Metabolic and paracrine heterogeneity ofpancreatic 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, [Ca²⁺]_i imaging and hormone release measurements to explore the intrinsic and paracrine regulation of glucagon secretion. Many α-cells were spontaneously active at 1mM glucose. However, up to ~50% of the α-cells were electrically silent. K_ATP channel blockade, amino acids and somatostatin receptor (SSTR) antagonism restored electrical activity in such α-cells. Termination of optoactivation resulted in K_ATP 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 -inhibition 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 K_ATP and somatostatin-sensitive K⁺ channels reflecting metabolic state and proximity to δ-cells, respectively.