Scientists discover how excess body fat can lead to the onset of diabetes

One out of 12 people in the western world suffers from type 2 (adult onset) diabetes. Worldwide, 150 million people are diabetic and their numbers are expected to double in the next 20 years, a result of the growing obesity epidemic. Yet, the reasons for the strong correlation between excess body fat and diabetes have been puzzling researchers.

Scientists at the Weizmann Institute of Science and the University of Umea, Sweden, have now unraveled a mechanism by which fat contributes to the onset of the disease. Their results were published in the April issue of Cell Metabolism.

Type 2 diabetes is a complex disease characterized by the body’s inability to efficiently utilize sugar. 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, which is 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; but exactly how does this happen? The culprit may be a receptor known as GPR40 found on the outer surface of pancreatic beta cells. GPR40 was recently discovered to respond to fatty acids, alerting beta cells to their presence in the bloodstream. Beta cells were known to be attuned to changes in blood glucose levels, responding to after-meal glucose surges with a sharp increase in insulin production. But when fat is present in addition to sugar, the GPR40 receptor causes even greater insulin output. Frequent overstimulation of the beta cells may be tied to persistently elevated insulin levels, hastening the onset of the disease.

How does this destructive cycle begin? To understand 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 post-doctoral fellow Dr. Per Steneberg of the University of Umea. Together, they developed two types of lab mice with modified GPR40 activity. In the first, the scientists used a technique known as gene knock-out to prevent production of the GPR40 receptor. The second type had overactive GPR40 genes creating 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 knock-out mice remained healthy, apparently suffering no ill-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.

Prof. Walker: “These studies show that excessive GPR40 action can trigger each of the two stages of the disease. Our results establish GPR40 as an important link between obesity and diabetes. This gives us a new tool to combat the diabetes epidemic: For example, 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; Ms. Ellen Rosenthal, Potomac, MD; Mr. & Mrs. Mitchell; and Cynthia Caplan, Bethesda, MD. Prof. Walker is the incumbent of the Marvin Myer & Jenny Cyker Professorial Chair for Diabetes Research.

The American Committee for the Weizmann Institute of Science (ACWIS), founded in 1944, develops philanthropic support for the Weizmann Institute of Science in Israel, one of the premier scientific research institutions. The Weizmann Institute in Rehovot, Israel is a center of basic interdisciplinary scientific research and graduate study, addressing crucial problems in technology, medicine and health, energy, agriculture and the environment, for the benefit of humanity.

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