Ryanodine Receptors in Islet Cell Function: Calcium Signaling, Hormone Secretion, and Diabetes

Ryanodine receptors (RyRs) are large intracellular Ca2+ release channels primarily found in muscle and nerve cells, and also present at low levels in pancreatic islet endocrine cells. This review examines the role of RyRs in islet cell function, focusing on calcium signaling and hormone secretion, while addressing the ongoing debate regarding their significance due to their limited expression. We explore conflicting experimental results and their potential causes, synthesizing current knowledge on RyR isoforms in islet cells, particularly in beta and delta cells. The review discusses how RyR-mediated calcium-induced calcium release enhances, rather than drives, glucose-stimulated insulin secretion. We examine the phosphorylation-dependent regulation of beta-cell RyRs, the concept of "leaky ryanodine receptors," and the roles of RyRs in endoplasmic reticulum stress, apoptosis, store-operated calcium entry, and beta-cell electrical activity. The relationship between RyR dysfunction and development of impaired insulin secretion in diabetes has been assessed, noting their limited role in human diabetes pathogenesis given the disease's polygenic nature. We highlight the established role of RyR-mediated CICR in the mechanism of action of common type 2 diabetes treatments, such as Glucagon-like peptide-1, which enhances insulin secretion. By integrating findings from electrophysiological, molecular, and clinical studies, this review provides a balanced perspective on RyRs in islet cell physiology and pathology, emphasizing their significance in both normal insulin secretion and current diabetes therapies.