The myokine irisin ameliorates the secretory dysfunction of pancreatic β cells in experimental and human type 2 diabetes
- Nicola Marrano
- Anna Borrelli
- Giuseppina Biondi
- Martina Rella
- Rossella D’Oria
- Valentina Annamaria Genchi
- Cristina Caccioppoli
- Valerio Galasso
- Giovanni Galluzzi
- Luca Roberto
- Anna Signorile
- Leonardo Vincenti
- Fabrizio Aquilino
- Rita Nano
- Federico Baruzzi
- Antonio Moretti
- Luigi Giovanni Lupo
- Piero Marchetti
- Lorenzo Piemonti
- Angelo Cignarelli
- Sebastio Perrini
- Luigi Laviola
- Francesco Giorgino
- Annalisa Natalicchio
2026-06-05
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.