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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), 1601 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 1602 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY 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 6 7 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