Heart Failure Triggers Mitochondrial Dysfunction and ER Stress in Pancreatic Beta Cells

Introduction: Diabetes and cardiovascular disease are important health concerns in United States and worldwide. However, while the increased risk of cardiovascular disease and heart failure (HF) in diabetic patients has been established, the reciprocal relationship, i.e. the augmented risk of glucose intolerance and type 2 diabetes mellitus (TD2M) in patients with cardiovascular disorders, has been evidenced in the clinical scenario but the underlying mechanisms remain essentially unclear. Hypothesis: HF causes pancreatic beta cell dysfunction via endoplasmic reticulum (ER) stress and impairment of mitochondrial dynamics. Methods/Results: In this study we focused on the beta cell function in a murine model of post-ischemic HF, obtained via ligation of the coronary artery. The HF group exhibited glucose intolerance and impaired glucose-stimulated insulin release, with no major differences in islet architecture when comparing HF and SHAM. Islets isolated from HF mice displayed upregulation of common markers of ER stress, including BiP and spliced XBP. Ultrastructural analysis revealed significant mitochondrial dysmorphology (fragmented cristae, swelling, and outer membrane disruption) in HF beta cells. We also found significantly altered mitochondrial dynamics in ex vivo experiments in HF vs SHAM, including reduced glucose-stimulated and glutamine/leucine-stimulated ATP production, impaired oxygen consumption rate (measured at Seahorse), decreased mtDNA/nDNA, aconitase activity, and NADPH following glucose stimulation, alongside with augmented generation of reactive oxygen species. Strikingly, we demonstrate that during HF beta cells display decreased intracellular calcium stores, and mitochondria exhibit a significantly reduced glucose-stimulated uptake of calcium, known activator of three matrix dehydrogenases in the tricarboxylic acid (aka Krebs) cycle. Moreover, the expression of mitochondrial calcium uniporter (MCU) was decreased in HF islets. Conclusions: Taken together, our in vivo and ex vivo findings establish that HF induces beta cell failure, characterized by mitochondrial dysfunction, ER stress, and overall impaired fuel-stimulated insulin release.