题名：Involvement of the Clock Gene Rev-erb alpha in the Regulation of Glucagon Secretion in Pancreatic Alpha-Cells.
作者：VIEIRA E; MARROQUI L; FIGUEROA AL; MERINO B; FERNANDEZ-RUIZ R; NADAL A; BURRIS TP; GOMIS R; QUESADA I;
来源：PLoS One. 2013 Jul 25;8(7):e69939. doi: 10.1371/journal.pone.0069939. Print 2013. [ IF= 3.73 ] ]
摘要：Disruption of pancreatic clock genes impairs pancreatic beta-cell function,
leading to the onset of diabetes. Despite the importance of pancreatic
alpha-cells in the regulation of glucose homeostasis and in diabetes
pathophysiology, nothing is known about the role of clock genes in these cells.
Here, we identify the clock gene Rev-erb alpha as a new intracellular regulator
of glucagon secretion. Rev-erb alpha down-regulation by siRNA (60-70% inhibition)
in alphaTC1-9 cells inhibited low-glucose induced glucagon secretion (p<0.05) and
led to a decrease in key genes of the exocytotic machinery. The Rev-erb alpha
agonist GSK4112 increased glucagon secretion (1.6 fold) and intracellular calcium
signals in alphaTC1-9 cells and mouse primary alpha-cells, whereas the Rev-erb
alpha antagonist SR8278 produced the opposite effect. At 0.5 mM glucose,
alphaTC1-9 cells exhibited intrinsic circadian Rev-erb alpha expression
oscillations that were inhibited by 11 mM glucose. In mouse primary alpha-cells,
glucose induced similar effects (p<0.001). High glucose inhibited key genes
controlled by AMPK such as Nampt, Sirt1 and PGC-1 alpha in alphaTC1-9 cells
(p<0.05). AMPK activation by metformin completely reversed the inhibitory effect
of glucose on Nampt-Sirt1-PGC-1 alpha and Rev-erb alpha. Nampt inhibition
decreased Sirt1, PGC-1 alpha and Rev-erb alpha mRNA expression (p<0.01) and
glucagon release (p<0.05). These findings identify Rev-erb alpha as a new
intracellular regulator of glucagon secretion via AMPK/Nampt/Sirt1 pathway.