Leucine suppresses α-cell cAMP and glucagon secretion via a combination of cell-intrinsic and islet paracrine signaling

Abstract

Glucagon is critical for the maintenance of blood glucose, however nutrient regulation of pancreatic α-cells remains poorly understood. Here, we identified a role for leucine, a well-known β-cell fuel, in the α-cell intrinsic regulation of glucagon release. In islet perifusion assays, physiological concentrations of leucine strongly inhibited alanine and arginine-stimulated glucagon secretion from human and mouse islets under hypoglycemic conditions. Mechanistically, leucine dose-dependently reduced α-cell cAMP, independently of Ca²⁺, ATP/ADP, or fatty acid oxidation. Leucine also reduced α-cell cAMP in islets treated with Sstr2 antagonists or diazoxide, compounds that limit paracrine signaling from β/δ‑cells. Studies in dispersed mouse islets confirmed an α-cell intrinsic effect. The inhibitory effect of leucine on cAMP was mimicked by glucose, α-ketoisocaproate, succinate, and the glutamate dehydrogenase activator BCH, and blocked by cyanide, indicating a mechanism dependent on mitochondrial metabolism. Glucose dose-dependently reduced the impact of leucine on α-cell cAMP, indicating an overlap in function, however leucine was still effective at suppressing glucagon secretion in the presence of elevated glucose, amino acids, and the incretin GIP. Taken together, these findings show that leucine plays an intrinsic role in limiting α-cell secretory tone across the physiological range of glucose levels, complementing the inhibitory paracrine actions of β/δ-cells.

Article Highlights

· Despite the critical role of pancreatic islets as nutrient sensors, the mechanisms by which amino acids regulate glucagon release remain incompletely understood.

· Here we show that leucine, a well-known β-cell fuel, regulates glucagon secretion via a combination of α‑cell intrinsic and islet paracrine signaling.

· Leucine intrinsically suppresses α-cell cAMP, independently of α-cell Ca²⁺, ATP/ADP, or fatty acid oxidation.

· Our findings demonstrate complimentary roles of leucine and glucose in the regulation of α‑cell cAMP and glucagon secretion.