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Nutrient Sensor mTORC1 Regulates Insulin Secretion by Modulating β-Cell Autophagy
Tal Israeli1, Yael Riahi1, Perla Garzon1
1Diabetes Unit and Endocrine Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Diabetes
|December 4, 2021
Summary
Autophagy in pancreatic beta cells is regulated by nutrient availability via mTORC1 signaling. This pathway impacts insulin secretion, with fasting promoting autophagy and low insulin, while nutrient-rich conditions in obesity may cause hyperinsulinemia by inhibiting autophagy.
Area of Science:
- Cellular biology
- Metabolic regulation
- Endocrinology
Background:
- Autophagy dynamically regulates beta-cell function, but its precise role in response to nutrient cues like fasting-feeding cycles remains unclear.
- Mechanistic target of rapamycin complex 1 (mTORC1) integrates nutrient signals (leucine, glucose) in beta-cells, influencing cellular processes.
Purpose of the Study:
- To investigate the dynamic regulation of autophagy in pancreatic beta-cells by nutrient availability (fasting-feeding cycles).
- To elucidate the role of mTORC1 signaling in controlling autophagy and insulin secretion under varying nutritional states.
Main Methods:
- Utilized Raptor knockout models to inhibit mTORC1 signaling in beta-cells.
- Assessed autophagy initiation (ULK1, TFEB) and insulin secretion in response to nutrient stimulation and mTORC1 inhibition.
Main Results:
- Nutrient stimulation of mTORC1 prevented autophagy by inhibiting ULK1 and TFEB, particularly under continuous nutrient exposure.
- mTORC1 inhibition (Raptor knockout) mimicked fasting, induced autophagy, and suppressed insulin secretion; partial autophagy inhibition rescued insulin secretion.
- Fasting-state autophagy, regulated by mTORC1, is essential for maintaining low insulin levels and preventing hypoglycemia.
Conclusions:
- mTORC1 acts as a critical regulator of insulin secretion by modulating autophagy in response to nutritional status.
- Elevated mTORC1 signaling, driven by nutrients like leucine and glucose common in obesity, may contribute to hyperinsulinemia through autophagy inhibition.
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