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Insulin Works in Brain, Affects Fertility
Versatile hormone also governs appetite and weight

HealthSCOUT - By Reporter Edward Edelson

THURSDAY, Sept. 21 (HealthSCOUT) —  Insulin can act not only throughout the body but also in the brain, affecting appetite control, obesity and even reproductive fertility, two studies show.

"Insulin has a previously unrecognized role in the brain," says Dr. C. Ronald Kahn, president of the Joslin Diabetes Center in Boston and leader of a team reporting the finding in the journal Science. "We now have evidence that we need to look in much more detail about what is going on in the brain."

The Joslin researchers, working with scientists at the University of Cologne and the European Molecular Biology Laboratory in Germany, made their discovery by creating mice whose brain cells lack the receptors needed for insulin activity.

"We found evidence of a decrease in the ability of insulin to lower blood glucose levels, increased appetite, obesity and increased infertility in the genetically altered mice," Kahn says. "Our data show a central role of insulin resistance in regulating energy disposal, metabolism and reproduction."

The discovery could lead to treatments to help the estimated 16 million Americans with Type II diabetes, in which insulin production by the pancreas is reduced and tissues such as the muscles and liver show resistance to insulin, Kahn says: "In the next two years, studies could tell us what therapeutic interventions are possible."

Decline in fertility a surprise

The NIRKO (neural-insulin receptor knock out) mice created in the Joslin laboratory showed an expected obesity reaction to the loss of insulin function. The female mice gained weight on a normal diet, and both males and females had weight gains ranging from 50 to 100 percent.

The link to reproduction was more surprising. The NIRKO mice of both sexes had reduced fertility, an effect that was traced to defective regulation by the hypothalamus of leutinizing hormone, which affects both sperm production and ovulation. That effect could help explain why some women with Type II diabetes who are overweight have menstrual disorders, with an increased incidence of polycystic ovary disease, the researchers say.

A second study, appearing in the journal Nature, was done on mice bred to lack a different gene, one for insulin receptor substrate-2 (IRS-2), a protein found in many body cells. IRS-2 is essential for the normal response of cells to insulin. In humans, Type II diabetes can occur when IRS-2 activity is lessened, so that the pancreas cannot make enough insulin to meet the need of cells in the liver, muscle and fatty tissues.

Male mice without IRS-2 die early, at 10 weeks of age. Female mice overeat, gain too much weight, have reduced fertility and develop diabetes between 18 and 20 weeks of age. Their weight gain occurs even though the body produces excess amounts of leptin, a protein that suppresses appetite.

That finding could change the textbook description of diabetes, which says that obesity is a risk factor for the disease, says Deborah J. Burks, lead author of the study and a research instructor at Joslin. Now it seems that it can work the other way around, with insulin resistance leading to obesity.

"The studies provide very strong evidence that insulin is involved in the regulation of appetite, body weight and the reproductive process," Burks says.

The reproductive problems of the female mice lacking IRS-2 begin early in life, when their ovaries develop fewer eggs. When the mice grow up and mature, they produce abnormally low amounts of gonadatropins, hormones that stimulate activity of the ovaries, and the ovaries are abnormally small and don't respond well to the hormones.

So IRS-2 might be the source of many diabetes-related problems, says Morris F. White, another member of the Joslin research team. "You can live with reduced IRS-2 function, but you might be glucose intolerant, overeat and gain weight, have a difficult time becoming pregnant and when you do, develop gestational diabetes."

What To Do

These discoveries may someday change the way diabetes is defined and treated, but you should probably heed the current guidelines on preventing and managing the disease.

Try the Joslin Diabetes Center or the American Diabetes Association for more information on the disease.