Body's anticipation of a meal can be a diabetes risk factor

When we anticipate or smell a meal, the parasympathetic nervous system triggers salivation and increases insulin production in response to the expectation that glucose will be entering the blood stream.

"We think this parasympathetic response is potentially important in type 2 diabetes," said Vann Bennett, the James B. Duke professor in the departments of cell biology, biochemistry, and neurobiology and Howard Hughes Medical Institute investigator. "Our study showed there is a novel mutation in the gene encoding ankyrin-B, which increases the risk of type 2 diabetes. This happens through an impairment of the insulin secretion that is added by the parasympathetic nervous system."

The study is being released online March 16 in Science Signaling.

Bennett was the first scientist to delineate a molecule called ankyrin and for years has been studying its roles in the heart and brain, as well as other organ systems. Bennett and colleagues discovered the importance of ankyrin-B in the insulin response and the source of a mutation that could lead to diabetes.

In earlier experiments, the group found that pancreatic beta cells that are ankyrin-B deficient display impaired insulin secretion in mice. Ankyrin-B-deficient mice had high blood sugar after eating a source of glucose, but not if the glucose bypassed the mouse's mouth. These findings indicated that ankyrin-B deficiency impaired the parasympathetic chain of events that enhance insulin secretion and had a measurable impact on blood sugar levels.

The scientists then asked whether mutations involving ankyrin-B loss of function were associated with diabetes in humans. They used the American Diabetes Association's GENNID genetic specimen collection from families with type 2 diabetes to genotype 524 people with diabetes disorders and 498 non-diabetic controls. They were searching for three ankyrin-B mutations that had previously been shown in heart muscle cells to create severe loss of function.

They found that one of these mutations of ankyrin-B (R1788W) was associated with type 2 diabetes in about 1 percent of Caucasian and Hispanic individuals. "Genomewide studies have failed to identify more than a small fraction of the genetic heritability in diabetes as well as in other complex diseases," Bennett said. "There are estimates that only 6 percent of the heritability of type 2 diabetes has been detected, by multiple genomewide studies."

Bennett said this implies there is a large reservoir of genes yet to be identified, that are risk factors in type 2 diabetes. "We are excited by our findings of a specific mutation with a known mechanism because of the potential for personalized treatment of diabetes," he said. "This particular mutation is likely to play a role in 1 percent of adults with diabetes. We hope our finding will lead to strategies to specifically benefit these individuals."

Support for the study came from the Howard Hughes Medical Institute and the American Diabetes Association for management of the GENNID database and DNA samples, as well as a pre-doctoral fellowship from the American Heart Association. The National Institutes of Health also supported the study as did the Swedish Council and the Family Erling-Persson Foundation.

Co-authors included lead author Jane A. Healy of the Duke Department of Biochemistry, Kent R. Nilsson, Hans E. Hohmeier and Christopher Newgard, lab director, of the Duke Department of Medicine (Hohmeier and Newargard also are in the Duke Department of Pharmacology and Cancer Biology and the Sarah W. Stedman Nutrition And Metabolism Center); Jonathan Davis and Janis Hoffman of the Howard Hughes Medical Institute; and Martin Kohler, Luo-Sheng Li and lab director Per-Olof Berggren from the Karolinska Institutet in Stockholm.