Sci. Aging Knowl. Environ., 24 August 2005
Tuning Up the Pancreas
Mammalian version of yeast longevity protein boosts efficiency of insulin-making cells
Even the most adept mechanic can't make a Ford Focus run like a Porsche. But genetic tinkering can transform base-model mouse pancreas cells into high-performance insulin producers, according to new research. Cranking up a protein that promotes longevity in yeast and worms helps mice control their blood sugar, suggesting a new target for drugs to prevent and treat diabetes.
Boosting quantities of the Sir2p protein extends yeast longevity (see "Kaeberlein Perspective"). The worm and fruit fly equivalents of Sir2 also enhance survival, but it's unclear whether the mammalian version, known as SIRT1, influences life span. However, several studies reveal that SIRT1 helps adjust metabolism. For example, the protein spurs cells to burn fat and helps hungry mice build up their supplies of glucose (see "Counterattack" and "Sugar Rush"). SIRT1 operates in many cell types, including cells of the pancreas, which release the hormone insulin that cuts blood sugar quantities. Cell biologist Shin-Ichiro Imai of Washington University School of Medicine in St. Louis, Missouri, and colleagues hypothesized that SIRT1 helps govern the release of insulin.
To evaluate the idea, they engineered mice to pump out extra SIRT1 only in cells, and then tested blood samples from young adult animals. Whether they were hungry or full, the altered rodents showed normal amounts of insulin and blood glucose. However, the mice excelled after the researchers injected them with sugar, simulating a meal full of sweets. The modified animals restored blood glucose amounts to normal faster than did controls, and they produced more insulin. To determine how SIRT1 adjusts insulin output, the researchers used microarrays to gauge gene activity in cells. Those experiments showed that SIRT1 quells several genes, including one called uncoupling protein 2 that hinders insulin release. The researchers don't yet know whether the altered mice will live longer, but the animals do carry their quick-release cells into middle age.
Previous findings suggest that quashing the insulin/insulin-like growth factor 1 pathway is beneficial--it can extend life span in worms and flies, for instance. But Imai emphasizes that the new results don't conflict with that idea. The altered mice don't have chronically high insulin, he says. Instead, their cells are more efficient and can emit extra amounts of the hormone swiftly to alleviate a glucose glut. The results suggest that stimulating SIRT1 might help diabetics rein in their oversupply of blood glucose, Imai says. Other scientists are already studying a compound in red wine called resveratrol that rouses SIRT1 (see "Resveratrol to the Rescue"). But prodding one of SIRT1's partners, a compound called NAD, might also do the trick, Imai says.
The study is the first to show that ramping up SIRT1 production in a mammal brings metabolic benefits, says molecular geneticist David Sinclair of Harvard Medical School in Boston, who discovered resveratrol's effects. A key follow-up question, he says, is whether the altered mice's hair-trigger cells will help them fend off diabetes. Researchers also need to determine whether cranking up SIRT1 throughout the body is salutary, he says. Finding those answers might reveal whether speedy cells can help patients outrace diabetes.
August 24, 2005
Science of Aging Knowledge Environment. ISSN 1539-6150