Gene variant increases risk of type 2 diabetes - but healthy lifestyle changes reduce genetic risk

Researchers have confirmed that a gene variant confers susceptibility to type 2 diabetes in participants of the Diabetes Prevention Program (DPP), a large clinical trial in adults at increased risk for developing type 2 diabetes.

The finding, published in the July 20, 2006, issue of the New England Journal of Medicine, follows the discovery by deCode Genetics that a variant in a gene called TCF7L2 predisposes people to type 2 diabetes.

"The DPP is an outstanding example of a robust clinical trial that continues to answer crucial questions about the etiology and prevention of type 2 diabetes, a complex disease that is steadily rising throughout the nation and the world," said National Institutes of Health (NIH) Director Elias A. Zerhouni, M.D. The NIH, which sponsored the DPP, continues to fund the follow-up study of DPP participants.

The researchers were delighted to observe that even the participants at highest genetic risk benefited from healthy lifestyle changes as much or perhaps more than those who did not inherit the variant. "The lifestyle intervention reduced risk even in those who carried both copies of the risk variant," said lead author Jose Florez, M.D., Ph.D., of Massachusetts General Hospital (MGH) in Boston. "This finding emphasizes that people at risk of diabetes, whether they're overweight, have elevated blood glucose levels, or have this particular genetic variant, can benefit greatly by implementing a healthy lifestyle."

Launched in 1995, the DPP ended in 2001, a year earlier than planned because the results were so clear. The researchers published their main findings in 2002 (http://www.nih.gov/news/pr/feb2002/hhs-06.htm). The 3,234 people who took part in the study were adults with blood glucose readings that were higher than normal but not yet in the diabetic range. Most were significantly overweight. Nearly half were minorities, who are at disproportionately high risk for diabetes. Those who lost 5 to 7 percent of weight by cutting calories in their diet and increasing physical activity (e.g., walking 5 days a week 30 minutes a day) reduced the onset of type 2 diabetes by 58 percent. Treatment with metformin lowered the chances of developing diabetes by 31 percent.

The DPP participants randomly assigned to lifestyle changes received guidance from a dietitian and lifestyle coach during the study. Most adults at risk for diabetes don't have access to such support. "Finding better ways to predict who is at greatest risk for developing diabetes might focus interventions on those most likely to benefit," says Sanford Garfield, Ph.D., of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), which spearheaded the DPP.

The newly identified gene variant, or allele, is located on chromosome 10q25.3. It is a single nucleotide polymorphism (SNP), or single base pair change, in the region of a gene that codes for a transcription factor - a protein that acts like a "master switch" regulating the expression of other genes. In their DNA analysis, the researchers found one copy of the risk variant in 40 percent of DPP participants, and two copies in 10 percent. "For the 10 percent of people who inherited two copies of the variant, the risk of developing diabetes is about 80 percent higher than it is for non-carriers," explained Dr. Florez.

The DPP Genetics subgroup conducted the study in a multi-institutional collaborative effort. Its findings build on the deCode Genetics report, published online in Nature Genetics in January 2006, by:

• confirming the finding in an independent population that included the racial and ethnic diversity typical of the U.S. population with diabetes
• showing that the gene variant increases risk in those with pre-diabetes, and in a prospective study where patients are followed over time
• examining for the first time the relationship between the genetic risk factor and interventions that delay diabetes onset, and
• showing that the gene variant affects insulin production, not cells' response to insulin.

The hallmarks of type 2 diabetes are insulin resistance - the inability of target tissues to respond to insulin - and a gradual failure of beta cells to produce enough insulin. "This variant of TCF7L2 is associated with decreased insulin production, but not with any increase in insulin resistance," said DPP study chair David M. Nathan, M.D., of MGH.

"Our data, combined with previous longitudinal studies and genetic findings, show that type 2 diabetes can be triggered by decreased insulin production and not just by insulin resistance. However, researchers need to learn more about this gene before they can even begin to translate the discovery into a drug treatment that benefits people with diabetes or those at risk," added Dr. Florez.

About 20.8 million people in the United States - 7 percent of the population - have diabetes, the most common cause of blindness, kidney failure, and amputations in adults and a major cause of heart disease and stroke. Type 2 diabetes accounts for up to 95 percent of all diabetes cases. The prevalence of this form of diabetes has skyrocketed in the last 30 years, due mostly to the upsurge in obesity. In addition, at least 54 million U.S. adults age 20 and older have pre-diabetes, which independently raises the risk of developing type 2 diabetes and cardiovascular disease.

While this genetic variant does predict a greater risk of developing type 2 diabetes in addition to the recognized risk factors such as being age 45 and older, overweight, inactive, and having history of gestational diabetes, the researchers are not recommending routine genetic testing for it. "We don't currently have evidence that such a test would mean better outcomes for patients or that it would be cost-effective," said principal investigator of the DPP Genetics Project, David Altshuler, M.D., Ph.D., of MGH and the Broad Institute of Harvard and MIT.

As scientists probe deeper into the genetic underpinnings of type 2 diabetes, they have found a number of genes that raise a person's risk for developing type 2 diabetes. Testing these variants in the DPP may lead to a better understanding of their role in the progression from "pre-diabetes" to overt diabetes, and whether they influence interventions shown to reduce risk of getting the disease.

The "Small Steps. Big Rewards. Prevent Type 2 Diabetes" campaign of the National Diabetes Education Program (NDEP) is based on the results of the DPP. The Program, sponsored by the NIH, the Centers for Disease Control and Prevention, and 200 partner organizations, is reaching out to people at risk for type 2 diabetes, e.g., the elderly, minorities, and women with a history of gestational diabetes, with the message that they have the power to turn the tide against this disease. The NDEP (www.ndep.nih.gov/) is providing those at risk and their health care providers with the tools for lifestyle change proven effective in the DPP.

The NIDDK funds a great deal of research to improve ways to treat and prevent diabetes. Recently, NIDDK's Central Repository (www.niddkrepository.org), which houses data collected in large clinical trials funded by the Institute, made data from the DPP available to researchers free of charge.

The NIDDK, part of the NIH, also conducts and supports research on other endocrine and metabolic diseases; digestive diseases, nutrition, and obesity; and kidney, urologic and hematologic diseases. Spanning the full spectrum of medicine and afflicting people of all ages and ethnic groups, these diseases encompass some of the most common, severe, and disabling conditions affecting Americans.

The National Institutes of Health (NIH) - The Nation's Medical Research Agency - includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.