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

Abstract

Objective: Stimulation of the ß-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 α-ketoisocaproate or glucose combined with α-ketoisovalerate (supplying mitochondrial oxaloacetate) was abolished within 14min after transition to medium devoid of fuels. After transition from medium containing glucose plus α-ketoisovalerate to medium containing solely glucose or α-ketoisovalerate, amplification (strong or weak, respectively) occurred until the end of the experiment. Glucose (alone or combined with α-ketoisovalerate) increased the total acetyl-CoA content as intensely as α-ketoisocaproate. Low concentrations of α-ketoisovalerate or α-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 ß-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.

Keywords: Acetyl-CoA; Beta cell; Glucose; Insulin secretion; α-ketoisocaproate.