Proper mTORC1 Activity Is Required for Glucose Sensing and Early Adaptation in Human Pancreatic β Cells

Context The mechanistic target of rapamycin complex I (mTORC1) is crucial for beta-cell identity and function in rodents. However, its possible relevance to the physiopathology of diabetes in humans remains unclear. Objective This work aimed to understand the participation of mTORC1 in human beta cells in prediabetes and diabetes. Design We evaluated the PS6 immunofluorescence intensity in islets of pancreatic sections from 12 nondiabetic (ND), 11 impaired fasting glucose (IFG), and 11 glycemic-controlled type 2 diabetic (T2D) individuals. We also assessed the dynamic change of mTORC1 activity in beta cells of db/db mice with new-onset diabetes. