VAMP7 regulates autophagy to maintain mitochondrial homeostasis and to control insulin secretion in pancreatic β-cells

VAMP7 is a SNARE protein that mediates specific membrane fusions in intracellular trafficking and was recently reported to regulate autophagosome formation. However, its function in pancreatic β-cells is largely unknown. To elucidate the physiological role of VAMP7 in β-cells, we generated pancreatic β-cell-specific VAMP7 knockout ( Vamp7 flox/Y ;Cre ) mice. VAMP7 deletion impaired glucose-stimulated ATP production and insulin secretion, though VAMP7 was not localized to insulin granules. VAMP7 deficient β-cells showed defective autophagosome formation and reduced mitochondrial function. p62/SQSTM1, a marker protein for defective autophagy, was selectively accumulated on mitochondria in VAMP7 deficient β-cells. These findings suggest that accumulation of dysfunctional mitochondria, to be degraded by autophagy, caused impairment of glucose-stimulated ATP production and insulin secretion in Vamp7 flox/Y ;Cre β-cells. Feeding a high-fat diet to Vamp7 flox/Y ;Cre mice exacerbated mitochondrial dysfunction, further decreased ATP production and insulin secretion and, consequently, induced glucose intolerance. Moreover, we found upregulated VAMP7 expression in high-fat diet-fed wild-type mice and in db/db mice, a model for diabetes. Thus, our data indicate that VAMP7 regulates autophagy to maintain mitochondrial quality and insulin secretion in response to pathological stress in β-cells.