Acute metabolic amplification of insulin secretion in mouse islets: Role of cytosolic acetyl-CoA

Objective. Stimulation of the beta-cell metabolism by glucose and other fuels triggers insulin release by enhancing the mitochondrial ATP production and acutely amplifies the secretory response by increase in mitochondrial export of metabolites. We aimed to narrow down the uniform final reaction steps mediating fuel-induced acute amplification of insulin secretion. Material/Methods. Insulin secretion and metabolic parameters were measured in isolated mouse islets exposed to the sulfonylurea glipizide in high concentration (closing all ATP sensitive K+ channels) during the entire experiment. Fuel-induced effects were examined after treating the islets for one hour with medium devoid of fuels. This experimental design prevented acute amplification, but only when glucose was the sole fuel. Results. Strong amplification of insulin secretion by alpha-ketoisocaproate or glucose combined with alpha-ketoisovalerate (supplying mitochondrial oxaloacetate) was abolished within 14 min after transition to medium devoid of fuels. After transition from medium containing glucose plus alpha-ketoisovalerate to medium containing solely glucose or alpha-ketoisovalerate, amplification (strong or weak, respectively) occurred until the end of the experiment. Glucose (alone or combined with alpha-ketoisovalerate) increased the total acetyl-CoA content as intensely as alpha-ketoisocaproate. Low concentrations of alpha-ketoisovalerate or alpha-ketoisocaproate were sufficient for saturation of acetyl-CoA increase, but caused no or only weak amplification, respectively. No acetyl-CoA increases occurred in the absence of glipizide. Conclusions. Glucose and other fuels regulate acute amplification of insulin secretion by controlling the supply of acetyl-CoA to the beta-cell cytosol. Cytosolic acetyl-CoA does not amplify by serving as substrate for syntheses of metabolic intermediates, but amplifies by acting as substrate for cytosolic protein acetylation. (C) 2016 Elsevier Inc. All rights reserved.