详细记录  
题名:Chronic High Glucose and Pyruvate Levels Differentially Affect Mitochondrial Bioenergetics and Fuel-stimulated Insulin Secretion from Clonal INS-1 832/13 Cells.
作者:GOHRING I; SHAROYKO VV; MALMGREN S; ANDERSSON LE; SPEGEL P; NICHOLLS DG; MULDER H;
来源:J Biol Chem. 2014 Feb 7;289(6):3786-98. doi: 10.1074/jbc.M113.507335. Epub 2013 [ IF= 0.00 ] ]
URL :10.1074/jbc.M113.507335
日期:20140317
摘要:Glucotoxicity in pancreatic beta-cells is a well established pathogenetic process
in type 2 diabetes. It has been suggested that metabolism-derived reactive oxygen
species perturb the beta-cell transcriptional machinery. Less is known about
altered mitochondrial function in this condition. We used INS-1 832/13 cells
cultured for 48 h in 2.8 mm glucose (low-G), 16.7 mm glucose (high-G), or 2.8 mm
glucose plus 13.9 mm pyruvate (high-P) to identify metabolic perturbations.
High-G cells showed decreased responsiveness, relative to low-G cells, with
respect to mitochondrial membrane hyperpolarization, plasma membrane
depolarization, and insulin secretion, when stimulated acutely with 16.7 mm
glucose or 10 mm pyruvate. In contrast, high-P cells were functionally
unimpaired, eliminating chronic provision of saturating mitochondrial substrate
as a cause of glucotoxicity. Although cellular insulin content was depleted in
high-G cells, relative to low-G and high-P cells, cellular functions were largely
recovered following a further 24-h culture in low-G medium. After 2 h at 2.8 mm
glucose, high-G cells did not retain increased levels of glycolytic or TCA cycle
intermediates but nevertheless displayed increased glycolysis, increased
respiration, and an increased mitochondrial proton leak relative to low-G and
high-P cells. This notwithstanding, titration of low-G cells with low
protonophore concentrations, monitoring respiration and insulin secretion in
parallel, showed that the perturbed insulin secretion of high-G cells could not
be accounted for by increased proton leak. The present study supports the idea
that glucose-induced disturbances of stimulus-secretion coupling by
extramitochondrial metabolism upstream of pyruvate, rather than exhaustion from
metabolic overload, underlie glucotoxicity in insulin-producing cells.

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