BOSTON, Sept. 20 (AScribe News) -- Research published in this week's issue of the journal Nature shows that insulin receptor substrate-2 (IRS-2), a protein inside of cells that is essential for normal response to insulin, might also promote fertility and fight against obesity.

The study shows that female mice lacking the IRS-2 gene rarely become pregnant, consume more food, and become fat.

"IRS-2 is like a switchboard that coordinates appetite, fat storage, and blood glucose together with energy demanding processes like reproduction, development, and tissue repair," says Morris F. White, Ph.D., of the Joslin Diabetes Center and the Howard Hughes Medical Institute.

Two years ago, a group of scientists led by Dr. White discovered that IRS-2 is required not only for normal insulin action, but also promotes the survival of pancreatic beta cells that secrete insulin into the blood. Insulin action and secretion are two of the important processes that fail in people with type 2 diabetes, and never before was the link between insulin use and production so closely established. Now, the addition of obesity and reproduction to the list of processes regulated by IRS-2 suggests that type 2 diabetes and its association with obesity, reduced fertility, and other complications might share a common molecular defect.

Dr. White's group began to study IRS-2 in mice because it helps them understand the problems that occur during type 2 diabetes. Type 2 diabetes is an increasingly common disease that occurs in people when the cells in the liver, muscle and fat require more insulin to control blood glucose than the pancreatic beta cells can make. When IRS-2 is present and working, surprisingly low levels of insulin can keep blood glucose under control. But like people with type 2 diabetes, genetically altered mice lacking IRS-2 need more insulin and eventually develop diabetes, not because the insulin resistance is so severe, but because their pancreatic islets fail to make enough insulin to keep up with the greater demand.

"IRS-2 failure is a double-edged sword," says Dr. White, "because IRS-2 is needed so peripheral tissues can use insulin, and needed to help keep pancreatic beta cells alive longer so they can secrete more insulin to the resistant tissues."

Female mice lacking IRS-2 develop diabetes between 18-20 weeks of age, much later in life than their male counterparts who die of diabetic complications around 10 weeks of age. But long before the female mice develop diabetes, they over-eat and become obese, and have reduced fertility.

"In the beginning, these findings surprised us," says Deborah J. Burks, Ph.D., of Joslin and the lead author of the study, "but now we're beginning to appreciate that the IRS-2 branch of the insulin signaling pathway might have an important job in the brain to help coordinate food intake and promote reproduction."

The IRS-2-deficient mice over-eat despite the presence of excess amounts of leptin in their blood. Leptin is a protein produced in fat cells that circulates to the hypothalamus, a special region of the brain, to suppress appetite. However, without IRS-2, female mice respond weakly to the appetite-suppressing effects of leptin, and thus over-eat and gain weight until enough leptin is finally produced to suppress their appetite. Since IRS-2 molecules transmit insulin signals within cells, these studies suggest that insulin itself might participate in the regulation of food intake.

The ability of the brain to detect and respond to blood insulin levels has been controversial for decades, but these results and other recent evidence suggest that to regulate appetite the brain must detect circulating insulin. Scientists and clinicians have known for a long time that obesity and chronic insulin resistance go hand-in-hand, but they usually say that obesity causes insulin resistance. That's one of the reasons why obesity is said to be a risk factor for type 2 diabetes. But evidence in this study suggests that it could be the other way around, with insulin resistance initially dysregulating appetite that contributes to obesity. The developing obesity exacerbates the insulin resistance, which further burdens the pancreatic beta cells.

"It appears that IRS-2 helps coordinates insulin production and nutrient metabolism to promote important biological processes that reflect our health and fitness such as appetite and fertility," Dr. Burks says. Female mice without IRS-2 have a difficult time getting pregnant weeks before they develop diabetes. The root of this deficiency begins before birth, as ovaries in IRS-2 deficient mice develop fewer primary oocytes. But in adults, the reproductive cycle fails, not only because the ovaries are small and unresponsive to gonadotropins, but also because cells in the pituitary secrete less of these hormones. Clinicians have known for years that women with polycystic ovarian syndrome (PCOS) are frequently obese, but they are starting to realize that these infertile women are usually insulin resistant. This combination of endocrine disorders might be related through the action of IRS-2.

"Type 2 diabetes is more than a problem with blood glucose," Dr. White says. "High blood glucose is the easiest thing to measure, but the underlying cause might reside in the IRS-2 branch of the insulin-signaling pathway. You can live with reduced IRS-2 function, but you might be glucose intolerant, over-eat and gain weight; have a difficult time becoming pregnant and when you do, develop gestational diabetes; and worst of all, face life with pancreatic beta cells that eventually fail to make enough insulin to avoid the life-threatening consequences of type 2 diabetes."

Standard treatments for diabetes don't target IRS-2 signaling. "Given the critical role of this molecule in the maintenance of glucose homeostasis and reproduction, it might be ideal to develop new drugs to repair IRS-2 function," say the researchers, "because these therapies might reduce weight gain and the amount of insulin needed in the body while ensuring adequate insulin production throughout life."
　　
　　(From HealthWorld Online)