Metabolic and paracrine heterogeneity of pancreatic glucagon-secreting α-cells

By stimulating hepatic glucose production, glucagon (released by islet α-cells) restores normal blood glucose levels when they fall below the normal range. We used optogenetics in conjunction with electrophysiology, cytoplasmic free Ca2+ concentration imaging, and hormone release measurements to explore the intrinsic and paracrine regulation of glucagon secretion. Many α-cells were spontaneously active at 1 mmol/L glucose. However, up to ∼50% of the α-cells were electrically silent. KATP channel blockade, amino acids, and somatostatin receptor antagonism restored electrical activity in such α-cells. Termination of optoactivation resulted in KATP channel–dependent (tolbutamide sensitive) membrane repolarization in active α-cells but long-lasting membrane depolarization and action potential firing in silent α-cells. The latter effect was associated with an increased cytoplasmic ATP:ADP ratio. Optoactivation or optoinhibition of somatostatin-releasing δ-cells inhibits and stimulates electrical activity in adjacent (but not distal) α-cells. There is an inverse relationship between basal glucagon secretion (a measure of the fraction active α-cells) and the relative stimulatory effects of amino acids. We conclude that islet α-cells are functionally heterogenous and that their electrical excitability and glucagon release are determined by K+ channel activity due to variable mosaic of KATP and somatostatin-sensitive K+ channels reflecting metabolic state and proximity to δ-cells, respectively.