Comment

in older adults because the absolute risks are so high;

national data indicate that these outcomes are hardly
rare: among American adults aged 60 years or older with
diabetes during the past decade, more than two-thirds
had mobility limitations, 16% had IADL limitations and
9% had ADL limitations,8 and incidence of new disability
ranges from 2% to 10% per year depending on the type
of disability, showing the almost ubiquitous nature of
functional decline with ageing.9
There are still several decits of the evidence base
related to diabetes and disability that could aect
prevention strategies. First, what are the dominant
mechanisms leading to functional decline, and to what
extent are they explained by vascular complications as
opposed to aetiological processes leading to diabetes,
such as insulin resistance, changes in muscle fat and
function, inammation, and hyperglycemia itself?
Second, do recommended therapeutic approaches such
as maintenance of glycaemic and cardiovascular disease
risk factor targets make a dierence? Third, in view of
how common disability is for older adults, should an
association in the opposite direction also be explored,
wherein the disability-associated disuse exacerbates
metabolic control in at-risk people, in turn increasing
diabetes incidence? Finally, Wong and colleagues
understandably focused on old age (most studies
meta-analysed had studied populations with mean
age of more than 65 years), and their literature search
exposed the scarcity of any population data outside of
high-income countries. However, diabetes often causes
more relative damage in middle age than in older age
(ie, relative to their same-aged, non-diabetic peers); the
same might be true for disability. In view of the fact that
the greatest increase in diabetes cases in low-income
and middle-income countries are expected in middleaged adults,10 and that a large prevalence of disability

could have damaging health and economic implications,

more thorough examination of function across the full
age spectrum of adults is also needed. Progress in the
reduction of diabetes-related complications globally will
ultimately benet from unied targets; more thorough
surveillance of diabetes-related disability might be a
good place to start.
Edward W Gregg
Division of Diabetes Translation, National Center for Chronic
Disease Prevention and Health Promotion, Centers for Disease
Control and Prevention, Atlanta, GA 30341, USA
edg7@cdc.gov
The ndings and conclusions in this report are mine and do not necessarily
represent the ocial positions of the Centers for Disease Control and Prevention.
I declare that I have no conicts of interest.
1

7
8

9
10

Lind M, Garcia-Rodriguez LA, Booth GL, et al. Mortality trends in patients

with and without diabetes in Ontario, Canada and the UK from 1996 to
2009: a population-based study. Diabetologia 2013; published online
June 22. DOI:10.1007/s00125-013-2949-2.
Wong E, Backholer K, Gearon E, et al. Diabetes and risk of physical disability
in adults: a systematic review and meta-analysis. Lancet Diabetes Endocrinol
2013; published online July 24. http://dx.doi.org/10.1016/S22138587(13)70046-9.
Statistics NCHS. Diabetes reported in interviews. United States July
19571959. Health Statistics from the US National Health Survey:
Series B-No 21 1960. http://www.cdc.gov/nchs/products/public_health.
htm (accessed July 17, 2013).
Lu FP, Lin KP, Kuo HK. Diabetes and the risk of multi-system aging
phenotypes: a systematic review and meta-analysis. PloS one 2009;
4: e4144.
Cheng YJ, Imperatore G, Geiss LS, et al. Secular changes in the age-specic
prevalence of diabetes among US adults: 19882010. Diabetes care 2013;
published online May 1. DOI: 10.2337/dc12-2074.
Ismail-Beigi F, Moghissi E, Tiktin M, Hirsch IB, Inzucchi SE, Genuth S.
Individualizing glycemic targets in type 2 diabetes mellitus: implications of
recent clinical trials. Ann Intern Med 2011; 154: 55459.
Rejeski WJ, Ip EH, Bertoni AG, et al. Lifestyle change and mobility in obese
adults with type 2 diabetes. NEJM 2012; 366: 120917.
Prevention CfDCa. Health status and disability: data and trends; national
diabetes surveillance system. http://wwwcdcgov/diabetes/statistics/
health_status_nationalhtm 2013 (accessed July 17, 2013).
Gregg EW, Mangione CM, Cauley JA, et al. Diabetes and incidence of
functional disability in older women. Diabetes care 2002; 25: 6167.
Whiting DR, Guariguata L, Weil C, Shaw J. IDF diabetes atlas: global
estimates of the prevalence of diabetes for 2011 and 2030.
Diabetes Res Clin Pract 2011; 94: 31121.

