339-LB: Modulation of Insulin and Glucagon Secretion by Optogenetic Control of Delta-Cell Electrical Activity in Pancreatic Islets

Abstract

Somatostatin secreted from pancreatic delta-cells is a strong paracrine inhibitor of both insulin and glucagon secretion in islets. However, little is known about the regulatory mechanisms of delta cells. This is mainly due to the scarcity of these cells (∼5-10% of islet cell population) and difficulties in maintaining their morphology and function after cell dispersion. Here, we developed an optogenetic approach, through tissue-specific expression of light-sensitive channels in delta cells, to investigate the paracrine modulation of alpha/beta cells by delta cells within intact islets. We generated a mouse model using Cre-loxp recombination to enable the specific expression of a light-sensitive cation channel Channelrhodopsin-2 (ChR2) in the pancreatic delta cells (SST-ChR2 mouse). In the presence of 1 mM glucose (when ?-cells are not electrically active), light activation of ChR2 (with 470 nm LED light) rapidly depolarised delta- cells (from -66±4 mV to -19±2 mV, n=4). Similar depolarising effect was observed in delta-cells exposed to 10 mM glucose (from -59±5 mV to -19±4 mV, n=4). Delta-cells activation with light transiently repolarised alpha cells by 5 mV (n=2) at 1 mM glucose and beta cells by 4 mV (n=3) at 10 mM glucose, which correlated with a mild decrease in intracellular Ca2+ concentration. Optoactivation of delta-cells inhibited glucagon secretion in islets exposed to 1 mM glucose by 48%. Whilst not affecting that at 20 mM glucose. Interestingly, despite the effects on beta-cell membrane potential, light exposure to SST-ChR2 islets did not affect insulin secretion stimulated by 20 mM glucose, possibly suggesting that insulin secretion is already maximally inhibited by glucose-induced somatostatin secretion. We propose that the SST-ChR2 mouse model represents a powerful tool for studying spatial and temporal paracrine crosstalk between different islet cells and the role of somatostatin in islet hormone secretion. Disclosure H. Dou: None. C.A. Miranda: None. Q. Zhang: None. P. Rorsman: None. J. Tolö: None. Funding Swedish Research Council