Two papers reported in Nature Genetics pinpointed 13 mutations and linked five to type 2 diabetes risk.

A transatlantic consortium of researchers has identified five new genetic variants that appear to increase the risk of type 2 diabetes. In one of two studies, the scientists identified a genetic variant in the gastric inhibitory polypeptide receptor (GIPR) gene that appears to reduce beta-cell function.

The studies, by the Meta-Analyses of Glucose and Insulin Related Traits Consortium (MAGIC), identified a total of 13 genetic variants that seem to influence blood glucose regulation, insulin resistance, and the function of insulin-secreting beta cells in people of European descent. The research is published in two papers in Nature Genetics titled “New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk” and “Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge.”

In the first study the researchers, led by Jose Florez, Ph.D., M.D., from Massachusetts General Hospital and Harvard Medical School, investigated genetic variations linked with fasting glucose and insulin levels as well as with beta-cell function and insulin resistance. Their meta-analysis evaluated about 2.5 million genetic variants in 21 genome-wide association studies that had included some 46,186 individuals who did not have type 2 diabetes and who had been tested for measures of glucose and insulin regulation.

Of 25 candidate SNPS identified in the initial analysis, further testing of genetic samples from about 77,000 additional individuals led to the identification of 16 SNPS that appeared to be clearly associated with fasting glucose and beta-cell function as well as another two SNPS associated with fasting insulin and insulin resistance. Of them, five were found to increase type 2 diabetes risk.

One is located in the ADCY5 region, which influences fasting and postprandial glucose levels. Another is in region FADS1, which is linked with fasting glucose and lipid traits. None of the variants were associated with type 1 diabetes.

“Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing, and circadian regulation,” the authors conclude. “Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.”

One of the interesting findings, according to Dr. Florez, is that glucose elevation in itself does not appear sufficient to increase the risk of type 2 diabetes. Rather, it is how the glucose is raised that determines risk. “The hallmarks of type 2 diabetes are insulin resistance and impaired beta-cell function,” notes lead author, Ins Barroso, Ph.D., from the Wellcome Trust Sanger Institute. “We were intrigued to find that most of the newly found variants influence insulin secretion rather than insulin resistance. Only one variant, near IGF1, is associated with insulin resistance.”

The second paper evaluated the genetic basis of glucose levels two hours after an oral glucose challenge in a subset of 15,234 participants. The authors claim the discovery that a variant of the GIPR gene influences blood glucose levels after glucose challenge highlights the role of incretin hormones in type 2 diabetes. “Our association results suggest a role for GIPR in the incretin effect and in early pathophysiologic pathways that could lead to impaired glucose tolerance and type 2 diabetes in humans,” they conclude.

The paper’s senior author, Richard Watanabe, Ph.D., from the University of Southern California, suggests the findings add to a growing body of evidence implicating the incretin pathway in type 2 diabetes risk. “These pathways, which stimulate insulin secretion in response to digestion of food, may offer a potential avenue for therapeutic intervention.”

Although the two studies focused on populations of European descent, the MAGIC researchers believe a number of the genetic variants will have similar effects in other populations. Nevertheless, as Dr. Florez concludes, “Even with the discovery of these variants, we’ve only explained about 10 percent of the genetic contribution to fasting glucose in people who do not have diabetes.”

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