Introduction and Objective: Alterations of glucose homeostasis and insulin secretory capacity increase with age and represent leading causes of morbidity and mortality. In order to prevent and/or improve diabetes-associated ailments of the pancreatic beta cell during aging we propose to leverage the therapeutic properties of ketone bodies. Specifically, a functional role as key signaling molecule is increasingly acknowledged for beta-hydroxybutyrate (BHB), the most abundant ketone circulating in the human body.
Methods: The effects of BHB on metabolic fitness have been tested: 1) in vivo in 18-month-old C57BL/6J mice fed with a standard or BHB-enriched diet for 6 months; 2) ex vivo in murine islets isolated from aging mice fed with standard or BHB diet 3) ex vivo in islets isolated from brain-dead aging donors treated or not with BHB.
Results: In our preliminary studies, we found that 18-month-old C57BL/6J mice fed with a BHB-enriched diet for 6 months displayed a significantly ameliorated response to GTT compared to sex and age-matched mice fed with standard diet. Furthermore, BHB treatment increased islet yield protecting pancreatic islets from apoptosis and oxidative stress. We also observed an impaired glucose stimulated insulin secretion in islets isolated from old mice fed with standard diet and from aging donors that was significantly reduced by BHB in both systems. Moreover, BHB preserved mitochondrial membrane potential, attenuated the impaired mitochondrial respiration and mitochondrial fragmentation and rescued mitochondrial biogenesis during aging. Finally, BHB significantly increased mitophagy in aging murine and human islets after treatment with BHB, compared with control islets; confirming its pivotal role in the modulation of mitochondrial fitness.
Conclusion: In this study we produced compelling evidence that mitochondrial alterations represent a targetable molecular signature in aging beta cells and that ketone bodies are potentially useful to address age-related beta cell dysfunction.
S. Jankauskas: None. C. Nieves Garcia: None. U. Kansakar: None. J. Gambardella: None. P. Mone: None. Y. Tomer: None. G. Santulli: None. A. Lombardi: None.
