The plant product quinic acid activates Ca ²⁺ ‐dependent mitochondrial function and promotes insulin secretion from pancreatic beta cells

Abstract

Background and Purpose Quinic acid (QA) is an abundant natural compound from plant sources which may improve metabolic health. However, little attention has been paid to its effects on pancreatic beta‐cell functions, which contribute to the control of metabolic health by lowering blood glucose. Strategies targeting beta‐cell signal transduction are a new approach for diabetes treatment. This study investigated the efficacy of QA to stimulate beta‐cell function by targeting the basic molecular machinery of metabolism–secretion coupling. Experimental Approach We measured bioenergetic parameters and insulin exocytosis in a model of insulin‐secreting beta‐cells (INS‐1E), together with Ca 2+ homeostasis, using genetically encoded sensors, targeted to different subcellular compartments. Islets from mice chronically infused with QA were also assessed. Key Results QA triggered transient cytosolic Ca 2+ increases in insulin‐secreting cells by mobilizing Ca 2+ from intracellular stores, such as endoplasmic reticulum. Following glucose stimulation, QA increased glucose‐induced mitochondrial Ca 2+ transients. We also observed a QA‐induced rise of the NAD(P)H/NAD(P) + ratio, augmented ATP synthase‐dependent respiration, and enhanced glucose‐stimulated insulin secretion. QA promoted beta‐cell function in vivo as islets from mice infused with QA displayed improved glucose‐induced insulin secretion. A diet containing QA improved glucose tolerance in mice. Conclusions and Implications QA modulated intracellular Ca 2+ homeostasis, enhancing glucose‐stimulated insulin secretion in both INS‐1E cells and mouse islets. By increasing mitochondrial Ca 2+ , QA activated the coordinated stimulation of oxidative metabolism, mitochondrial ATP synthase‐dependent respiration, and therefore insulin secretion. Bioactive agents raising mitochondrial Ca 2+ in pancreatic beta‐cells could be used to treat diabetes.