP. Diabetes mellitus: its differentiation into insulin-sensitive and
insulin-insensitive types. Lancet 1936;227:12730.
16 Yalow RS, Berson SA. Immunoassay of endogenous plasma insulin in man. J Clin
Invest 1960;39:115775.
17 Atkinson MA, Eisenbarth GS, Michels AW. Type 1 diabetes. Lancet
2014;383:6982.
18 Eisenbarth GS. Update in type 1 diabetes. J Clin Endocrinol Metab
2007;92:24037.
19 [No authors listed]. Classication and diagnosis of diabetes mellitus and other
categories of glucose intolerance. National Diabetes Data Group. Diabetes
1979;28:103957.
20 Singal DP, Blajchman MA. Histocompatibility (HL-A) antigens, lymphocytotoxic
antibodies and tissue antibodies in patients with diabetes mellitus. Diabetes
1973;22:42932.
21 Abbas A, Lichtman AH, Pillai S. Cellular and molecular immunology. 8th edn.
Elsevier Health Sciences, 2015.
22 Eisenbarth GS, Srikanta S, Jackson R, et al. Anti-thymocyte globulin and prednisone
immunotherapy of recent onset type 1 diabetes mellitus. Diabetes Res
1985;2:2716.
23 Stiller CR, Dupre J, Gent M, et al. Effects of cyclosporine immunosuppression in
insulin-dependent diabetes mellitus of recent onset. Science 1984;223:13627.
24 Willcox A, Richardson SJ, Bone AJ, et al. Analysis of islet inammation in human
type 1 diabetes. Clin Exp Immunol 2009;155:17381.
25 Bottazzo GF, Florin-Christensen A, Doniach D. Islet-cell antibodies in diabetes
mellitus with autoimmune polyendocrine deciencies. Lancet 1974;304:127983.
26 Ziegler AG, Nepom GT. Prediction and pathogenesis in type 1 diabetes. Immunity
2010;32:46878.
27 Ziegler AG, Bonifacio E, BABYDIAB-BABYDIET Study Group. Age-related islet
autoantibody incidence in offspring of patients with type 1 diabetes. Diabetologia
2012;55:193743.
28 Eisenbarth GS. Type I diabetes mellitus. A chronic autoimmune disease. N Engl J
Med 1986;314:13608.
6 Zaccardi F, et al. Postgrad Med J 2015;0:17. doi:10.1136/postgradmedj-2015-133281
29 Atkinson MA, Eisenbarth GS. Type 1 diabetes: new perspectives on disease
pathogenesis and treatment. Lancet 2001;358:2219.
30 Herold KC, Vignali DA, Cooke A, et al. Type 1 diabetes: translating mechanistic
observations into effective clinical outcomes. Nat Rev Immunol 2013;13:24356.
31 Chmelova H, Cohrs CM, Chouinard JA, et al. Distinct roles of -cell mass and
function during type 1 diabetes onset and remission. Diabetes 2015;64:214860.
[Epub].
32 Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and
cardiovascular disease in patients with type 1 diabetes. N Engl J Med
2005;353:264353.
33 Picardi A, Visalli N, Lauria A, et al. Metabolic factors affecting residual beta cell
function assessed by C-peptide secretion in patients with newly diagnosed type 1
diabetes. Horm Metab Res 2006;38:66872.
34 Shen SW, Reaven GM, Farquhar JW. Comparison of impedance to insulin-mediated
glucose uptake in normal subjects and in subjects with latent diabetes. J Clin Invest
1970;49:215160.
35 DeFronzo R, Deibert D, Hendler R, et al. Insulin sensitivity and insulin binding to
monocytes in maturity-onset diabetes. J Clin Invest 1979;63:93946.
36 Reaven GM. Insulin resistance in noninsulin-dependent diabetes mellitus. Does it
exist and can it be measured? Am J Med 1983;74:317.
37 DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin North Am
2004;88:787835, ix.
38 Saad MF, Knowler WC, Pettitt DJ, et al. Sequential changes in serum insulin
concentration during development of non-insulin-dependent diabetes. Lancet
1989;333:13569.
