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Protein that regulates aging may provide key to new diabetes therapies

August 19, 2005

Opening the possibility of new therapies for type 2 diabetes, researchers at Washington University School of Medicine in St. Louis have found that a protein called Sirt1 enhances the secretion of insulin in mice and allows them to better control blood glucose levels. Their study will appear in the August 17 issue of Cell Metabolism.

According to senior author Shin-ichiro Imai, M.D., the finding suggests that therapies that increase the activity of Sirt1 could be of benefit in type 2 diabetes. "We are especially interested in how we can activate Sirt1 in a natural way," says Imai, assistant professor of molecular biology and pharmacology. "One option we are investigating is increasing the body's synthesis of NAD, a necessary cofactor for Sirt1's function. Because Vitamin B3, often called niacin, is a building block of NAD, it has interesting potential."

Sirt1 is referred to as Sir2 in lower organisms where it has previously proven to be a key to aging and longevity: Increasing the amount of Sir2 dramatically extends life spans in experimental yeast, worms and flies.

"Researchers, such as myself, who study aging are enthusiastically investigating Sir2," Imai says. "In 2000, I found that Sir2 responds to the level of energy in the form of NAD available in cells. Further research has shown that Sir2 connects nutrient status and longevity."

In mammals, scientists have shown that restricting calories can extend life span and also leads to an increase in Sirt1, the mammalian version of Sir2. Sirt1 reacts to changes in nutrient availability in a wide variety of tissues.

Uptake of the basic nutrient glucose is controlled by insulin, and Imai's research group found that the cells responsible for secreting insulin-Beta cells in the pancreas-also produce Sirt1. So they investigated the effects of increasing the amount of Sirt1 in pancreatic Beta cells in mice to better understand the link between Sirt1 and glucose metabolism.

They designed transgenic mice with a genetic switch that turned up the gene that makes Sirt1 in Beta cells. "We confirmed that the mice overexpress Sirt1 proteins specifically in pancreatic Beta cells, not in other kinds of pancreatic cells, and not in brain, liver, kidney, fat or muscle," says Kathryn Moynihan, graduate research assistant.

Compared to wild-type mice, the transgenic mice had the same levels of blood glucose and insulin both when well-fed and during fasting. They were of similar weights and their pancreatic cells looked very similar in size and structure.

But when the two sets of mice were given a large dose of glucose, a difference became apparent. The transgenic mice produced more insulin and cleared glucose from their blood streams significantly faster than did wild-type mice.

Challenging the mice's systems with glucose in this manner mimics the glucose tolerance tests used to check for diabetes in human patients. Diabetic patients clear glucose more slowly than do non-diabetics in these tests.

"If your system reacted like that of these transgenic mice, you could process sugar more quickly and much more efficiently after eating sweets," Imai says.

The research group found that the transgenic mice retained their unique Beta cell function as they aged from three months to eight months, the equivalent of middle age in humans. The researchers are continuing to track the progress of the mice, which are now about 20 months old.

An analysis of the activity of genes in the Beta cells showed that several genes linked to insulin secretion were affected by the increased expression of Sirt1. Most prominently, Sirt1 turned down the activity of a gene that decreases insulin secretion.

"The gene makes uncoupling protein 2, which is intimately connected to ATP production," Imai says. "ATP is a fundamental source of energy for metabolism, and by downregulating uncoupling protein 2, Sirt1 not only enhances insulin secretion, but increases ATP energy. This is a further indication of the connection between Sirt1 and energy status."

Imai feels that Sirt1 is probably a very important regulator that integrates cellular response to different types of nutrients, such as glucose, amino acids, and fatty acids. Continued research in the lab will use the transgenic mice to further investigate Sirt1's role in this response.

Washington University School of Medicine