Abstract
BackgroundIn 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.ResultsExposure 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.ConclusionsOur 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.
Highlights
In the progression towards diabetes, glucolipotoxicity is one of the main causes of pancreatic beta cell pathology
Chronic glucolipotoxicity reduces insulin secretion in rat pancreatic islets To evaluate the effect of high glucose and fatty acid concentrations on insulin secretion, we incubated rat pancreatic islets as mentzioned above for 72 h; untreated islets were used as control
Mitochondrial number/activity and cytosolic ATP levels are reduced under chronic glucolipotoxic conditions Since a primary outcome of glucose metabolism is ATP synthesis from mitochondria [27], we investigated the effect of chronic glucolipotoxic conditions on mitochondrial DNA copy number/activity and cellular ATP
Summary
In the progression towards diabetes, glucolipotoxicity is one of the main causes of pancreatic beta cell pathology. Over a period of time, consistently elevated levels of blood glucose and free fatty acids lead to glucolipotoxicity- mediated pancreatic beta cell dysfunction [3,4]. It is accepted that elevated glucose levels are required to mediate the lipotoxic effects, including inhibition of glucose-stimulated insulin secretion (GSIS), impaired insulin gene expression and apoptosis [4,5,6,7,8]. Mitochondrial oxaloacetate generates citrate, a cataplerotic signal, which is transported to the cytosol and broken down into acetyl-CoA initiating fatty acid synthesis. Malonyl-CoA inhibits carnitine-palmitoyl transferase-1 (CPT-1) blocking fatty acid oxidation and resulting in the buildup of longchain acyl-CoA esters (LC-CoA) in the cytosol [10]. Voltage-gated calcium channels open, causing an influx of extracellular calcium and exocytosis of insulin granules [13]
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