Protein That Regulates Aging May Provide Key To New Diabetes Therapies

According to senior author Shin-ichiro Imai,M.D., the finding suggests that therapies that increase the activity ofSirt1 could be of benefit in type 2 diabetes. "We are especiallyinterested in how we can activate Sirt1 in a natural way," says Imai,assistant professor of molecular biology and pharmacology. "One optionwe are investigating is increasing the body's synthesis of NAD, anecessary cofactor for Sirt1's function. Because Vitamin B3, oftencalled niacin, is a building block of NAD, it has interestingpotential."

Sirt1 is referred to as Sir2 in lower organisms whereit has previously proven to be a key to aging and longevity: Increasingthe amount of Sir2 dramatically extends life spans in experimentalyeast, worms and flies.

"Researchers, such as myself, who studyaging are enthusiastically investigating Sir2," Imai says. "In 2000, Ifound that Sir2 responds to the level of energy in the form of NADavailable in cells. Further research has shown that Sir2 connectsnutrient status and longevity."

In mammals, scientists have shownthat restricting calories can extend life span and also leads to anincrease in Sirt1, the mammalian version of Sir2. Sirt1 reacts tochanges in nutrient availability in a wide variety of tissues.

Uptakeof the basic nutrient glucose is controlled by insulin, and Imai'sresearch group found that the cells responsible for secretinginsulin—Beta cells in the pancreas—also produce Sirt1. So theyinvestigated the effects of increasing the amount of Sirt1 inpancreatic Beta cells in mice to better understand the link betweenSirt1 and glucose metabolism.

They designed transgenic mice witha genetic switch that turned up the gene that makes Sirt1 in Betacells. "We confirmed that the mice overexpress Sirt1 proteinsspecifically in pancreatic Beta cells, not in other kinds of pancreaticcells, and not in brain, liver, kidney, fat or muscle," says KathrynMoynihan, graduate research assistant.

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

But when the two sets of mice were given a large doseof glucose, a difference became apparent. The transgenic mice producedmore insulin and cleared glucose from their blood streams significantlyfaster than did wild-type mice.

Challenging the mice's systemswith glucose in this manner mimics the glucose tolerance tests used tocheck for diabetes in human patients. Diabetic patients clear glucosemore slowly than do non-diabetics in these tests.

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

Theresearch group found that the transgenic mice retained their uniqueBeta cell function as they aged from three months to eight months, theequivalent of middle age in humans. The researchers are continuing totrack the progress of the mice, which are now about 20 months old.

Ananalysis of the activity of genes in the Beta cells showed that severalgenes linked to insulin secretion were affected by the increasedexpression of Sirt1. Most prominently, Sirt1 turned down the activityof a gene that decreases insulin secretion.

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

Imai feels thatSirt1 is probably a very important regulator that integrates cellularresponse to different types of nutrients, such as glucose, amino acids,and fatty acids. Continued research in the lab will use the transgenicmice to further investigate Sirt1's role in this response.

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MoynihanKA, Grimm AA, Plueger MM, Bernal-Mizrachi E, Ford E, Cras-Méneur C,Permutt MA, Imai S. Increased dosage of mammalian Sir2 in pancreatic ßcells enhances glucose-stimulated insulin secretion in mice. CellMetabolism, August 17, 2005.

Funding from the National Instituteon Aging, the National Institute of Diabetes & Digestive &Kidney Diseases through the Washington University Diabetes ResearchTraining Center, the National Center for Research Resources, theWashington University Center for Aging, the Lucille P. Markey SpecialEmphasis Pathway in Human Pathology and the Glenn/AFAR Scholarship forResearch in the Biology of Aging supported this research.