Newly Identified Genes Influence Insulin and Glucose Regulation
Five of These Variants Raise Type 2 Diabetes Risk
An international research consortium has found 13 new genetic variants that influence blood glucose, also called blood sugar, regulation; insulin resistance; and the function of insulin-secreting beta cells in populations of European descent. Five of the newly discovered variants increase the risk of developing type 2 diabetes, the most common form of diabetes.
The results of two studies, conducted by the Meta-Analyses of Glucose and Insulin Related Traits Consortium (MAGIC), provide important clues about the role of beta cells in the development of type 2 diabetes. The studies, which were funded in part by the National Institutes of Health, appeared in the January 17, 2010, online issue of Nature Genetics.
Researchers in one study analyzed about 2.5 million genetic variants in 21 genome-wide association studies that had enrolled 46,186 people who did not have diabetes and had been tested for measures of glucose and insulin regulation. Genome-wide association studies look for common genetic associations by scanning the DNA of thousands of people. The huge numbers of genetic samples boost the chances of finding subtle associations of genetic variants with specific diseases or traits. The most common variation is a change in a single nucleotide polymorphism (SNP), or single base pair change, in one of the building blocks of DNA.
The initial analysis yielded 25 candidate SNPs that were further tested in genetic samples from about 77,000 additional individuals. This step led to 16 SNPs that were clearly associated with fasting glucose and beta cell function and two SNPs associated with fasting insulin and insulin resistance. The investigators then asked whether any of the SNPs raise type 2 diabetes risk by comparing gene variants from thousands of people with and without type 2 diabetes.
"The hallmarks of type 2 diabetes are insulin resistance and impaired beta cell function. 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," said lead author Inês Barroso, Ph.D., of the Wellcome Trust Sanger Institute, Cambridge, England.
Beta cell impairment may play a larger role in type 2 diabetes than previously recognized, the authors suggest. Also, the environment may contribute to insulin resistance more than it does to insulin secretion. Learning how the genes influence cell signaling and development, glucose sensing, and hormonal regulation will assist the development of targeted methods to prevent and treat diabetes, they conclude.
"Our study shows that genetic studies of glycemic traits can identify loci for type 2 diabetes risk," said lead co-author Jose Florez, M.D., Ph.D., of Massachusetts General Hospital and Harvard Medical School. "However, not all loci that influence blood glucose regulation are associated with greater risk for type 2 diabetes. Some loci elevate fasting glucose slightly but do not raise diabetes risk. It appears that it's not the mere elevation in glucose, but how glucose is raised, that determines type 2 diabetes risk."
In the second study, MAGIC researchers evaluated genetic associations with glucose levels 2 hours after an oral glucose challenge test in a subset of 15,234 participants. They found that a genetic variant influences blood glucose levels after a glucose challenge test. Individuals with the risk variant have reduced beta cell function.
The discovery highlights the role of incretin hormones, which are released from endocrine cells in the gut. "This finding adds to a growing body of evidence implicating the incretin pathways 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," said senior author Richard Watanabe, Ph.D., of the University of Southern California.
"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," Florez cautioned. Yet undiscovered genes may be found by studies that increase sample sizes to detect smaller effects and look for less common variants as well as non-SNP variants—for example, insertions, deletions, and duplications of DNA that have'nt been well studied yet.
The National Institute of Diabetes and Digestive and Kidney Diseases has fact sheets and easy-to-read booklets about diabetes. For more information, visit www.diabetes.niddk.nih.gov.
NIH Publication No. 10-4562
Page last updated: December 5, 2011