Download Commentary: Sub-types of diabetes—what`s new

1600
INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
assumed an important research leadership role. His
academic and clinical research leadership was recognized when he became Secretary (Chief Executive) of
the UK Medical Research Council (MRC) in 1949, a
post he held until 1968. Other accolades followed; he
was knighted in 1952, in 1953 he was appointed
Honorary Physician to the Queen and in 1955 he
was elected Fellow of the Royal Society. His biographers for the Royal Society noted that he ‘dominated’ the MRC during his tenure as Secretary, a
tribute to his ‘profound scientific understanding;
acknowledged experience in clinical medicine and research; administrative abilities of the highest
order . . . and enthusiasm’.5
It was not until 1979 that the United States
National Diabetes Data Group sponsored an international consensus meeting to discuss the classification
and diagnosis of diabetes and glucose intolerance.6
This introduced the first universally accepted classification system, distinguishing type 1 (insulin dependent) and type 2 (non-insulin dependent) and thus
effectively institutionalizing Himsworth’s formulation
of insulin resistance.7 These distinctions assisted
in clinical practice and decision making on diets,
although the classification remains an inexact science
with genetic research revealing further subtypes of
type 2 diabetes which could lead to more diverse
and effective therapies.8 Already in the 1930s
Himsworth had appreciated that there were atypical
cases both within the groups and between them, but
the broad typology which he established has proved
enduring and useful in the aetiology and treatment of
diabetes.
Conflict of interest: None declared.
References
1
2
3
4
5
6
7
8
Himsworth HP. Diabetes Mellitus: The differentiation into
insulin-sensitive and insulin-insensitive types. Lancet
1936;227:127–30, Reprinted Int J Epidemiol 1594–8.
Himsworth R. Sir Harold Himsworth. Diabet Med 2011;28:
1438–39.
Lancereaux E. Le diabète maigre: ses symptomes, son
évolution, son prognostic et son traitement; ses rapports
avec les altérations du pancréas. Union Med Paris 1880;29:
161–69.
Himsworth HP. Mechanism of diabetes mellitus. (The
Goulstonian Lectures.) Lancet 1939;234:171–76.
Black D, Gray J. Sir Harold Percival Himsworth, KCB 19
May 1905 – 1 November 1993. Elected F.R.S. 1955. Biogr
Mem Fellows R Soc 1995;41:201–18.
National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose
intolerance. Diabetes 1979;28:1039–57.
Barnett DM, Krall LP. The history of diabetes. In: Kahn R,
Weir GC, King GL, Jacobson AM, Moses AC, Smith RJ
(eds). 14th edn. Boston, MA: Joslin Diabetes Center, 2005.
Smith RJ, Nathan DM, Arslanian SA, Groop L, Rizza RA,
Rotter JI. Individualizing Therapies in Type 2 Diabetes
Mellitus Based on Patient Characteristics: What We
Know and What We Need to Know. J Clin Endocrinol
Metab 2010;95:1566–74.
Published by Oxford University Press on behalf of the International Epidemiological Association
ß The Author 2013; all rights reserved.
International Journal of Epidemiology 2013;42:1600–1602
doi:10.1093/ije/dyt201
Commentary: Sub-types of diabetes—what’s
new and what’s not
Sarah H Wild1* and Christopher D Byrne2
1
Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK 2Nutrition and Metabolism, Faculty of Medicine,
University of Southampton, UK Southampton and 3National Institute for Health Research Biomedical Research Centre, University
Hospital Southampton, UK
*Corresponding author. Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, UK.
E-mail: [email protected]
Accepted
22 July 2013
The article by Himsworth published in 1936 proposed
that diabetes could be differentiated into insulinsensitive and insulin-insensitive types.1 The purpose
of this commentary is to review that concept and to
consider how differentiation of sub-types of diabetes
has evolved since Himsworth’s work was performed.
SUB-TYPES OF DIABETES—WHAT’S NEW AND WHAT’S NOT
Himsworth proposed that, in addition to being
caused by lack of insulin, diabetes could exist because
of inadequate amounts of an ‘unknown factor which
renders the body sensitive to insulin’. He developed
the first test of insulin sensitivity and presented
results of the test in four people. The test involved
injection of five units of insulin and drinking 30
grams of glucose dissolved in water per square
metre of body surface area. People with diabetes
whose blood glucose fell rapidly after insulin injection, in a pattern similar to that observed among
people without diabetes, were identified as ‘insulinsensitive’ and other people, whose blood glucose
levels responded less quickly, were identified as
‘insulin-insensitive’.
