1781-P: Leptin Regulates Delta-Cell Somatostatin Secretion from Human and Mouse Islets

Abstract

The delta cell is uniquely positioned in the islet to integrate local signals and circulating nutrient cues to regulate alpha and beta cell function through somatostatin (SST) secretion. In type 2 diabetes (T2D), delta cell responses to ambient glucose are disproportionate and consequently alter insulin and glucagon secretion leading to dysglycemia. However, we know relatively little about the mechanisms influencing delta cells. Thus, understanding factors that regulate delta cell SST secretion may reveal pathogenic mechanisms contributing to T2D and direct new therapies to achieve glucose homeostasis. Leptin is a circulating hormone that potently inhibits insulin and glucagon secretion, but notably, the leptin receptor (LepR) is exclusively expressed on delta cells of human islets. Our preliminary studies demonstrate for the first time that leptin stimulates SST secretion from human islets. Leptin-induced SST corresponded with decreased glucagon and insulin secretion. Leptin effects were conserved in mouse islets and required delta cell specific LepR expression. Our single-cell RNA-seq studies revealed Stat3 target genes become depleted in delta cells that lack LepR, suggesting canonical leptin signals regulate transcriptional activity in delta cells. Along these lines, delta cell specific Stat3 KO islets (Sst-Cre+/wt;Stat3fl/fl) do not respond to leptin. On-going studies in human islets employ pharmacologic and genetic interventions with live functional imaging and unbiased approaches that will reveal the mechanisms of leptin action in human delta cells. These studies are the first to describe leptin effects on delta cells and uncover a unifying mechanism whereby leptin acts indirectly on alpha and beta cells through paracrine SST signaling. As such, our findings are expected to reveal new signaling mechanisms governing islet function that potentially exert therapeutic benefits for T2D. Disclosure S.M.Hartig: None. A.Cox: None.