Gene's forecast of diabetes not carved in stone
The genetic web of type 2 diabetes is particularly tangled. Although a handful of genetic suspects have been implicated, their specific contributions remain largely unknown. In an article appearing in the July 20 issue of the New England Journal of Medicine, a scientific team including researchers from the Broad Institute confirms that a recently identified variation in the gene TCF7L2 is associated with type 2 diabetes. While the variant imparts an even greater risk of developing the disease to patients already predisposed to it (based on their body weights and metabolic profiles), lifestyle changes such as eating a healthy diet and exercising regularly can significantly reduce this risk. The work also sheds light on the pathophysiological beginnings of type 2 diabetes in patients who carry the gene differences, and suggests that defects in insulin production, rather than an inability of cells to respond to the hormone's signals, may be to blame.
In a study first published online last January in Nature Genetics, researchers at deCODE Genetics reported two common genetic differences, called single nucleotide polymorphisms (SNPs), which lie within the TCF7L2 gene and are associated with type 2 diabetes. To replicate this association in an independent sample population, a group of researchers led by David Altshuler, the director of the Broad's Program in Medical and Population Genetics and an associate professor at Massachusetts General Hospital and Harvard Medical School, studied DNA from patients who were enrolled in a clinical trial known as the Diabetes Prevention Program (DPP). For three years, this prospective, NIH-sponsored study followed individuals from a range of ethnic groups who were particularly prone to develop type 2 diabetes, as determined by their increased body weight and elevated blood glucose levels — the readings were above normal but not yet at a sufficiently high level to diagnose overt diabetes. These "pre-diabetic" participants were randomly designated to receive dietary and exercise counseling, treatment with the diabetes drug metformin, or a placebo. The primary findings of the DPP trial, published in 2002, revealed that trimming both calorie consumption and body fat could decrease the risk of developing type 2 diabetes by 58% and that treatment with metformin could achieve a similar, though less substantial, risk reduction.
The researchers analyzed the DNA of the trial's participants and noted that about 10% had two identical copies of either of the previously identified risk variants in TCF7L2. For such homozygous carriers, the risk of developing type 2 diabetes was about 80% higher than other study participants. However, if these individuals received counseling on diet and exercise, scientists discovered that they were not any more likely to develop type 2 diabetes than non-carriers. Treatment with the drug, metformin, also reduced this risk, but not as dramatically as lifestyle changes.
"The lifestyle intervention reduced risk even in those who carried both copies of the risk variant," said the study’s first author José Florez, an endocrinologist at Massachusetts General Hospital and a Broad researcher. "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."
From their work, the researchers also gained insight into the triggers for diabetes in patients who inherit the TCF7L2 variants. Type 2 diabetes typically has a heterogeneous beginning, and can include signs of insulin resistance — the inability of cells to properly react to the hormone's signals — as well as decreased insulin production. Among DPP participants who carried the gene differences, the scientists observed evidence of compromised hormone production but not insulin resistance, suggesting that TCF7L2 might play a role in regulating the hormone’s synthesis or release.
Although the TCF7L2 variants do have predictive value beyond other measurements that can also foretell diabetes, further studies must be done to determine whether a routine genetic test would drastically improve the results that are achieved using current treatments or if developing and administering such a test would be cost-effective.
Florez JC, Jablonski KA, Bayley N, Pollin TI, de Bakker PIW, Shuldiner AR, Knowler WC, Nathan DM, Altshuler DA. (2006) TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. New England Journal of Medicine; 355:241-250.