Exercise helps find genetic regions linked to prediabetes

People's bodies respond to exercise in different ways, and their genetic makeup is partly responsible.

For one, people differ in how greatly exercise alters their blood sugar equilibrium, an effect demonstrated in a new study by researchers at Washington University School of Medicine in St. Louis and other institutions in the HERITAGE Family Study.

The divergence in exercise response allowed the researchers to identify regions on chromosomes 6, 7, and 19 that are linked to prediabetes. Their report appears in the June issue of Diabetologia.

Prediabetes is characterized by the body's elevated resistance to insulin, the hormone that regulates blood glucose levels and energy storage. The condition generally advances to type 2 diabetes as the pancreas works to secrete insulin to compensate for increased insulin resistance in the body's liver, muscle and fat cells. When the pancreas can no longer make enough insulin to keep blood sugar levels down in the normal range, clinically overt type 2 diabetes results.

"There's no question at all that prediabetes and type 2 diabetes have a genetic basis," says lead author Ping An, M.D., research assistant professor in genetics and biostatistics. "The rising incidence of type 2 diabetes makes it more and more important to locate the genes so they can lead to effective intervention and treatments."

Four hundred and forty-one nondiabetic, sedentary parents and offspring in 98 white and 90 black families were studied. Each participant put aside their inactive lifestyle for a 20-week, supervised program of aerobic exercise. Researchers made sophisticated measurements of insulin action and glucose metabolism at the start of the program and then again after it was done.

"At the end of the exercise program, the insulin sensitivity of the participants had improved overall--they needed to produce less insulin to handle the same amount of glucose intake," says An. "But the amount of improvement varied across families and family members. This variation allowed us to locate sites on the chromosomes associated with dynamic prediabetes traits."

An area on chromosome 19 showed the strongest link to training response among black participants. That link was revealed by the effect of exercise on a measurement of glucose metabolism and indicates the chromosomal location is likely to contain gene variants that influence the propensity for prediabetes.

Very close to the area identified is a gene vital for storing glucose in the form of glycogen within skeletal muscles. Patients with type 2 diabetes often have impaired glycogen storage.

Although not as strong, other links to prediabetes traits were found on chromosomes 6 and 7 among the white participants in the study. These locations have been shown to contain several genes related to fat and glucose metabolism, insulin sensitivity and glucose-induced insulin secretion.

"Genetic dissection of type 2 diabetes is challenging because the disease is affected by many genes and environmental factors like eating habits or amount of exercise," An says. "We need to employ insightful study designs and analysis strategies. By selecting nondiabetic, sedentary people and then looking at their exercise response in this study, we were able to analyze a unique sample and directly measure insulin secretion and action. What we found is consistent with other kinds of studies of type 2 diabetes traits, and the replication of findings from independent studies and samples, although difficult, is important for establishing genetic links."

The study was part of the HERITAGE (Health, Risk factors, Exercise Training and Genetics) Family Study, a multicenter study of human genetic variation and its influence on cardiovascular and metabolic responses to aerobic exercise training. Initiated by Claude Bouchard, Ph.D., director of the Pennington Biomedical Research Center in Baton Rouge, the study has a center at Washington University School of Medicine maintained in the Division of Biostatistics, directed by D.C. Rao, Ph.D.

An P, Teran-Garcia M, Rice T, Rankinen T, Weisnagel SJ, Bergman RN, Boston RC, Mandel S, Stefanovski D, Leon AS, Skinner JS, Rao DC, Bouchard C. Genome-wide linkage scans for prediabetes phenotypes in response to 20 weeks of endurance exercise training in nondiabetic whites and blacks: the HERITAGE Family Study. Diabetologia 48(6):1142-1149, 2005.

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