Regulation of insulin secretion by energy metabolism in pancreatic B-cell mitochondria. Studies with a non-metabolizable leucine analogue.
In mouse pancreatic islets the kinetics of insulin secretion and O2 uptake in response to the non-metabolizable leucine analogue (+/-)-BCH (2-endo- aminonorbornane -2-carboxylic acid) were compared. In addition, the fuel-mobilizing effect of (+/-)-BCH was studied with a mitochondrial fraction from islets. (1) Within 2 min 20 mM-(+/-)-BCH markedly enhanced insulin release or O2 consumption by islets respiring in the absence of exogenous fuels. During prolonged exposure to 20 mM-(+/-)-BCH secretion declined more rapidly than O2 uptake. (2) L-Glutamine (10 mM) prevented the decrease of both insulin release and O2 uptake of islets exposed to 20mM-(+/-)-BCH. During the second phase of insulin release in response to 20 mM-(+/-)-BCH + 10 mM-L-glutamine, kinetics of secretion and respiration correlated closely. (3) Initial peaks were consistently seen in the (+/-)-BCH-induced secretory profiles, but never in the respiratory profiles. (4) In contrast with L-glycerol 3-phosphate, L-malate or pyruvate, L-glutamine or L-glutamate maintained low rates of oxidative phosphorylation in B-cell mitochondria. The effects of L-glutamine or L-glutamate were potentiated severalfold by (+/-)-BCH. (5) The effects of other branched-chain amino acids on oxidative phosphorylation resembled their effects on insulin release, redox state of nicotinamide nucleotides and glutamate dehydrogenase activity. (6) The results support the view that (+/-)-BCH stimulates insulin secretion via a primary enhancement of hydrogen supply to the respiratory chain of B-cell mitochondria.
D000255:Adenosine Triphosphate / Q000378:metabolism; D000596:Amino Acids / Q000494:pharmacology*; D000597:Amino Acids, Branched-Chain / Q000494:pharmacology; D000598:Amino Acids, Cyclic; D000818:Animals; D004734:Energy Metabolism / Q000187:drug effects; D005973:Glutamine / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008293:Malates / Q000494:pharmacology; D008297:Male; D051379:Mice; D008820:Mice, Obese; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D011773:Pyruvates / Q000494:pharmacology; D019289:Pyruvic Acid; D012636:Secretory Rate / Q000187:drug effects
D000596:Amino Acids; D000597:Amino Acids, Branched-Chain; D000598:Amino Acids, Cyclic; D007328:Insulin; D008293:Malates; D011773:Pyruvates; D005973:Glutamine; C006504:2-aminobicyclo(2,2,1)heptane-2-carboxylic acid; C030298:malic acid; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate