Glucose Controls Glucagon Secretion by Regulating Fatty Acid Oxidation in Pancreatic α-Cells

Abstract

Whole-body glucose homeostasis is coordinated through secretion of glucagon and insulin from pancreatic islets. When glucose is low, glucagon is released from α-cells to stimulate hepatic glucose production. However, the mechanisms that regulate glucagon secretion from pancreatic α-cells remain unclear. Here we show that in α-cells the interaction between fatty acid oxidation and glucose metabolism controls glucagon secretion. The glucose dependent inhibition of glucagon secretion relies on pyruvate dehydrogenase and carnitine palmitoyl transferase 1a activity and lowering of mitochondrial fatty acid oxidation by increases in glucose. This results in reduced intracellular ATP and leads to membrane repolarisation and inhibition of glucagon secretion. These findings provide a new framework for the metabolic regulation of the α-cell, where regulation of fatty acid oxidation by glucose accounts for the stimulation and inhibition of glucagon secretion.

Regulatory Role of Fatty Acid Metabolism on Glucose-Induced Changes in Insulin and Glucagon Secretion by Pancreatic Islet Cells

“…Therefore, one should demonstrate that FFAs inhibit islet glycolysis to conclude that the cycle is operative in alpha cells. Specific overexpression of pyruvate dehydrogenase kinase 4 (PDK4) was shown to suppress glucose reduction in cellular ATP and glucagon release [ 85 ], as expected. Blocking pyruvate dehydrogenase activity by its hyperphosphorylation turns it inactive, impairing the citric acid cycle via a shortage of acetyl-CoA derived from glucose and not FFAs, resulting in diminished ATP production.…”

“…Recent experimental evidence suggests that inhibition of mitochondrial FFA oxidation by glucose is responsible for the suppression of glucagon release via a decrease in cellular ATP and membrane repolarization in α-cells [ 85 ]. It is difficult to understand why murine α-cells in islets preincubated for 1 h with 1 mM glucose were disabled, decreasing their glucagon release during a further incubation with 5 mM glucose, unless 0.36 (or higher?)…”

The Regulation and Secretion of Glucagon in Response to Nutrient Composition: Unraveling Their Intricate Mechanisms

“…One very recent study stated that glucagon secretion is inhibited by glucose through the involvement of pyruvate dehydrogenase and carnitine palmitoyl transferase 1a activity. This is accompanied by reduced mitochondrial fatty acid oxidation due to increased glucose levels, leading to lower intracellular ATP [ 64 ].…”

The endoplasmic reticulum plays a key role in α-cell intracellular Ca2+ dynamics and glucose-regulated glucagon secretion in mouse islets

“… 13 , 14 ). Some hypotheses suggest opposing effects of glucose on the α-cell membrane potential: either to depolarize via K ATP channel- 10 or SGLT2-dependent mechanisms 13 , 14 ; or to repolarize by TASK1-, 12 SOC- 11 and fatty acid oxidation-dependent 15 mechanisms.…”