Acute metabolic amplification of insulin secretion in mouse islets is mediated by mitochondrial export of metabolites, but not by mitochondrial energy generation

作者：Panten Uwe^*; Willenborg Michael; Schumacher Kirstin; Hamada Asmaa; Ghaly Hany; Rustenbeck Ingo

来源：Metabolism-Clinical and Experimental, 2013, 62(10): 1375-1386.

DOI：10.1016/j.metabol.2013.05.006

• Beta-cell
• Glucose
• alpha-Ketoisocaproate
• Acetyl-CoA
• Acetoacetate

Objective. The beta-cell metabolism of glucose and of some other fuels (e.g. alpha-ketoisocaproate) generates signals triggering and acutely amplifying insulin secretion. As the pathway coupling metabolism with amplification is largely unknown, we aimed to narrow down the putative amplifying signals.
Materials/Methods. An experimental design was used which previously prevented glucose-induced, but not alpha-ketoisocaproate-induced insulin secretion. Isolated mouse islets were pretreated for one hour with medium devoid of fuels and containing the sulfonylurea glipizide in high concentration which closed all ATP-sensitive K+ channels. This concentration was also applied during the subsequent examination of fuel-induced effects. In perifused or incubated islets, insulin secretion and metabolic parameters were measured.
Results. The pretreatment decreased the islet ATP/ADP ratio. Whereas glucose and alpha-ketoisovalerate were ineffective or weakly effective, respectively, when tested separately, their combination strongly enhanced the insulin secretion. Compared with glucose, the strong amplifier alpha-ketoisocaproate caused less increase in NAD(P)H-fluorescence and less mitochondrial hyperpolarization. Compared with alpha-ketoisovalerate, alpha-ketoisocaproate caused greater increase in NAD(P)H-fluorescence and greater mitochondrial hyperpolarization. Neither alpha-ketoacid anion enhanced the islet ATP/ADP ratio during onset of the insulin secretion. alpha-Ketoisocaproate induced a higher pyruvate content than glucose, slowly elevated the citrate content which was not changed by glucose and generated a much higher acetoacetate content than other fuels. alpha-Ketoisovalerate alone or in combination with glucose did not increase the citrate content.
Conclusions. In beta-cells, mitochondrial energy generation does not mediate acute metabolic amplification, but mitochondrial production of acetyl-CoA and supplemental acetoacetate supplies cytosolic metabolites which induce the generation of specific amplifying signals.

• 出版日期2013-10