Genetic Variation Linked to Diabetes

Researchers at Stanford University School of Medicine have identified genetic variations in a hormone involved in insulin secretion that occur more frequently in some human populations than others. The variants are believed to have first occurred 2,000 to 12,000 years ago, and are associated with higher fasting levels of blood glucose compared with the ancestral form of the gene.

The researchers identified 207 genetic regions associated with diabetes or obesity, and then examined which had increased in prevalence in the time since humans moved out of Africa some 60,000 years ago. Their investigation yielded 59 genetic regions; the researchers were most interested in those occurring in at least 30% of people included in the HapMap project, a worldwide survey of genetic differences among people of Nigerian, Chinese, Japanese and European ancestry.

Fives genes with genetic differences that occurred frequently in Asians and Europeans, but infrequently in Africans, were identified. The researchers chose GIP, one of the five genes, to study further because of its known involvement in insulin secretion stimulation after a meal.

“We thought GIP was the most interesting because the newly selected form occurs in about 50% of people from Europe or Asia, but in only about 5% of Africans. That indicates this gene is highly adaptable to new environments,” Sheau Yu Hsu, PhD, assistant professor of obstetrics and gynecology at Chang Gung Memorial Hospital in Taiwan, said in a press release.

The researchers identified three individual changes in the regulatory region of GIP that were associated with reduced levels of the glucose-dependent insulinotropic polypeptide (GIP) hormone. The changes were also likely to occur with another mutation in the coding region, resulting in a different form of the protein. According to the press release, in human blood the alternate form is degraded more slowly.

“So now we know there are two different forms of the protein, which allowed one form to be selected in one population, and the other in a different population,” Hsu said. “But we still needed to show that these variants led to phenotypic differences in modern humans.”

Conclusive differences in GIP variants among human carriers have not been previously shown, so Hsu and colleagues focused their research on 123 East Asian pregnant women due to their important role in evolutionary success and their metabolically challenged nature.

According to their results, women carrying two copies of the new variant had significantly lower levels of circulating GIP in their blood and were at a significantly higher risk for fasting blood glucose levels exceeding the recommended 140 mg/dL (48.3% vs. 20.9% for those carrying the ancestral variant).

This finding could help clinicians identify pregnant women at higher risk for gestational diabetes, according to Hsu. In addition, the results demonstrate how our ancestors handled environmental change.

“Like other humans at the time, the Eurasian population really had to fight for survival. Now we’re starting to pinpoint how they did that on a molecular level. These gene variants, and the resulting higher blood sugar levels it fostered, may have helped women maintain successful pregnancies in the face of the inevitable famines that occur in an agriculturally based society. Now, in a more food-secure environment, variations in GIP could contribute to the development of diabetes or obesity.

“These studies are fascinating because it shows how much the selection process has affected human energy-balance regulation in just a few thousand years and how complex it could be for the future practice of personalized medicine,” Hsu said.


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