There is great interest in whether and how new findings from human genetics will impact clinical medicine. Our paper offers an early look at this question in the context of a very common disease and a positive clinical trial.

“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...”

Specifically, we 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. This finding, published in the July 20, 2006, issue of the New England Journal of Medicine, followed the Icelandic discovery by deCode Genetics and collaborators that a variant in a gene called TCF7L2 predisposes people to type 2 diabetes. 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. Our paper was also of interest because it was the first to show that TCF7L2 acts by reducing insulin secretion – perhaps a surprise given that recently there has been more attention to insulin resistance as the core defect in type 2 diabetes.

Our paper provides clinical information about a recently discovered genetic variation. The genetic findings were based on the Diabetes Prevention Program. 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 (The Diabetes Prevention Program Research Group. "Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin." N. Engl. J. Med. 2002 [346]:393-403, 2002). 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% of their body 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%. Treatment with metformin lowered the chances of developing diabetes by 31%.

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 our DNA analysis, we found one copy of the risk variant in 40% of DPP participants, and two copies in 10%. For the 10% of people who inherited two copies of the variant, the risk of developing diabetes is about 80% higher than it is for non-carriers.

We 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. 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.

While this genetic variant does predict a greater risk of developing type 2 diabetes in addition to the recognized risk factors such as being overweight, inactive, and having a history of gestational diabetes, we are not recommending routine genetic testing for it. This is because there is no evidence yet that knowledge of genotype at this locus leads to better patient outcomes, and it is not clear that such testing is cost-effective.

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 treatment that benefits people with diabetes or those at risk. In the near term, we are studying how additional type 2 diabetes gene discoveries play out in the DPP.

  Are there any social or political implications for your research?