39 Lillioja S, Mott DM, Howard BV, et al. Impaired glucose tolerance as a disorder of
insulin action. Longitudinal and cross-sectional studies in Pima Indians. N Engl J
Med 1988;318:121725.
40 Warram JH, Martin BC, Krolewski AS, et al. Slow glucose removal rate and
hyperinsulinemia precede the development of type II diabetes in the offspring of
diabetic parents. Ann Intern Med 1990;113:90915.
41 Martin BC, Warram JH, Krolewski AS, et al. Role of glucose and insulin resistance in
development of type 2 diabetes mellitus: results of a 25-year follow-up study.
Lancet 1992;340:9259.
42 Saad MF, Knowler WC, Pettitt DJ, et al. The natural history of impaired glucose
tolerance in the Pima Indians. N Engl J Med 1988;319:15006.
43 Lillioja S, Mott DM, Spraul M, et al. Insulin resistance and insulin secretory
dysfunction as precursors of non-insulin-dependent diabetes mellitus. Prospective
studies of Pima Indians. N Engl J Med 1993;329:198892.
44 Haffner SM, Miettinen H, Gaskill SP, et al. Decreased insulin secretion and increased
insulin resistance are independently related to the 7-year risk of NIDDM in
Mexican-Americans. Diabetes 1995;44:138691.
45 Sicree RA, Zimmet PZ, King HO, et al. Plasma insulin response among Nauruans.
Prediction of deterioration in glucose tolerance over 6 yr. Diabetes
1987;36:17986.
46 Jallut D, Golay A, Munger R, et al. Impaired glucose tolerance and diabetes in
obesity: a 6-year follow-up study of glucose metabolism. Metabolism
1990;39:106875.
47 Tabk AG, Jokela M, Akbaraly TN, et al. Trajectories of glycaemia, insulin
sensitivity, and insulin secretion before diagnosis of type 2 diabetes: an analysis
from the Whitehall II study. Lancet 2009;373:221521.
48 Pilkis SJ, Granner DK. Molecular physiology of the regulation of hepatic
gluconeogenesis and glycolysis. Annu Rev Physiol 1992;54:885909.
49 DeFronzo RA. Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion
responsible for NIDDM. Diabetes 1988;37:66787.
50 DeFronzo RA, Ferrannini E, Simonson DC. Fasting hyperglycemia in
non-insulin-dependent diabetes mellitus: contributions of excessive hepatic glucose
production and impaired tissue glucose uptake. Metabolism 1989;38:38795.
51 Birkenfeld AL, Shulman GI. Nonalcoholic fatty liver disease, hepatic insulin
resistance, and type 2 diabetes. Hepatology 2014;59:71323.
52 Taylor R. Pathogenesis of type 2 diabetes: tracing the reverse route from cure to
cause. Diabetologia 2008;51:17819.
53 Sattar N, Gill JM. Type 2 diabetes as a disease of ectopic fat? BMC Med
2014;12:123.
54 Kahn SE, Prigeon RL, McCulloch DK, et al. Quantication of the relationship
between insulin sensitivity and beta-cell function in human subjects. Evidence for a
hyperbolic function. Diabetes 1993;42:166372.
55 Ahlqvist E, Ahluwalia TS, Groop L. Genetics of type 2 diabetes. Clin Chem
2011;57:24154.
56 Halban PA, Polonsky KS, Bowden DW, et al. -cell failure in type 2 diabetes:
postulated mechanisms and prospects for prevention and treatment. Diabetes Care
2014;37:17518.
57 Xu E, Kumar M, Zhang Y, et al. Intra-islet insulin suppresses glucagon release via
GABA-GABAA receptor system. Cell Metab 2006;3:4758.
58 Drucker DJ. The biology of incretin hormones. Cell Metab 2006;3:15365.
59 Holst JJ, Knop FK, Vilsbll T, et al. Loss of incretin effect is a specic, important,
and early characteristic of type 2 diabetes. Diabetes Care. 2011;34(Suppl 2):
S2517.
 Downloaded from http://pmj.bmj.com/ on December 2, 2015 - Published by group.bmj.com

