223-LB: Jagged 1- Notch Signaling Determines ß-Cell Maturity and Function

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Obesity-induced Type 2 Diabetes (T2DM) continues to increase at an alarming rate resulting in a substantial burden of long-term complications and healthcare costs. As such, understanding mechanisms of T2DM pathogenesis is key in tackling the growing prevalence. Although insulin resistance is the hallmark of T2DM, it manifests as hyperglycemia only in the setting of β cell insufficiency. Pathophysiologic mechanisms underlying this failure requires further elucidation. We have recently shown that Notch signaling is a novel regulator of β cell function, and glucose homeostasis. Notch activity is regulated by ligand (Jagged 1/2, and Delta-like 1/3/4) availability. We find that islets isolated from HFD-fed or leptin receptor-deficient db/db mice have increased Jagged1 expression as compared to chow or db/+ controls, without change in other Notch ligands, in parallel to increased Notch activity. These data led us to hypothesize that Jagged1 is both sufficient and necessary to transduce Notch signaling in β cells and is a potential regulator of β cell function, maturity and glucose homeostasis. To investigate this, we generated novel β cell specific Jagged1 gain-of-function and knock-out mice. Preliminary data from our inducible gain of function model show progressively impaired glucose intolerance through decreased insulin secretion in parallel with an increase in Notch activity, despite normal weight and adiposity. By identifying the ligand-receptor interaction, we postulate that we can take advantage of this knowledge for therapeutic benefit. To this end, we have generated dominant negative mutants of the Notch receptor lacking the intracellular Notch domain that specifically block either Jagged or Delta-like ligands. The current data on Notch signaling in β cells shows promise for furthering the understanding of the pathophysiology in T2DM. In studying this mechanism further, we hope to provide a novel therapeutic strategy in preventing a disease that continues to be a growing concern worldwide. Disclosure N. Suda: None. U. Pajvani: None. Funding Endocrine Fellows Foundation