Scientists Link Role of Insulin Receptors in Brain to Type 2 Diabetes, Appetite Control, Obesity and Infertility

BOSTON — September, 2000 — A new study led by scientists at Joslin Diabetes Center and a German university links the insulin signaling system in the brain not only to the onset of type 2 (adult onset) diabetes, but also to appetite control, obesity and even infertility. Using genetically-altered laboratory mice, the researchers found that the mice in which insulin action was blocked gained weight at a considerably higher rate than their counterparts, developed resistance to insulin action in other tissues of the body, and exhibited a 50 percent decrease in fertility.

In a report appearing in this week's journal Science, C. Ronald Kahn, M.D., and Deborah J. Burks, Ph.D., of Joslin and their colleagues at the University of Cologne and the European Molecular Biology Laboratory in Germany studied the effects of "turning off" or deactivating insulin receptors in the brains of specially bred, genetically-altered mice.

"We found evidence of a decrease in the ability of insulin to lower blood glucose (sugar) levels, increased appetite, obesity and increased infertility in the genetically altered mice in which the insulin receptor in the brain had been genetically knocked out," said Dr. Kahn, the Mary K. Iacocca Professor of Medicine at Harvard Medical School.

Type 2 diabetes, which affects an estimated 16 million people in the U.S., often is associated with obesity. In Type 2 diabetes, tissues of the body such as muscle, liver and fat are resistant to the action of insulin, (known as insulin resistance) while the pancreas produces some, but not enough, insulin, to overcome this resistance. As a result, blood sugar (glucose) backs up in the bloodstream. If poorly managed over time, elevated blood sugar levels can lead to such complications as blindness, leg and foot amputations, kidney disease, heart disease and stroke.

Scientists have known for some time that insulin resistance and beta cell dysfunction in the pancreas are the major contributors to Type 2 diabetes in people, but exactly how insulin resistance might affect the brain has been unclear. Previous studies have shown that insulin receptors and even insulin itself may be present in the brain, and some work has demonstrated that insulin signaling in the brain may contribute to eating behavior. Disruption of the insulin signaling system also has been suggested to occur in such disorders as Alzheimer's and Parkinson's disease.

Previous studies have suggested a role for insulin signaling in the brain and hypothalamus in the regulation of food "uptake" and body weight. Since insulin acts as a growth factor in nerves in cultured cells, the research team wanted to learn how brain development and well-being would be affected when insulin receptors were deleted in the laboratory mice. This new study indicates that insulin receptors and insulin signaling proteins throughout the central nervous system play an integral role in regulating and metabolism, as well as appetite and fertility.

"We created Neural (brain)-Insulin Receptor Knock Out (NIRKO) mice with a neuron-specific disruption of the insulin receptor gene," Dr. Kahn said. "Our data demonstrates the central role of insulin resistance signaling in regulating energy disposal, fuel metabolism and reproduction."

Although only the female mice exhibited an increase in body weight on a normal chow diet, both males and females exhibited obesity on a high fat diet. In addition, both male and female mice had increased body fat by 1.5 to two-fold on the regular diet. The females also ate 20 percent more food compared to the female controls. Blood leptin levels (a measure of fat mass) were elevated 2.5 times in the females and 1.5 times in the male NIRKO mice. Leptin normally suppresses appetite, but this effect was also apparently reduced in the NIRKO mice.

A very surprising finding was the link between brain insulin signaling and reproduction.

The NIRKO mice exhibited reduced fertility due to defective regulation by the hypothalamus in the brain of a hormone (luteinizing hormone) that impairs sperm production and ovulation. The authors state that this may explain why some women with diabetes and obesity experience menstrual disorders and even polycystic ovary disease.

The authors concluded that when considered with previous studies, this study demonstrates that genetically determined insulin resistance in classical insulin target tissues, such as muscle and fat, may combine with insulin resistance in non-classical target tissues, such as the brain and beta cell. This interaction may occur synergistically, resulting in obesity, insulin resistance, glucose intolerance, and high blood fat levels, leading to the complex metabolic syndrome associated with type 2 diabetes.

Authors of the study include: C. Ronald Kahn, M.D., and Deborah J. Burks, Ph.D., of Joslin; Jens C. Bruning, Dinesh Gautam, Jennifer Gillette, Markus Schubert, Wilhelm Krone, and Dirk Muller-Wieland of the University of Cologne, Germany; Paul C. Orban and Rudiger Klein of the European Molecular Biology Laboratory in Heidelberg, Germany.

This research was supported by grants from the National Institutes of Health, Joslin Diabetes Center, Deutsche Forschungsgemeinschaft, and the Volkswagenstiftung.

Established in 1898, Joslin Diabetes Center in Boston is an internationally recognized leader in diabetes and endocrine disease treatment, research, and patient and professional education affiliated with Harvard Medical School. In addition to its headquarters in Boston's Longwood Medical Area, Joslin has affiliated treatment centers across the country.