The nuclear option for insulinomas

Published Online
July 25, 2013
http://dx.doi.org/10.1016/
S2213-8587(13)70060-3
See Articles page 115

82

Although insulinomas are rare tumours, they have

fascinated clinicians for many years because of the
variety in clinical presentation, close association
between symptoms and biochemistry, and striking
response to surgical cure. In a patient who is otherwise
healthy, and in the absence of a history of diabetes
mellitus, intermittent hypoglycaemia is usually

attributable to inappropriate insulin activity.1 If other

causes can be excludedwhich is not always easy if,
for example, patients are knowingly injecting insulin or
taking drugs that stimulate insulin releaseinsulinoma
should be seriously considered as a diagnosis.
Diagnosis can be proven by conrmed hypoglycaemia
in the presence of inappropriate insulin secretion;
www.thelancet.com/diabetes-endocrinology Vol 1 October 2013

Comment

however, threshold criteria for measurements of

glucose and insulin are somewhat controversial. Recent
guidelines suggest that blood glucose concentrations
should be lower than 3 mmol/L to be regarded as
hypoglycaemia,1 but at the Churchill Hospital in Oxford,
UK, we noted that this cuto produced too many false
positives and have reverted to a stricter threshold
of 22 mmol/L. Equally, the inappropriate level of
insulin in the presence of hypoglycaemia has been set
at 3 mIU/L, but because insulin assays have become
more specic, this crucial concentration of insulin
has decreased. Indeed, we have reported a conrmed
insulinoma in a patient with an insulin concentration
of 27 mIU/L.2 As in other areas of endocrinology,
improved assays have led to more dicult diagnostic
decisions. However, a C-peptide concentration of more
than 200 pmol/L is a useful and potentially robust
determinant of inappropriate insulin secretion.1
After the diagnosis of insulinoma has been made,
localisation of the tumour is the biggest challenge. Most
tumours are benign and small, with almost all less than
2 cm in maximum diameter, so identication can be
problematic. Previously, surgeons would operate and
trust that they could feel the tumour by direct palpation,
but nowadays this technique is rarely practised (although
intraoperative ultrasound is still used). CT scanning
has good resolution but the dierence in tissue density
might not allow clear discrimination of the tumour. We
reported that MRI was the most sensitive discriminatory
imaging technique, identifying about 75% of tumours,
and this sensitivity might be improved with diusionweighted imaging.3 Other groups have emphasised the
role of endoscopic ultrasound.4 Intra-arterial injection
of calcium with measurement of hepatic vein insulin is
often used, but is invasive and only regionalises rather
than localises the tumour; however, it can help conrm
an anatomically identied abnormality.35 Thus, a need
remains for precise localisation of these tumours.
Nuclear medicine has been suggested to be useful in
this context because it depends on functional aspects
rather than simple anatomical size, but somatostatin
scintigraphy and F-uorodeoxyglucose (F-FDG) PET
have not proved useful for these benign tumours.
In The Lancet Diabetes & Endocrinology, Emanuel Christ
and colleagues6 ingeniously speculated that because
most insulin cells contain receptors for incretins
specically the glucagon-like peptide-1 receptor
www.thelancet.com/diabetes-endocrinology Vol 1 October 2013

(GLP-1R)injection of radiolabelled exendin-4, a GLP1R agonist, might identify these tumours where other
techniques have failed. Following on from an initial
pilot study7 showing the feasibility of this technique,
the group now report on 30 patients who were referred
for exendin-4 scanning in centres in Switzerland,
Germany, and the UK. All patients had either no lesion
or only a suspicion of one on CT or MRI scanning,
to exclude patients with evidence of malignant
insulinoma. Christ and colleagues were able to report
on 25 patients who had histological conrmation
of insulinoma after surgery; of these, 23 had both
CT/MRI and In-DTPA-exendin-4 scanning.6 CT/MRI
correctly identied 47% (95% CI 2768) of insulinomas
in this study and endoscopic ultrasound correctly
diagnosed seven of nine patients assessed using this
technique. In-DTPA-exendin-4 scanning was 95%
(75100) sensitive, and was the only modality to
correctly identify the tumour in all ten instances of
histologically conrmed insulinoma where the other
imaging was negative, although there were four false
positives. Patients had a mean fall in blood glucose
concentrations of 13 mmol/L (IQR 0821) during
the study so glucose infusions are required with the
technique. Notably, the investigators used a dierent
chelating agent, DPTA, in this study than in previous
studies,7 which might cause fewer side eects (such as
nausea and hypoglycaemia).
The radiotracer technique seems to be less eective
for malignant tumours than benign tumours
(radiolabelled octreotide might be more useful) and is
not yet commercially available.8 However, it might allow
for the identication of tumours not otherwise readily
visualised, and should decrease the number of blind
laparotomies, decreasing surgical morbidity, and could
also allow for an increased rate of laparoscopic removal.
Furthermore, some 510% of these tumours are a
manifestation of multiple endocrine neoplasia type 1
(MEN1), in which multiple lesions frequently occur in the
pancreas and identication of insulinomas is dicult. In
Christ and colleagues study, two patients had MEN1
and their insulinomas were identied and successfully
removed after In-DTPA-exendin-4 scanning.
A few points warrant emphasis. All patients in the
study were selected for inclusion and had uncertain
imaging, and at some point a direct comparison against
optimum MRI and possibly endoscopic ultrasound and
83

