Abstract
Sir2 and insulin/IGF-1 are the major pathways that impinge upon aging in lower organisms. In Caenorhabditis elegans a possible genetic link between Sir2 and the insulin/IGF-1 pathway has been reported. Here we investigate such a link in mammals. We show that Sirt1 positively regulates insulin secretion in pancreatic β cells. Sirt1 represses the uncoupling protein (UCP) gene UCP2 by binding directly to the UCP2 promoter. In β cell lines in which Sirt1 is reduced by SiRNA, UCP2 levels are elevated and insulin secretion is blunted. The up-regulation of UCP2 is associated with a failure of cells to increase ATP levels after glucose stimulation. Knockdown of UCP2 restores the ability to secrete insulin in cells with reduced Sirt1, showing that UCP2 causes the defect in glucose-stimulated insulin secretion. Food deprivation induces UCP2 in mouse pancreas, which may occur via a reduction in NAD (a derivative of niacin) levels in the pancreas and down-regulation of Sirt1. Sirt1 knockout mice display constitutively high UCP2 expression. Our findings show that Sirt1 regulates UCP2 in β cells to affect insulin secretion.
Highlights
Glucose homeostasis is maintained, in part, by pancreatic b cells, which secrete insulin in a highly regulated sequence of dependent events [1]. b cells metabolize glucose, resulting in an increase in the ATP/ADP ratio, the closing of the ATPdependent Kþ channel, the activation of the voltage-gated Caþ channel and Caþ influx, and the fusion of secretory vesicles to the plasma membrane to release insulin
We describe a new level of regulation in which Homolog of the yeast silencing information regulator2 (Sirt1) represses UCP2 to modulate the amplitude of insulin induction by glucose in b cells
We suggest that this mechanism serves to regulate chronic levels of insulin in accord with levels of food intake
Summary
In part, by pancreatic b cells, which secrete insulin in a highly regulated sequence of dependent events [1]. b cells metabolize glucose, resulting in an increase in the ATP/ADP ratio, the closing of the ATPdependent Kþ channel, the activation of the voltage-gated Caþ channel and Caþ influx, and the fusion of secretory vesicles to the plasma membrane to release insulin. Short-term food limitation (i.e., overnight [O/N] fasting) will elicit the mobilization of glycogen stores and fat from WAT for metabolism, and the lower level of blood glucose during fasting will result in low levels of insulin production by b cells. In mammals a characteristic set of physiological changes takes place during long-term CR, which overlaps the rapid physiological adaptations to short-term food limitation. One such change is the use of dietary fat or fat mobilized from WAT for energy [4]. These changes keep glucose available for the brain, and are closely associated with the longevity elicited by CR. The paucity of fat in WAT appears to be sufficient per se to promote a degree of longevity, since mice engineered for leanness—for example, a WAT-specific knockout (KO) of the insulin receptor—live longer [6,7]
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