286-LB: A Trailblazing Approach to Target Mitochondrial Dysfunction in Diabetic Beta Cells

Abstract

Rationale: Currently no curative treatment exists to reverse or prevent autoimmune destruction of pancreatic islets in type 1 diabetes (T1D), and the disease can only be managed with insulin replacement therapy. We propose to leverage the therapeutic properties of ketone bodies to prevent and/or improve diabetes-associated ailments of beta cells. Of note, although excessive production of ketones leads to life-threatening ketoacidosis in diabetic patients under glucose lowering treatment, emerging lines of evidence suggest that modest levels of ketone bodies play adaptive and beneficial roles. Specifically, a functional role as key signaling molecule is increasingly acknowledged for beta-hydroxybutyrate (BHB), the most abundant ketone circulating in the human body. However, therapeutic applications of BHB have never been considered in T1D. Results: In NOD mice BHB treatment significantly increased survival and delayed diabetes onset, protecting pancreatic islets from apoptosis, reducing insulitis, and decreasing serum levels of pro-inflammatory cytokines. Furthermore, islet yield and total pancreatic insulin were markedly higher in BHB treated mice compared to controls. In addition, in NOD pancreatic islets and in human islets isolated from healthy donors treated with a cocktail of pro-inflammatory cytokines (i.e. IL-1β, TNF-α, and IFN-γ) BHB had a protective effect on oxidative stress, significantly reducing the production of ROS. Finally, in both systems BHB significantly increased the mitophagy flux improving mitochondrial fitness and preserving mitochondrial functions. Conclusion: The proposed studies are highly significant and are attempting for the first time to dissect the role of ketones in pancreatic beta cell death and dysfunction during T1D. Indeed, if our preliminary studies are confirmed BHB might emerge as a glucose-lowering agent that, acting synergistically with pharmacotherapy, could be able to improve the quality of life in patients with T1D. Disclosure S. Jankauskas: None. U. Kansakar: None. C. Nieves garcia: None. J. Gambardella: None. P. Mone: None. Y. Tomer: None. G. Santulli: None. A. Lombardi: None.