Fig. 7.

A model for the age-associated loss of the glucose-responsive phenotypes in aged BESTO mice. Sirt1 promotes insulin secretion through two independent mechanisms in pancreatic β cells. In one mechanism, Sirt1 mediates the repression of Ucp2 expression and thereby increases ATP content, resulting in the enhancement of GSIS. In the other mechanism, Sirt1 regulates the expression of an unidentified factor that acts downstream of β cell depolarization and possibly stimulates insulin granule exocytosis, resulting in the enhancement of (KCl)-stimulated insulin secretion (KSIS). Aging affects systemic NAD biosynthesis, perhaps at the level of biosynthesis of NMN in plasma, and decreases Sirt1 activity in pancreatic β cells of aged BESTO mice.