Type 2 Diabetes Tied to Obesity, but Predisposition to Obesity Poorly Understood

Jacquelyn K. Beals, PhD

December 08, 2010

December 8, 2010 — Attempts to find more effective therapeutic and preventive approaches to type 2 diabetes and obesity have been frustrated by inadequate understanding of the pathology. However, genetic variants associated with risk may provide insight into how these diseases develop, according to a review article published December 9 in the New England Journal of Medicine.

The article, by Mark I. McCarthy, MD, professor of diabetes, Oxford Centre for Diabetes, Endocrinology and Metabolism; the Oxford National Institute of Health Research Biomedical Research Centre; and the Wellcome Trust Centre for Human Genetics, University of Oxford, in the United Kingdom, describes genetic research on diabetes and obesity during the past decade.

Initial studies used family-based linkage analyses to identify genes causing familial forms and early-onset diabetes inherited as single-gene disorders. For severe childhood obesity, identifying the genes encoding leptin and the leptin receptor increased our understanding of energy balance, glucose homeostasis, and functions of pancreatic beta cells and the hypothalamus.

However, more powerful association studies were required to elucidate common forms of these diseases. Several genetic variants identified have a "modest" effect on susceptibility to type 2 diabetes — among these are KCNJ11 and PPARG — and 2% to 3% of severe obesity was explained by variants of MC4R.

Although these studies focused on candidate genes, the newest research approaches involve unbiased investigation of links between genetic variants and diseases. These large-scale investigations found the association between type 2 diabetes and TCF7L2 variants, with the encoded protein affecting the function of pancreatic islets.

Since 2007, genomewide association studies have demonstrated that variants in 6 additional genes are associated with type 2 diabetes. In most cases, the allele conferring susceptibility increases diabetes risk 15% to 20%. At this time, variants of about 40 genes have been associated with type 2 diabetes risk.

The story is similar for genetic variants affecting the risk for obesity. To date, genomewide association studies have found around 30 genetic loci whose variants influence obesity risk and body mass index (BMI). FTO exerts the dominant effect, but variants in loci near NEGR1, SH2B1, and BDNF are also associated with obesity. Interestingly, these 3 genes are also involved in neural function, which supports the role of the hypothalamus in obesity risk.

Little Influence on Clinical Management

Although studies have identified 30 or 40 loci associated with obesity and type 2 diabetes, respectively, this information has little influence on clinical management of diabetes or obesity.

Dr. McCarthy points to several reasons for this: the modest effect size of the variants, the challenge of determining molecular effects of "noncoding" variants (ie, variants that affect gene regulation rather than amino acid sequence of a protein), and the difficulty of telling which transcript(s) within a locus mediate the effects on disease risk.

Several areas must be developed to realize the potential influence of genetic information on disease risk: characterize disease mechanisms accessible to treatment or prevention, improve processes of risk prediction and diagnosis, and develop individualized approaches to treatment and prevention.

In discussing disease mechanisms, the article mentions the "cluster of traits referred to as the metabolic syndrome" and observes that little or no genetic evidence supports the existence of such a "pathophysiological entity."

"No doubt that these traits do tend to cluster in certain individuals," Dr. McCarthy explained to Medscape Medical News in an email, "but [there is] some argument in the literature as to whether this really deserves designation of a syndrome. So far, we haven't been very successful at finding variants influencing the metabolic syndrome as a whole.

"That may be because [the variants] are there and we didn't find them yet," added Dr. McCarthy, "or [because] the metabolic syndrome has more to do with environment and aging (perhaps via epigenetics) than with genetic variation."

On the subject of prediction and diagnostics, Dr. McCarthy noted the value of genetic information in monogenic diseases but acknowledged the limitations of molecular diagnostic techniques that require sequencing because of its expense and because of causal mutations that are unique to an affected family. Fortunately, developing technologies and improved biomarkers promise more precise targeting for diagnostic sequencing of genetic variants.

For many individuals, however, risk can be determined by BMI or family history, and genetic information adds little that would guide long-term behavior modification. "There are pros and cons of family history, of course.... It integrates genetics and perhaps epigenetics and other aspects of shared family environment in a useful way that is predictive of risk," said Dr. McCarthy.

"However, equally, it falls afoul of inaccurate diagnostics, inaccurate recollection, etc. I don't think we should abandon family history as a clinical tool by any means, but I would hope that we will get better and better at using genetic and other tools to refine the individual risk predictions that come from family history," Dr. McCarthy added.

We Still Have Much to Learn

Finally, discussing treatment and prevention, the article highlighted the importance of genetic testing in selecting a therapy for monogenic diabetes. However, the contribution of genetics is less clear in managing more common forms of obesity and type 2 diabetes. At present, the greatest influence of genetic information on therapy may be through drug discovery.

"Both [obesity and type 2 diabetes] are strongly heritable conditions influenced by environmental factors, and advances in risk prediction, prevention, and therapy are sorely needed," commented W. Gregory Feero, MD, PhD, guest coeditor of the New England Journal of Medicine's series in genomic medicine, and special advisor to the director for genomic medicine, National Human Genome Research Institute, National Institutes of Health, in Bethesda, Maryland, in an email to Medscape Medical News.

"Dr. McCarthy...is a leading investigator who has contributed tremendously to our understanding of the genomic underpinnings of these conditions," noted Dr. Feero. "His work continues to shape the future of investigation in this area.... Though we have much yet to learn, these insights are helping to drive important downstream efforts to develop clinical tools to reduce morbidity and mortality from these conditions," Dr. Feero said.

Dr. McCarthy reported receiving consulting fees from Prosidion Pharmaceuticals and lecture fees from Novo Nordisk. Dr. Feero has disclosed no relevant financial relationships.

New Engl J Med. 2010;363:2339-2350.

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