Comment

calcium-stimulated venous catheterisation should be

done. At the moment, the new radiotracer technique
is probably best reserved for those cases in which
conventional localisation techniques have not worked.
In time, PET isotopes might become available that are
more sensitive and can reduce scan times (although
whether this would work well for the pancreas is
unknown). Endocrinologists should nevertheless regard
the nuclear technique as oering great potential benet
to our patients in the future.
Ashley Grossman
Churchill Hospital, University of Oxford, Oxford OX3 7LE, UK
ashley.grossman@ocdem.ox.ac.uk
I declare that I have no conicts of interest.
1

7
8

Coelho C, Druce MR, Grossman AB. Diagnosis of insulinoma in a patient

with hypoglycemia without obvious hyperinsulinemia. Nat Rev Endocrinol
2009; 5: 62831.
Druce MR, Muthuppalaniappan VM, OLeary B, et al. Diagnosis and
localisation of insulinoma: the value of modern magnetic resonance
imaging in conjunction with calcium stimulation catheterisation.
Eur J Endocrinol 2010; 162: 97178.
Morganstein DL, Lewis DH, Jackson J, et al. The role of arterial stimulation
and simultaneous venous sampling in addition to cross-sectional imaging
for localisation of biochemically proven insulinoma. Eur Radiol 2009;
19: 246773.
Guettier JM, Kam A, Chang R, et al. Localization of insulinomas to regions
of the pancreas by intraarterial calcium stimulation: the NIH experience.
J Clinical Endocrinol Metab 2009; 94: 107480.
Christ E, Wild D, Ederer S, et al. Glucagon-like peptide-1 receptor imaging
for the localisation of insulinomas: a prospective multicentre imaging
study. Lancet Diabetes Endocrinol 2013; published online July 25. http://dx.
doi.org/10.1016/S2213-8587(13)70049-4.
Christ E, Wild D, Forrer F, et al. Glucagon-like peptide-1 receptor imaging
for localization of insulinomas. J Clin Endocrinol Metab 2009; 94: 4398405.
Wild D, Christ E, Caplin ME, et al. Glucagon-like peptide-1 versus
somatostatin receptor targeting reveals 2 distinct forms of malignant
insulinomas. J Nucl Med 2011; 52: 107378.

Cryer PE, Axelrod L, Grossman AB, et al. Evaluation and management of

adult hypoglycemic disorders: an Endocrine Society Clinical Practice
Guideline. J Clin Endocrinol Metab 2009; 94: 70928.

BSIP, Villareal/Science Photo Library

Identifying post-partum diabetes after gestational diabetes

mellitus: the right test

Published Online
June 28, 2013
http://dx.doi.org/10.1016/
S2213-8587(13)70044-5

84

Post-partum glucose testing is recommended for

women who had gestational diabetes mellitus
during pregnancy to identify those with persistent
glucose intolerance. Guidelines from several medical
organisations disagree about which glucose test should
be used and when (table).
Traditionally, glucose testing in women who had
gestational diabetes is done 6 weeks post partum,
because of the coincident health-care visit and,
theoretically, to allow the temporary increases in
glucose during pregnancy to return to normal. However,
Lawrence and colleagues1 reported that fasting plasma
glucose (FPG) and postprandial glucose (measured
by a 75 g, 2 h oral glucose tolerance test [OGTT])
concentrations assessed before 6 weeks are not higher
than those obtained 612 weeks post partum, suggesting
that earlier testing would not lead to falsely increased
measurements. After the rst measurement, testing is
recommended from annually to every 3 years (table).
Although few studies have compared the benets of
testing every year or every 3 years, mathematical models
suggest that, if FPG is measured, annual testing might
yield the lowest cost per case, whereas if OGTT is used,
testing every 3 years would have the lowest cost.2

The HbA1c test can identify individuals at risk for

future diabetes and diabetes complications, is easily
done, and has little intra-individual variation in people
who have not recently given birth.3 Additionally,
HbA1c concentration is not known to be aected by
breastfeeding during the actual blood draw, unlike
fasting or postprandial glucose.4 However, because
HbA1c concentrations 6 weeks post partum could be
aected by perinatal haemoglobin shifts and prenatal
treatments, HbA1c measured post partum correlates
weakly with glucose concentrations.5 Therefore, the
American Diabetes Association has recommended that
HbA1c should not be used as a measure of blood glucose
concentration at the rst post-partum visit (table).3
Whether or not it is used at subsequent visits was not
addressed in the guidelines,3 because data for several
years after pregnancy are scarce. Notably, measurement
of HbA1c in addition to FPG does not increase sensitivity
or specicity 1 year post partum.6
Thus, the primary choice for post-partum glucose
testing should be either FPG measurements or
the OGTT. The postprandial glucose test identies
a dierent population of women with glucose
dysregulation from the FPG test,7 and therefore the
www.thelancet.com/diabetes-endocrinology Vol 1 October 2013