A Discovery: Link Between Obesity and Type 2 Diabetes

A newly discovered hormone produced by fat cells may provide a long-sought explanation for how obesity triggers insulin resistance and type 2 diabetes, a Penn School of Medicine team reports in the January 18 issue of Nature. The discovery of the hormone, called resistin (resistance to insulin), is also helping researchers understand how a new class of antidiabetic drugs promotes insulin sensitivity in people with type 2 diabetes. Insulin resistance, a disorder in which target tissues--muscle, fat, and liver cells--fail to use insulin effectively, accompanies and usually precedes type 2 diabetes. Eighty percent of people with type 2 diabetes are overweight, but the mechanism by which obesity sets the stage for insulin resistance and diabetes has long puzzled scientists.

A research team led by Dr. Mitchell Lazar, director of the Penn Diabetes Center at the School of Medicine, discovered resistin while studying thiazolidinediones (TZDs), a group of insulin-sensitizing drugs that include the oral diabetes medications pioglitazone (Actos(tm)) and rosiglitazone (Avandia(tm)). The researchers knew that the TZDs activate a nuclear receptor in fat cells called PPARgamma, which belongs to a family of receptors that regulate gene expression in response to hormones, vitamins, and some drugs. The researchers discovered resistin by screening fat cells for a gene that was inhibited by TZDs.

"It seemed likely that the TZDs were acting on PPARgamma to regulate a gene," says Dr. Lazar. "We reasoned that this gene might encode a previously undiscovered fat cell hormone that impaired the actions of insulin on peripheral tissues. If the gene were overactive in obesity, it could explain the association between diabetes and obesity. And, if TZDs reduced the expression of this gene, we'd have an explanation for some of the benefit of the TZDs in diabetes."

Resistin circulates in the blood of normal mice, falling after a fast and rising after a feeding, and it dramatically rises in mouse models with genetic as well as diet-induced obesity. When the researchers administered resistin to normal mice, the animals developed impaired insulin action and glucose intolerance, precursors to type 2 diabetes.

Treatment with the TZD rosiglitazone, however, decreased blood levels of resistin. Alternatively, administration of an agent that blocked resistin's effects in mice with diet-induced obesity improved both insulin action and blood glucose.

"I don't think it's an exaggeration to say this is a blockbuster paper with potentially major clinical impact," said Dr. Allen Spiegel, director of the National Institute of Diabetes and Digestive and Kidney Diseases, the part of the National Institutes of Health that funded the research. "In one fell swoop, Dr. Lazar and colleagues have discovered a novel hormone secreted by fat cells, possibly explained how TZDs act as antidiabetic agents, and provided a key link between obesity and type 2 diabetes."

Not only do blood levels of resistin in mice correlate with insulin resistance and diabetes, Dr. Lazar's work suggests that increased resistin levels are one of the causes of type 2 diabetes. "If this observation also turns out to be true in humans, measuring resistin levels could help diagnose people at risk for type 2 diabetes. If resistin is really causing insulin resistance, then lowering levels of the hormone or blocking its action could constitute a new treatment for type 2 diabetes," says Dr. Lazar.

About 16 million people in the United States have diabetes, the most common cause of blindness, kidney failure, and amputations in adults. Type 2, which accounts for about 90 percent of diabetes in the United States, is most common in people who are overweight, inactive, over age 40, and have a family history of diabetes. The disease is also more common in minorities: African Americans, Hispanic/Latino Americans, American Indians, and some Asian Americans and Pacific Islanders are at particularly high risk for this form of diabetes. With the onset of insulin resistance, the pancreas compensates by producing more insulin, but gradually its capacity to secrete insulin in response to meals falters, and the timing of insulin secretion becomes abnormal. After diabetes develops, pancreatic production of insulin continues to decline. Many people can control their blood glucose by following a careful diet and exercise program, losing excess weight, and taking oral medication. However, the longer a person has type 2 diabetes, the more likely he or she will need insulin injections, either alone or combined with oral drugs.

About 10 percent, or 1.6 million of people with diabetes, have type 1, formerly known as juvenile onset diabetes or insulin-dependent diabetes. This form of diabetes, which usually occurs in children and adults under age 30, develops when the body's immune system attacks the insulin-producing cells of the pancreas.

This research was funded by the NIDDK. Claire Steppan was supported by an unrestricted postdoctoral grant from Pfizer, Inc. Ronadip Banerjee is an M.D./Ph.D. trainee in the NIH-sponsored Medical Scientist Training Program. Elizabeth Brown was supported by a medical student research fellowship from the American Diabetes Association.

Almanac, Vol. 47, No. 19, January 23, 2001