题名：Chronic glucolipotoxic conditions in pancreatic islets impair insulin secretion due to dysregulated calcium dynamics, glucose responsiveness and mitochondrial activity.
作者：SOMESH BP; VERMA MK; SADASIVUNI MK; MAMMEN-OOMMEN A; BISWAS S; SHILPA PC; REDDY AK; YATEESH AN; PALLAVI PM; NETHRA S; SMITHA R; NEELIMA K; NARAYANAN U; JAGANNATH MR;
来源：BMC Cell Biol. 2013 Jul 1;14:31. doi: 10.1186/1471-2121-14-31. [ IF= 0.00 ] ]
摘要：BACKGROUND: In the progression towards diabetes, glucolipotoxicity is one of the
main causes of pancreatic beta cell pathology. The aim of this study was to
examine the in vitro effects of chronic glucolipotoxic conditions on cellular
responses in pancreatic islets, including glucose and fat metabolism, Calcium
mobilization, insulin secretion and insulin content. RESULTS: Exposure of islets
to chronic glucolipotoxic conditions decreased glucose stimulated insulin
secretion in vitro. Reduced protein levels of Glut2/slc2a2, and decreased
glucokinase and pyruvate carboxylase mRNA levels indicated a significant lowering
in glucose sensing. Concomitantly, both fatty acid uptake and triglyceride
accumulation increased significantly while fatty acid oxidation decreased. This
general suppression in glucose metabolism correlated well with a decrease in
mitochondrial number and activity, reduction in cellular ATP content and
dampening of the TCA cycle. Further, we also observed a decrease in IP3 levels
and lower Calcium mobilization in response to glucose. Importantly, chronic
glucolipotoxic conditions in vitro decreased insulin gene expression, insulin
content, insulin granule docking (to the plasma membrane) and insulin secretion.
CONCLUSIONS: Our results present an integrated view of the effects of chronic
glucolipotoxic conditions on known and novel signaling events, in vitro, that
results in reduced glucose responsiveness and insulin secretion.