The dynamic regulation of
autophagy in b-cells by cycles of
fasting-feeding and its effects on insulin secretion are unknown. In b-cells mTORC1 is inhibited
while fasting, and is rapidly stimulated during refeeding by a single amino
acid, leucine, and glucose. Stimulation of mTORC1 by nutrients inhibited the
autophagy initiator ULK1 and the transcription factor TFEB, thereby preventing autophagy
when b-cells are continuously
exposed to nutrients. Inhibition
of mTORC1 by <i>Raptor</i> knockout mimicked the effects of fasting and
stimulated autophagy while inhibiting insulin secretion, whereas moderate
inhibition of autophagy under these conditions rescued insulin secretion. These
results show that mTORC1 regulates insulin secretion through modulation of
autophagy under different nutritional situations. In the fasting state, autophagy is regulated in an mTORC1-dependent manner and its stimulation is
required to keep insulin levels low, thereby preventing hypoglycemia.
Reciprocally, stimulation of mTORC1 by elevated leucine and glucose, which is
common in obesity, may promote hyperinsulinemia by inhibiting autophagy.