Himsworth summarized differences between the
groups in subsequent lectures as follows: ‘On the
whole the sensitive diabetics tend to be younger and
thin and to have a normal blood pressure and normal
arteries, and as a rule their disease is of sudden and
severe onset. The insensitive diabetics, on the other
hand, tend to be elderly and obese and to have hypertension and arteriosclerosis, and in these patients the
onset is insidious’.2 He proposed the following mechanisms for insulin insensitivity: excessive production
of glucose, failure of glucose uptake by the liver and
failure of peripheral glucose uptake. Himsworth
demonstrated failure of peripheral glucose uptake in
the insulin-insensitive group by comparing glucose
levels in capillary and venous blood in a limb after
insulin administration. Direct measurement of hepatic
glucose uptake in humans is still not feasible
although a variety of other measures of insulin sensitivity have been developed (as reviewed by Kim in a
recent tribute to Himsworth3).
Reaven comments on the limited impact that
Himsworth’s seminal work had on clinical teaching
and practice, research and dietary guidelines in subsequent years.4 Following development of an insulin
assay in 1960 it was shown that people with the insulin-insensitive type of diabetes had higher levels of
insulin following an oral glucose challenge than
people without diabetes, and the term ‘insulin resistance’ is now well established. It has become clear that
increasing prevalence of obesity and sedentary lifestyles underlie recent increases in global incidence
of ectopic fat accumulation that result in insulin
resistance and the cluster of associated metabolic
abnormalities including hypertension, dyslipidaemia,
non-alcoholic fatty liver disease (NAFLD) and type 2
diabetes.
In an attempt to standardize diagnostic criteria and
descriptive terms, the World Health Organization
(WHO) published the first widely used classification
of diabetes mellitus in 1980, with a revision in
1985.5,6 Two main types, named insulin-dependent
diabetes mellitus (IDDM) and non insulin-dependent
diabetes mellitus (NIDDM), were identified as well as
malnutrition-related diabetes mellitus (MRDM),
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gestational diabetes and other types of diabetes. In
the 1999 revision of WHO criteria, it was recognized
that the terms IDDM and NIDDM reflect treatment
rather than aetiology and it was recommended that
these terms be replaced with type 1 and type 2 diabetes, essentially re-naming the types that Himsworth
identified as insulin-sensitive and insulin-insensitive,
respectively.7
Subsequent recommendations have focused on diagnostic criteria for type 2 diabetes. These include:
lowering the cutpoint for fasting plasma glucose
level from 7.8 mmol/l (140 mg/dl) to 7.0 mmol/l
(126 mg/dl), between 1985 and 1999 WHO criteria;
using fasting glucose alone (rather than in combination with a 2-h post-oral glucose challenge) as recommended by the American Diabetes Association;
and the recent introduction of glycated haemoglobin
(HbA1c) level as a diagnostic test for diabetes8. These
changes have implications for interpreting secular
trends in diabetes prevalence because the different
criteria identify different sub-groups of individuals,
with the effects differing by age, sex, distribution of
obesity and ethnicity of the population studied. This
issue highlights the challenge of identifying diagnostic cut-points for continuous variables. Similar difficulties exist around the definition of gestational
diabetes.
The boundaries between type 1 and type 2 diabetes
are not always clear. A small proportion of people
with type 2 diabetes are lean, have early pancreatic
beta-cell failure and require insulin treatment relatively early. Associations between genetic risk factors
and type 2 diabetes appear to be stronger for lean
than obese people.9 Insulin resistance may occur
among people with type 1 diabetes,often as a consequence of obesity, to produce ‘double diabetes’.10
People with monogenic diabetes (thought to account
for 1–2% of all cases of diabetes) may be misdiagnosed with type 1 or type 2 diabetes, and identifying
the correct diagnosis can result in better treatment
and improved control of diabetes. For example, activating mutations in the KCNJ11 and ABCC8 genes,
encoding the Kir6.2 and SUR1 subunits of the pancreatic K-ATP channel have been found to cause diabetes that is normally diagnosed in the six months
after birth.11 The finding that these patients secrete
insulin in response to sulphonylurea treatment has
resulted in successful cessation of insulin treatment
and improved glycaemic control in people with this
condition.12 The aetiology of other types of diabetes,
that have been described as intermediate between
type 1 and type 2 diabetes including latent autoimmune diabetes in adults and ketosis-prone diabetes
(possibly related to malnutrition-related diabetes mellitus), remains poorly understood.
