Metabolic amplification of insulin secretion is differentially desensitized by depolarization in the absence of exogenous fuels

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• 作者：Torben Schulze¹ ; Mai Morsi¹ ; Kirstin Reckers ; Dennis Brü ; ning ; Nele Seemann ; Uwe Panten ; Ingo Rustenbeck ; ^{i.rustenbeck@tu-bs.de}
• 关键词：Cytosolic calcium concentration ; Glucose ; Glutamate ; Insulin secretion ; Metabolic amplification ; Mitochondria
• 刊名：Metabolism
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：67
• 期：Complete
• 页码：1-13
• 全文大小：890 K
• 卷排序：67

文摘

The metabolic amplification of insulin secretion is the sequence of events which enables the secretory response to a fuel secretagogue to exceed the secretory response to a purely depolarizing stimulus. The signals in this pathway are incompletely understood. Here, we have characterized an experimental procedure by which the amplifying response to glucose is reversibly desensitized, while the response to α-ketoisocaproic acid (KIC) is unchanged.Materials/MethodsInsulin secretion, NAD(P)H- and FAD-autofluorescence, Fura-2 fluorescence and oxygen consumption were measured in perifused NMRI mouse islets. The ATP- and ADP-contents were measured in statically incubated mouse islets. All islets were freshly isolated.ResultsWhile the original observation on the dissociation between glucose- and KIC-amplification was obtained with islets that had been exposed to a high concentration of the sulfonylurea glipizide in the absence of glucose, we now show that in the absence of exogenous fuel a moderate depolarization, irrespective of its mechanism, progressively decreased the amplification in response to both glucose and KIC. However, the amplification in response to glucose declined faster, so a time window exists where glucose was already inefficient, whereas KIC was of unimpaired efficiency. Measurements of adenine nucleotides, NAD(P)H- and FAD-autofluorescence, and oxygen consumption point to a central role of the mitochondrial metabolism in this process. The desensitization could be quickly reversed by increasing oxidative deamination of glutamate and consequently anaplerosis of the citrate cycle.ConclusionDepolarization in the absence of exogenous fuel may be a useful model to identify those signals which are indispensable for the generation of metabolic amplification.