Diabetes has become epidemic in the Western world: One out of 12 suffers from type 2 (adult onset) diabetes, and the number of diabetics (presently 150 million worldwide) is expected to double in the next 20 years. Though studies have laid the blame on the growing obesity scourge, the reasons for the strong correlation between excess body fat and diabetes have been puzzling scientists. New research at the Weizmann Institute and in Sweden has revealed exactly how one protein’s response to fat in the bloodstream contributes to the disease.
Type 2 diabetes is a complex disorder characterized by the body’s inability to utilize sugar efficiently. Two stages of the disease have been identified: In the first, “silent” stage, the body’s cells lose their ability to respond properly to the crucial hormone, insulin, responsible for moving sugar from the blood into cells. If sugar remains in the bloodstream, the insulin-producing beta cells in the pancreas compensate by stepping up production. Eventually this leads to beta cell exhaustion, reduced insulin output and the appearance of full-blown diabetes.
Elevated fat in the bloodstream appears to accelerate both stages of the disease. Exactly how does this happen? Beta cells are attuned to changes in blood sugar levels, responding to after-meal surges with a sharp increase in insulin production. But a recently discovered protein, a receptor on the surface of the beta cell called GPR40, responds not to sugar, but to fatty acids. When fat is present in addition to sugar, the GPR40 receptor causes an even higher spike in insulin output. If beta cells are frequently overstimulated and overworked, persistently elevated insulin levels may hasten the onset of the disease.
To investigate GPR40’s role, Prof. Michael Walker and students Nir Rubins and Reut Bartoov-Shifman of the Weizmann Institute’s Biological Chemistry Department teamed up with Prof. Helena Edlund and postdoctoral fellow Dr. Per Steneberg of the University of Umea in Sweden. Together, they developed two types of lab mice with modified GPR40 activity. In the first, the scientists used a technique known as gene knockout to prevent production of the GPR40 receptor. In the second type, overactive GPR40 genes created a surfeit of fat-signaling receptors that tricked the beta cells into sensing high fatty acid levels, even on a normal diet.
Throughout the trial, the GPR40 knockout mice remained healthy, apparently suffering no adverse effects from the deletion of the receptor, even when the fat content of their diet was raised substantially. In contrast, normal mice on a high-fat diet displayed typical symptoms of the first stage of diabetes. But strikingly, in the animals with extra GPR40 receptors, the disease progression was swift: They soon began to exhibit the classic symptoms of full-blown diabetes, including failure of the beta cells to produce adequate amounts of insulin.
Walker: “Our results establish GPR40 as an important link between obesity and diabetes. This gives us a new tool to combat the diabetes epidemic: It might be possible in the future to treat the condition using drugs that block the action of this receptor.”
Prof. Michael Walker’s research is supported by the Laufer Charitable Trust; Ellen Rosenthal; and Mitchell and Cynthia Caplan. Prof. Walker is the incumbent of the Marvin Myer and Jenny Cyker Professorial Chair for Diabetes Research.