Sci. Aging Knowl. Environ., 4 January 2006
Vol. 2006, Issue 1, p. nf1
[DOI: 10.1126/sageke.2006.1.nf1]


Uncoupling Insulin

SIRT1 boosts insulin release by blocking mitochondrial protein

Mitch Leslie

Like a good actor, the Sir2 proteins don't stick to the same role. That's the message of a new study confirming that the proteins exert opposite effects on the glucose-regulating hormone insulin depending on whether they are in worms or mammals. The work fills in details of how the mammalian protein governs insulin.

Sir2 got typecast after researchers discovered that extra doses of its gene hike the number of times yeast cells can duplicate, one gauge of fungal life span. Further work revealed that cranking up the number of copies of worm Sir2 also boosts survival and suggested that the enzyme promotes longevity by squelching the insulin/insulin-like growth factor 1 pathway. But recent research indicates that SIRT1, the mammalian equivalent of Sir2, breaks the pattern. Earlier this year, cell biologist Shin-Ichiro Imai of Washington University School of Medicine in St. Louis, Missouri, and colleagues engineered mice to fashion extra SIRT1 in the {beta} cells of the pancreas, which pump out insulin, a hormone that spurs body cells to absorb blood sugar. Compared with control mice, the altered rodents released more of the hormone and were better at maintaining normal blood glucose amounts (see "Tuning Up the Pancreas"). The group's microarray studies suggested that SIRT1 ramps up insulin release by blocking production of a molecule called uncoupling protein 2 (UCP2).

To nail down how SIRT1 controls insulin, molecular biologist Laura Bordone of the Novartis Institutes for BioMedical Research in Cambridge, Massachusetts, and colleagues scrutinized mice that lack SIRT1. The animals fashioned less insulin and harbored more UCP2 in their cells than did normal mice, consistent with the Imai team's results. Dosing normal pancreatic cells with a molecule that reduces SIRT1 output also boosted UCP2 quantities. After a jolt of glucose, these SIRT1-suppressed cells exude less insulin than usual. However, adding a UCP2-blocking molecule bumped up insulin release. SIRT1 latches onto the on-off switch for UCP2's gene, the team showed. These findings "provide a mechanism to explain the role of SIRT1 in insulin secretion," says Bordone. Uncoupling proteins are best known for their ability to shift mitochondria from making ATP to producing heat that warms the body. But these two studies suggest that UCP2 also helps SIRT1 manage insulin.

The group found further evidence that SIRT1's actions differ from Sir2's. Calorie restriction jacks up Sir2 activity in flies and worms. Although the team didn't put the rodents on this drastic diet, their results did hint that SIRT1 activity falls during short periods of hunger. Researchers still need to determine how SIRT1 responds to calorie restriction, Bordone says. Why SIRT1 seems to deviate from the norm is a mystery, she adds, but it might enable mammals to fine-tune insulin release according to food availability and different tissues' sensitivity to the hormone.

"I'm really glad to see this paper," Imai says, because two independent labs using opposite methods have now demonstrated that SIRT1 cranks up insulin export by controlling UCP2. The roles of the Sir proteins in different organisms aren't necessarily contradictory, he adds. In mammals, SIRT1 might be a master regulator that quashes insulin and related molecules in some tissues and stimulates them in other tissues, Imai says. Further research might reveal which other parts SIRT1 can play.

January 4, 2006
  1. L. Bordone et al., Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic {beta} cells. PLoS Biol. 4, e31 (2006). doi:10.1371/journal.pbio.0040031
Citation: M. Leslie, Uncoupling Insulin. Sci. Aging Knowl. Environ. 2006 (1), nf1 (2006).

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