Lifestyle Can Fend off Type 2 Diabetes Genetic Risk

BOSTON, July 20 -- Two common genetic variants appear to contribute to the development of type 2 diabetes for some patients with impaired glucose tolerance, found researchers here. But lifestyle moves seem to be able to combat the enhanced risk.

The genetic finding helps to elucidate diabetes risk mechanisms, but it may not have an immediate therapeutic payoff, reported investigators with the Diabetes Prevention Program in the July 20 issue of the New England Journal of Medicine. The authors of an accompanying editorial agreed.

"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," said Jose Florez, M.D., Ph.D., of Massachusetts General Hospital here.

"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."

The investigators found that although the genetic variants can put people at highest genetic risk for developing type 2 diabetes, diet and exercise for these patients were highly successful at fending off the disease.

"The lifestyle intervention reduced risk even in those who carried both copies of the risk variant," said Jose Florez, M.D., Ph.D., of Massachusetts General Hospital here. "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."

Yet he and colleagues stopped short of recommending testing for the genetic variants, which are polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene.

"We don't currently have evidence that such a test would mean better outcomes for patients or that it would be cost-effective," said David Altshuler, M.D., Ph.D., of MGH, a co-author. He was principal investigator of the Diabetes Prevention Program Genetics Project.

The Diabetes Prevention Program was a three-year, 27-center placebo-controlled study of 3,234 participants who were overweight and had impaired glucose tolerance. The results, published in the Feb. 7, 2002, issue of the New England Journal of Medicine, showed that diet and exercise could, to a large degree, prevent or delay the onset of type 2 diabetes, and that the use of Glucophage (metformin) could also contribute to delaying the onset.

In the current study, Dr. Florez and colleagues looked for two common single-nucleotide polymorphisms in TCF7L2 that have recently been associated with type 2 diabetes in the original study cohort.

Their goal was to determine whether the two variants that are most strongly associated with type 2 diabetes could predict the progression to full blown diabetes among the trial participants.

To do this, they genotyped 3,548 men and women, including 585 people who were assigned to receive Rezulin (troglitazone) as part of the original Diabetes Prevention Program cohort, but had to drop out of the study due to toxicities. The genotyping focused on two risk alleles with the romantic labels rs7903146 and rs12255372.

The authors performed a Cox regression analysis using as predictors for type 2 diabetes genotype, type of intervention the participants had been assigned to, and the interactions between the interventions. They also looked at the effect of genotype on measures of insulin secretion and insulin sensitivity at baseline and at one year.

They found that over an average of three years, those participants who were homozygous for the risk-conferring T allele at rs7903146 were significantly more likely than others to progress to type 2 diabetes than were people who were homozygous for the C allele at the same location. The hazard ratio for the TT versus CC alleles was 1.55 (95 % confidence interval, 1.20 to 2.01; P