详细记录  
题名:The loss of Sirt1 in mouse pancreatic beta cells impairs insulin secretion by disrupting glucose sensing.
作者:LUU L; DAI FF; PRENTICE KJ; HUANG X; HARDY AB; HANSEN JB; LIU Y; JOSEPH JW; WHEELER MB;
来源:Diabetologia. 2013 Jun 20. [ IF= 6.81 ] ]
URL :10.1007/s00125-013-2946-5
日期:20130702
摘要:AIMS/HYPOTHESIS: Sirtuin 1 (SIRT1) has emerged as a key metabolic regulator of
glucose homeostasis and insulin secretion. Enhanced SIRT1 activity has been shown
to be protective against diabetes, although the mechanisms remain largely
unknown. The aim of this study was to determine how SIRT1 regulates insulin
secretion in the pancreatic beta cell. METHODS: Pancreatic beta cell-specific
Sirt1 deletion was induced by tamoxifen injection in 9-week-old
Pdx1CreER:floxSirt1 mice (Sirt1BKO). Controls were injected with vehicle. Mice
were assessed metabolically via glucose challenge, insulin tolerance tests and
physical variables. In parallel, Sirt1 short interfering RNA-treated MIN6 cells
(SIRT1KD) and isolated Sirt1BKO islets were used to investigate the effect of
SIRT1 inactivation on insulin secretion and gene expression. RESULTS: OGTTs
showed impaired glucose disposal in Sirt1BKO mice due to insufficient insulin
secretion. Isolated Sirt1BKO islets and SIRT1KD MIN6 cells also exhibited
impaired glucose-stimulated insulin secretion. Subsequent analyses revealed
impaired alpha-ketoisocaproic acid-induced insulin secretion and attenuated
glucose-induced Ca2+ influx, but normal insulin granule exocytosis in Sirt1BKO
beta cells. Microarray studies revealed a large cluster of mitochondria-related
genes, the expression of which was dysregulated in SIRT1KD MIN6 cells. Upon
further analysis, we demonstrated an explicit defect in mitochondrial function:
the inability to couple nutrient metabolism to mitochondrial membrane
hyperpolarisation and reduced oxygen consumption rates.
CONCLUSIONS/INTERPRETATION: Taken together, these findings indicate that in beta
cells the deacetylase SIRT1 regulates the expression of specific
mitochondria-related genes that control metabolic coupling, and that a decrease
in beta cell Sirt1 expression impairs glucose sensing and insulin secretion.

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