β-cell autophagy: A novel mechanism regulating β-cell function and mass: Lessons from β-cell-specific Atg7-deficient...

Autophagy is a membrane-trafficking mechanism that delivers cytoplasmic components into the lysosome to form autophagic vacuoles for bulk protein degradation. While previous studies have reported enhanced autophagosome formation in pancreatic β-cells under some pathophysiological conditions, the role of autophagy remains largely unknown. We have reported that low-level constitutive basal autophagy was observed in β-cells of C57BL/6 mice fed standard diet; however, autophagy was markedly up-regulated in mice fed high-fat diet. Free fatty acids (FFAs), which can cause peripheral insulin resistance associated with diabetes, induced autophagy in β-cells. Genetic inactivation of autophagic machinery in β-cells resulted in reduced glucose-stimuated insulin secretion with progressive intracellular accumulation of ubiquitinated proteins and deformed mitochondria. These results suggest that the degradation of cellular components by basal autophagy is essential for the maintenance of normal architecture and function of β-cells. We will also discuss the role of inductive autophagy as a crucial element of stress responses to protect β-cells, which supports compensatory β-cell growth in the presence of insulin resistance.