The myokine irisin ameliorates the secretory dysfunction of pancreatic β cells in experimental and human type 2 diabetes

Irisin is a myokine that enhances insulin secretion and β cell viability in both rodent and human β cells. Here, we investigated whether irisin preserves β cell functional mass in vivo in diabetic mice and ex vivo in human pancreatic islets from subjects with type 2 diabetes (T2D). In mice made diabetic by a high-fat diet and streptozotocin, irisin administration improved glycemic homeostasis by increasing islet insulin content and glucose-stimulated insulin secretion while also markedly stimulating β cell proliferation. In islets from T2D subjects, which typically display substantial structural and functional impairments, irisin restored insulin content and glucose-stimulated insulin secretion. Mechanistic studies in INS-1E cells showed that chronic exposure to high glucose blunted glucose-triggered cytoplasmic calcium increases, essential for insulin secretion. Under these glucotoxic conditions, while irisin was unable to activate CREB and AKT, it induced AMPK-mTORC1-S6K-dependent mobilization of endoplasmic reticulum calcium stores, resulting in enhancement of insulin secretion. Overall, these findings highlight irisin's multifaceted ability to counteract β cell failure in experimental and human T2D.