Mitochondria and Pancreatic β-Cells: Central Role in Insulin Secretion and Therapeutic Target for Diabetes

Pancreatic β-cell dysfunction plays a central role in the development and progression of diabetes. For decades, numerous studies have placed mitochondria at the core of this process. In β-cells, mitochondrial metabolism couples glucose sensing to insulin secretion through ATP production, calcium handling, redox signaling and metabolic coupling factors. Conversely, defects in oxidative phosphorylation, mitochondrial dynamics, mitophagy and redox homeostasis impair glucose-stimulated insulin secretion, promote β-cell stress, the loss of β-cell identity and survival. Moreover, inflammation and metabolic stresses amplify mitochondrial dysfunction in both type 1 and type 2 diabetes, highlighting mitochondria as therapeutic targets. In this review, we aimed to summarize main mitochondrial mechanisms governing β-cell function and to discuss how their disruption contributes to diabetes onset. We also explored emerging strategies aimed at restoring mitochondrial homeostasis, including antioxidant defenses, mitophagy modulation and bioenergetic improvement. Finally, we discussed the impact of skeletal muscle/pancreas crosstalk in insulin secretion. In particular, we emphasized how exercise-induced mitochondrial adaptation and myokines release may influence β-cell survival, insulin secretion and mitochondrial activity. Finally, understanding how β-cell intrinsic mitochondrial quality control integrates with systemic signals from skeletal muscle may open new therapeutic perspectives to preserve β-cell function and improve metabolic control in diabetes.