PMJ 90th anniversary review

60 Rask E, Olsson T, Soderberg S, et al. Impaired incretin response after a mixed meal 76 Sidossis L, Kajimura S. Brown and beige fat in humans: thermogenic
is associated with insulin resistance in nondiabetic men. Diabetes Care adipocytes that control energy and glucose homeostasis. J Clin Invest
2001;24:16405. 2015;125:47886.
61 Muscelli E, Mari A, Casolaro A, et al. Separate impact of obesity and glucose 77 Lee P, Greeneld JR, Ho KK, et al. A critical appraisal of the prevalence and
tolerance on the incretin effect in normal subjects and type 2 diabetic patients. metabolic signicance of brown adipose tissue in adult humans. Am J Physiol
Diabetes 2008;57:13408. Endocrinol Metab 2010;299:E6016.
62 Hjberg PV, Vilsbll T, Rabl R, et al. Four weeks of near-normalisation of blood 78 Sandoval D. Bariatric surgeries: beyond restriction and malabsorption. Int J Obesity
glucose improves the insulin response to glucagon-like peptide-1 and (Lond) 2011;35(Suppl 3):S459.
glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes. 79 Papamargaritis D, Panteliou E, Miras AD, et al. Mechanisms of weight loss,
Diabetologia 2009;52:199207. diabetes control and changes in food choices after gastrointestinal surgery. Curr
63 Abdul-Ghani MA, DeFronzo RA. Inhibition of renal glucose reabsorption: a novel Atheroscler Rep 2012;14:61623.
strategy for achieving glucose control in type 2 diabetes mellitus. Endocr Pract 80 Miras AD, le Roux CW. Can medical therapy mimic the clinical efcacy or
2008;14:78290. physiological effects of bariatric surgery?. International journal of obesity
64 Hasan FM, Alsahli M, Gerich JE. SGLT2 inhibitors in the treatment of type 2 2014;38:32533.
diabetes. Diabetes Res Clin Pract 2014;104:297322. 81 Hartstra AV, Bouter KE, Bckhed F, et al. Insights into the role of the microbiome in
65 Farber SJ, Berger EY, Earle DP. Effect of diabetes and insulin of the maximum obesity and type 2 diabetes. Diabetes Care 2015;38:15965.
capacity of the renal tubules to reabsorb glucose. J Clin Invest 1951;30:1259. 82 Turnbaugh PJ, Ley RE, Mahowald MA, et al. An obesity-associated gut microbiome
66 Rahmoune H, Thompson PW, Ward JM, et al. Glucose transporters in human renal with increased capacity for energy harvest. Nature 2006;444:102731.
proximal tubular cells isolated from the urine of patients with non-insulin-dependent 83 Vrieze A, Van Nood E, Holleman F, et al. Transfer of intestinal microbiota from lean
diabetes. Diabetes 2005;54:342734. donors increases insulin sensitivity in individuals with metabolic syndrome.
67 Fajans SS, Bell GI. MODY: history, genetics, pathophysiology, and clinical decision Gastroenterology 2012;143:91316.e7.
making. Diabetes Care 2011;34:187884. 84 Aron-Wisnewsky J, Dor J, Clement K. The importance of the gut microbiota after
68 National Diabetes Audit201112. http://www.hscic.gov.uk/searchcatalogue? bariatric surgery. Nat Rev Gastroenterol Hepatol 2012;9:5908.
productid=13129&q=%22National+diabetes+audit% 85 Maldonado M, Hampe CS, Gaur LK, et al. Ketosis-prone diabetes: dissection of a
22&sort=Relevance&size=10&page=1#top. Last access 27 March 2015. heterogeneous syndrome using an immunogenetic and beta-cell functional
69 Thanabalasingham G, Owen KR. Diagnosis and management of maturity onset classication, prospective analysis, and clinical outcomes. J Clin Endocrinol Metab
diabetes of the young (MODY). BMJ 2011;343:d6044. 2003;88:50908.
70 Kobayashi T, Tamemoto K, Nakanishi K, et al. Immunogenetic and clinical 86 Nolan CJ, Ruderman NB, Kahn SE, et al. Insulin resistance as a physiological
characterization of slowly progressive IDDM. Diabetes Care 1993;16:7808. defense against metabolic stress: implications for the management of subsets of
71 Leslie RD, Williams R, Pozzilli P. Clinical review: Type 1 diabetes and latent type 2 diabetes. Diabetes 2015;64:67386.
autoimmune diabetes in adults: one end of the rainbow. J Clin Endocrinol Metab
2006;91:16549.
72 Naik RG, Palmer JP. Latent autoimmune diabetes in adults (LADA). Rev Endocr
Metab Disord 2003;4:23341.
Answers
73 Pozzilli P, Guglielmi C, Caprio S, et al. Obesity, autoimmunity, and double diabetes
in youth. Diabetes Care 2011;34(Suppl 2):S16670.
74 Schmidt F, Kapellen TM, Wiegand S, et al. Diabetes mellitus in children and
1. A (F); B (T); C (T).
adolescents with genetic syndromes. Exp Clin Endocrinol Diabetes 2. A (F); B (F); C (T).
2012;120:57985. 3. A (T); B (T); C (T).
75 Sacks H, Symonds ME. Anatomical locations of human brown adipose tissue: 4. A (F); B (F); C (F).
functional relevance and implications in obesity and type 2 diabetes. Diabetes
5. A (F); B (T); C (F).
2013;62:178390.

Zaccardi F, et al. Postgrad Med J 2015;0:17. doi:10.1136/postgradmedj-2015-133281 7

 Downloaded from http://pmj.bmj.com/ on December 2, 2015 - Published by group.bmj.com

Pathophysiology of type 1 and type 2

diabetes mellitus: a 90-year perspective
Francesco Zaccardi, David R Webb, Thomas Yates and Melanie J Davies

Postgrad Med J published online November 30, 2015

Updated information and services can be found at:

http://pmj.bmj.com/content/early/2015/11/30/postgradmedj-2015-133
281

These include:

References This article cites 82 articles, 24 of which you can access for free at:
http://pmj.bmj.com/content/early/2015/11/30/postgradmedj-2015-133
281#BIBL
Email alerting Receive free email alerts when new articles cite this article. Sign up in the
service box at the top right corner of the online article.

Topic Articles on similar topics can be found in the following collections

Collections Diabetes (125)
Metabolic disorders (196)
Hypertension (147)
Immunology (including allergy) (358)

Notes

To request permissions go to:

http://group.bmj.com/group/rights-licensing/permissions

To order reprints go to:

http://journals.bmj.com/cgi/reprintform

To subscribe to BMJ go to:

http://group.bmj.com/subscribe/