706-P: DIRAS2—A Novel Regulator of Glucose Metabolism and Pancreatic Islet Survival

Introduction and Objective: Diras2 is a small Ras-related GTPase, primarily expressed in the brain that is implicated in attention-deficit/hyperactivity disorder (ADHD). Our lab has identified Diras2 in mouse pancreatic islets in response to stress conditions. Methods: To elucidate the novel role of Diras2 in pancreatic islets and its physiological significance, we characterized global Diras2-/- knockout male mice on C57B6N/J background compared to C57B6N/J wildtype (WT) mice with functional Diras2. Results: The glucose tolerance test (GTT) and insulin tolerance test (ITT) under chow and high fat diet revealed enhanced glucose tolerance and insulin sensitivity in Diras2-/- mice, while body weight showed no significant differences compared to WT controls. Functional studies on islets isolated through collagenase digestion showed no significant difference in insulin secretion and content between both studied groups under 11mM and 28mM glucose concentrations over 72 hours, as quantified by ELISA. Stress response studies using beta-cell-specific stressors such as thapsigargin (1цM), rotenone (50nM), and proinflammatory cytokines (IL-1β-5ng/mL, TNF-α 10ng/mL and IFN-ϒ, 100ng/mL) demonstrated that Diras2-/- mice were significantly protected against cytokine-induced apoptosis after overnight treatment when measured through cell death using propidium iodide and annexinV. Conclusion: These findings suggest that improved glucose tolerance and insulin sensitivity in the absence of Diras2 may originate from the alterations in neural signals, given the high expression of Diras2 in the brain. Furthermore, Diras2 may possess a proapoptotic role in islets and reducing Diras2 expression may reduce cytokine-induced damage which further offer insights into its potential contribution to metabolic homeostasis, and its relevance as a therapeutic target for diabetes. Disclosure N. Ajmal: None. K. Corbin: None. N. Cunningham: None. P. Khan: None. M.A. Kalwat: Stock/Shareholder; Eli Lilly and Company, Pfizer Inc. C.S. Nunemaker: None.