Diabetes

Review article
Genomic Medicine
W. Gregory Feero, M.D., Ph.D., and Alan E. Guttmacher, M.D., Editors

Genomics, Type 2 Diabetes, and Obesity
Mark I. McCarthy, M.D. ype 2 diabetes, though poorly understood, is known to be a disease characterized by an inadequate beta-cell response to the progressive insulin resistance that typically accompanies advancing age, inactivity, and weight gain.1 Thedisease accounts for substantial morbidity and mortality from adverse effects on cardiovascular risk and disease-specific complications such as blindness and renal failure.2 The increasing global prevalence of type 2 diabetes is tied to rising rates of obesity2 — in part a consequence of social trends toward higher energy intake and reduced energy expenditure. However, the mechanisms thatunderlie individual differences in the predisposition to obesity remain obscure. Failure to understand the pathophysiology of diseases such as type 2 diabetes and obesity frustrates efforts to develop improved therapeutic and preventive strategies. The identification of DNA variants influencing disease predisposition will, it is hoped, deliver clues to the processes involved in disease pathogenesis. Thiswould not only spur translational innovation but also provide opportunities for personalized medicine through stratification according to an individual person’s risk and more precise classification of the disease subtype. In this article, I consider the extent to which these objectives have been realized.

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From the Oxford Centre for Diabetes, Endocrinology and Metabolism; the OxfordNational Institute of Health Research Biomedical Research Centre; and the Wellcome Trust Centre for Human Genetics, University of Oxford — all in Oxford, United Kingdom. Address reprint requests to Dr. McCarthy at the Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Oxford OX3 7LJ, United Kingdom. N Engl J Med 2010;363:2339-50.
Copyright © 2010 Massachusetts MedicalSociety.

Disc ov er y of Suscep t ibil i t y Gene s
For type 2 diabetes and obesity, the discovery of causal genes (Fig. 1 and 2) has followed three main waves. The first wave consisted of family-based linkage analyses (see the Glossary) and focused candidate-gene studies. These proved effective in identifying genes responsible for extreme forms of early-onset disease segregating as single-gene(mendelian) disorders. Genes underlying several distinct, familial forms of nonautoimmune diabetes — including maturity-onset diabetes of the young, mitochondrial diabetes with deafness, and neonatal diabetes — were characterized (see the review by Waterfield and Gloyn3). Similar approaches revealed mutations in genes responsible for rare forms of severe childhood obesity, including the genesencoding leptin, the leptin receptor, and proopiomelanocortin (see the review by O’Rahilly4). These discoveries have provided insights into processes critical for the maintenance of normal glucose homeostasis and energy balance and clues to the inner workings of the pancreatic beta cell and hypothalamus. For many families, this information has led to improved diagnostic and therapeutic options(described in more detail below). Attempts to apply similar approaches to families in which either common forms of diabetes or obesity is segregating have proved to be largely unrewarding,5 and the second wave of discovery involved a switch to tests of association. Although intrinsically more powerful than linkage analysis, association analysis suffers from the disadvantage that the signal can be detectedonly if one examines
n engl j med 363;24 nejm.org december 9, 2010

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The New England Journal of Medicine Downloaded from nejm.org on January 4, 2011. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved.

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