The mitochondrial citrate/isocitrate carrier plays a regulatory role in glucose-stimulated insulin secretion.
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.
Joseph
Jamie W
JW
Sarah W. Stedman Nutrition and Metabolism Center, Department of Pharmacology, Duke University Medical Center, Durham, North Carolina 27704, USA.
Jensen
Mette V
MV
Ilkayeva
Olga
O
Palmieri
Ferdinando
F
Alárcon
Cristina
C
Rhodes
Christopher J
CJ
Newgard
Christopher B
CB
D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D017920:Antiporters / Q000737:chemistry* / Q000502:physiology*; D001555:Benzene Derivatives / Q000494:pharmacology; D001692:Biological Transport; D002352:Carrier Proteins / Q000737:chemistry / Q000502:physiology*; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007425:Intracellular Membranes / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism*; D027361:Organic Anion Transporters / Q000737:chemistry* / Q000502:physiology*; D051381:Rats; D014233:Tricarboxylic Acids / Q000494:pharmacology
D017920:Antiporters; D001555:Benzene Derivatives; D002352:Carrier Proteins; D007328:Insulin; D026901:Membrane Transport Proteins; D027361:Organic Anion Transporters; D014233:Tricarboxylic Acids; C020723:citrate-binding transport protein; C515964:citrate-isocitrate carrier, rat; C004288:benzene 1,2,3-tricarboxylic acid; D005947:Glucose