(A) Sirt1 gene expression in alphaTC1-9 cells treated with 0.5 mM, 11 mM glucose or 500 nM FK 866 for 6 hours (n = 7). (B) PGC-1 alpha gene expression in alphaTC1-9 cells treated with 0.5 mM, 11 mM glucose or 500 nM FK 866 for 6 hours (n = 6–7). (C) Rev-erb alpha gene expression in alphaTC1-9 cells treated with 0.5 mM, 11 mM glucose or 500 nM FK 866 for 6 hours (n = 7). (D) Per2 gene expression in alphaTC1-9 cells treated with 0.5 mM, 11 mM glucose or 500 nM FK 866 for 6 hours (n = 7–8). (E) Glucagon secretion from mouse pancreatic islets stimulated for 1.5 hour with 0.5 mM, 11 mM glucose or 500 nM FK 866 (n = 6). *p<0.05, **p<0.01, *** p<0.001. Data are expressed as mean ±S.E.M. (F) Proposed model for regulation of glucagon secretion via an AMPK-Nampt-Sirt1-Rev-erb alpha mechanism. At low glucose concentrations AMPK is activated which will trigger the Nampt-Sirt pathway increasing Rev-erb alpha expression levels and glucagon secretion. Conversely, high glucose will inhibit AMPK-Nampt-Sirt pathway and consequently Rev-erb alpha expression levels leading to a decrease in glucagon release.