CPT1a-Dependent Long-Chain Fatty Acid Oxidation Contributes to Maintaining Glucagon Secretion from Pancreatic Islets

Linford J.B Briant,Michael S Dodd,Margarita V Chibalina,Nils J.G Rorsman,Paul R.V Johnson,Peter Carmeliet,Patrik Rorsman,Jakob G Knudsen

doi:10.1016/j.celrep.2018.05.035

Linford J.B Briant, Michael S Dodd + Show 6 more

Open Access

https://doi.org/10.1016/j.celrep.2018.05.035

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Abstract

SummaryGlucagon, the principal hyperglycemic hormone, is secreted from pancreatic islet α cells as part of the counter-regulatory response to hypoglycemia. Hence, secretory output from α cells is under high demand in conditions of low glucose supply. Many tissues oxidize fat as an alternate energy substrate. Here, we show that glucagon secretion in low glucose conditions is maintained by fatty acid metabolism in both mouse and human islets, and that inhibiting this metabolic pathway profoundly decreases glucagon output by depolarizing α cell membrane potential and decreasing action potential amplitude. We demonstrate, by using experimental and computational approaches, that this is not mediated by the KATP channel, but instead due to reduced operation of the Na+-K+ pump. These data suggest that counter-regulatory secretion of glucagon is driven by fatty acid metabolism, and that the Na+-K+ pump is an important ATP-dependent regulator of α cell function.

Highlights

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by hyperglycemia, insulin resistance, and insufficient insulin secretion from islet b cells (Leahy, 2005)
Glucagon Secretion from Mouse a Cells Depends on fatty acid oxidation (FAO) We first explored the dependence of glucagon secretion under hypoglycemic conditions on FAO (Figure 1)
Carnitine palmitoyltransferase 1 (CPT1) is a mitochondrial transmembrane enzyme responsible for the formation of acyl-carnitine from long-chain acyl-coenzyme A’s (CoA), which can subsequently be transported into the mitochondria and used for b-oxidation

Summary

Introduction

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by hyperglycemia, insulin resistance, and insufficient insulin secretion from islet b cells (Leahy, 2005). It is becoming increasingly apparent that over-secretion of glucagon from pancreatic a cells contributes to the increased hepatic glucose production and associated hyperglycemia in T2DM. Despite the centrality of glucagon in the etiology of T2DM, the mechanisms by which glucagon secretion is regulated at low glucose have not been fully elucidated. In low glucose, glucagon secretion is controlled by mechanisms intrinsic to the a cell (Vieira et al, 2007; Zhang et al, 2013)

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