2-Oxocarboxylic acids and function of pancreatic islets in obese–hyperglycaemic mice. Insulin secretion in relation to 45Ca uptake and metabolism

摘要

pThe effects of aliphatic 2-oxocarboxylic acids, at concentrations of up to 40mm, on the function of pancreatic islets from iob/ob/i (obese–hyperglycaemic) mice were investigated. 1. 2-Oxopentanoate, dl-3-methyl-2-oxopentanoate, 4-methyl-2-oxopentanoate and 2-oxohexanoate all induced insulin release by isolated incubated islets and a biphasic insulin-secretory pattern in perfused mouse pancreas. The last two substances were similar in potency to glucose. Pyruvate, 2-oxobutyrate, 3-methyl-2-oxobutyrate and 2-oxo-octanoate did not induce insulin release significantly. 2. 2-Oxocarboxylic acids with significant insulin-secretory potency also induced significant sup45/supCa uptake by isolated incubated islets. 3. The rates of decarboxylation of [1-sup14/supC]pyruvate, 3-methyl-2-oxo[1-sup14/supC]butyrate and 4-methyl-2-oxo[1-sup14/supC]pentanoate were twice as high as the rates of oxidation of the corresponding U-sup14/supC-labelled compounds. However, whereas the rates of metabolism of labelled pyruvate and 3-methyl-2-oxobutyrate steadily increased over the concentration range 1–40mm, those of labelled 4-methyl-2-oxopentanoate and d-[U-sup14/supC]glucose levelled off at concentrations above 10mm. 4. Omission of sup40/supCaClsub2/sub from the incubation medium reduced the rate of oxidation of the insulin secretagogue [U-sup14/supC]4-methyl-2-oxopentanoate, but left that of the non-(insulin secretagogue) [U-sup14/supC]3-methyl-2-oxobutyrate unaffected. 5. Only glucose, and not pyruvate, 3-methyl-2-oxobutyrate and 4-methyl-2-oxopentanoate, significantly inhibited oxidation of endogenous fatty acids. 6. It is suggested that stimulus–secretion coupling and the resulting exocytosis of insulin in pancreatic β-cells may modulate both fuel oxidation and sup45/supCa uptake./p