340-LB: Optogenetic Control of a-Cell Electrical Activity and Glucagon Secretion in Intact Islets

Glucagon, the body9s main hyperglycemic hormone, is produced by α-cells of the islets of Langerhans. A fall in plasma glucose stimulates glucagon release and it acts by increasing hepatic glucose production. How glucose regulates glucagon secretion remains debated and both intrinsic and paracrine mechanisms have been proposed. The fact that glucagon secretion becomes dysregulated in diabetes warrants detailed studies of the cell physiology of its release. We generated mice that express the light-sensitive cation channel Channelrhodopsin-2 (ChR2) under the control of the proglucagon promoter in the α-cells. This allowed us to selectively depolarize the plasma membrane of α-cells within intact isolated islets (using 488 nm laser) and record membrane potential, cytoplasmic Ca2+ ([Ca2+]i) glucagon release in response to the optical activation. At low (1mM) glucose, optoactivation depolarized the α-cells, induced a transient increase in [Ca2+]i, decreased peak voltage of the action potentials (from -2±1mV to -11±1mV, n=5, p Disclosure C.A. Miranda: None. H. Dou: None. J. Tolo: None. A.I. Tarasov: Employee; Spouse/Partner; Vaccitech Ltd, Oxford, UK. P. Rorsman: None. Funding Swedish Research Council