Abstract
Glucose-stimulated insulin secretion (GSIS) is mediated in part by glucose metabolism-driven increases in ATP/ADP ratio, but by-products of mitochondrial glucose metabolism also play an important role. Here we investigate the role of the mitochondrial citrate/isocitrate carrier (CIC) in regulation of GSIS. Inhibition of CIC activity in INS-1-derived 832/13 cells or primary rat islets by the substrate analogue 1,2,3-benzenetricarboxylate (BTC) resulted in potent inhibition of GSIS, involving both first and second phase secretion. A recombinant adenovirus containing a CIC-specific siRNA (Ad-siCIC) dose-dependently reduced CIC expression in 832/13 cells and caused parallel inhibitory effects on citrate accumulation in the cytosol. Ad-siCIC treatment did not affect glucose utilization, glucose oxidation, or ATP/ADP ratio but did inhibit glucose incorporation into fatty acids and glucose-induced increases in NADPH/NADP+ ratio relative to cells treated with a control siRNA virus (Ad-siControl). Ad-siCIC also inhibited GSIS in 832/13 cells, whereas overexpression of CIC enhanced GSIS and raised cytosolic citrate levels. In normal rat islets, Ad-siCIC treatment also suppressed CIC mRNA levels and inhibited GSIS. We conclude that export of citrate and/or isocitrate from the mitochondria to the cytosol is an important step in control of GSIS.
Highlights
The mechanism of glucose-stimulated insulin secretion (GSIS)2 from pancreatic islet -cells is not completely understood
Insulin secretion in the presence of low glucose ϩ 30 mM KCl was not different in Ad-siCIC compared with Ad-siControl-treated cells (430 Ϯ 14 versus 412 Ϯ 19 microunits/mg of protein; control versus Ad-siCIC), indicating that suppression of citrate/isocitrate carrier (CIC) expression does not interfere with nutrient-independent stimulation of insulin secretory granule exocytosis
The studies summarized demonstrate that the mitochondrial tricarboxylate or citrate/isocitrate carrier (CIC) plays an important role in GSIS
Summary
The mechanism of glucose-stimulated insulin secretion (GSIS)2 from pancreatic islet -cells is not completely understood. Recent reports indicate that mouse islets lack malic enzyme activity [25] and that siRNA-mediated suppression of cytosolic NADP-dependent ICDc activity strongly impairs GSIS, pyruvate cycling, and NADPH production [18], suggesting that CIC could play a important role in regulation of insulin secretion.
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