In summary, Himsworth’s view that distinguishing
sub-types of diabetes may be useful for providing
advice on dietary and pharmacological treatment has
stood the test of time. The Dose Adjustment for
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Normal Eating programme (http://www.dafne.uk.
com) has been developed to help people with type 1
diabetes adjust their insulin dose to match their
carbohydrate intake, and increasing understanding
of the causes of insulin resistance has informed the
development of treatment options for people with
type 2 diabetes. Lifestyle intervention, including balancing calorie intake with physical activity levels,
remains the cornerstone of primary and secondary
prevention of type 2 diabetes and other consequences
of obesity and ectopic fat storage that affect millions
of people around the world. If epidemiological studies
are not able to distinguish between different types of
diabetes, their findings are more likely to relate to
type 2 diabetes as it forms 90–95% of all diabetes in
most adult populations. Major challenges remain
in understanding the aetiology of type 1 diabetes, in
implementing effective lifestyle changes to prevent
and manage obesity-related conditions and in finding
effective treatments with acceptable levels of side
effects for people who are unable to achieve lifestyle
changes.
2
3
4
5
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8
9
10
Conflict of interest: None declared.
11
References
1
Himsworth HP. Diabetes mellitus: its differentiation into
insulin-sensitive and insulin-insensitive types. Lancet
1936;227:127–30, Reprinted Int J Epidemiol 1594–8.
12
Himsworth HP. The mechanism of diabetes mellitus.
Lancet 1939;234:171–76.
Kim SH. Measurement of insulin action: a tribute to Sir
Harold Himsworth. Diabet Med 2011;28:1487–93.
Reaven G. A toast to Sir Harold Himsworth. Diabet Med
2011;28:1436–37.
World Health Organization. Expert Committee on Diabetes
Mellitus:
Second
Report.
Geneva:
World
Health
Organization, 1980.
World Health Organization. Diabetes Mellitus: Report of a
WHO Study Group. Geneva: World Health Organization,
1985.
World Health Organization Consultation. Definition,
Diagnosis and Classification of Diabetes Mellitus and Its
Complications, Part 1: Diagnosis and Classification of Diabetes
Mellitus. Geneva: World Health Organization, 1999.
World
Health
Organization.
Use
of
Glycated
Haemoglobin(HbA1c) in the Diagnosis of Diabetes Mellitus.
Geneva: World Health Organization, 2011.
Perry JR, Voight BF, Yengo L et al. Stratifying type 2
diabetes cases by BMI identifies genetic risk variants in
LAMA1 and enrichment for risk variants in lean compared to obese cases. PLoS Genet 2012;8:e1002741.
Cleland SJ, Fisher BM, Colhoun HM, Sattar N, Petrie JR.
Insulin resistance in type 1 diabetes: what is ‘double
diabetes’ and what are the risks? Diabetologia 2013;56:
1462–70.
Gloyn AL, Pearson ER, Antcliff JF et al. Activating mutations in the gene encoding the ATP-sensitive potassiumchannel subunit Kir6.2 and permanent neonatal diabetes.
N Engl J Med 2004;350:1838–49.
Pearson ER, Flechtner I, Njolstad PR et al. Switching from
insulin to oral sulfonylureas in patients with diabetes due
to Kir6.2 mutations. N Engl J Med 2006;355:467–77.
Published by Oxford University Press on behalf of the International Epidemiological Association
ß The Author 2013; all rights reserved.
International Journal of Epidemiology 2013;42:1602–1607
doi:10.1093/ije/dyt202
Commentary: The hedgehog and the fox:
Sir Harold Himsworth (1905–93)
Edwin AM Gale
Diabetes and Metabolism, University of Bristol, Learning and Research Building, Southmead Hospital, Bristol BS10 5NB, UK
E-mail: [email protected]
Accepted
28 August 2013
The history of modern knowledge is concerned in
no small degree with man’s attempt to escape
from his previous concepts.
Harold Himsworth1
Citation classics tend to be cited more often than read,
and this has been the fate of the article by Harold
Himsworth published in this issue of the IJE.2
Commentators (with what E.P. Thompson has called
the ‘immense condescension of history’) are quick to