103-OR: Signaling Mechanisms Underlying Islet Compensation in a Novel Mouse Model of ß-Cell Replication Deficiency

Diabetes is associated with insulin insufficiency arising from a loss of β-cell function and mass. Disinhibited glucagon secretion, arising from the loss of β-cells, is thought to be responsible for as much as half of hyperglycemia in diabetes. An alternative possibility is that increased glucagon release from α-cells is an adaptive mechanism essential to preserving β-cell function in response to the loss of β-cell mass. To study islet compensation in response to β-cell mass deficiency, we used CRISPR to generate a novel strain of β-cell replication deficient (βRD) mice (Cdk1f/f:Ucn3-Cre). We examined in vivo and ex vivo glucagon and insulin secretion in response to β-cell and α-cell stimuli, performed scRNA-seq on isolated islets, and utilized cAMP and Ca2+ biosensors to test the impact of α-cell paracrine signaling on β-cell function. In the setting of reduced β-cell mass, adult βRD mice exhibited glucose intolerance and reduced insulin secretion that was rescued by α-cell engagement with a mixed meal or intraperitoneal alanine. ScRNA-seq revealed rewiring of α-cell metabolic and secretory genes in isolated βRD islets, and glucagon secretion was increased both in vivo and ex vivo. Correspondingly, antagonism of GLP-1 and glucagon receptors resulted in defective glucose-stimulated insulin secretion in βRD islets, which was otherwise equivalent to controls, indicating that α-cell signaling is necessary to preserve β-cell function in the βRD islets. β-cell cAMP was upregulated in β-cells from βRD islets, and Ca2+ oscillations activated at lower levels of glucose than controls, suggesting that β-cell cAMP production is a key mechanism of compensation. Our results suggest that increased glucagon secretion is initially an adaptive compensation for β-cell mass deficiency. Understanding islet reprogramming under physiological and pathophysiological circumstances could accelerate development of novel therapeutics to ameliorate α and β-cell dysfunction in diabetes. Disclosure H.R. Foster: None. S. Sdao: None. M. Adams: Employee; Genentech, Inc. B. Blum: None. M.J. Merrins: None. Funding National Institutes of Health (RO1DK113103, T32AG000213, R01AG062328, R01DK127637); U.S. Department of Veterans Affairs (I01BX005113); Health Resources and Services Administration (T32HP10010)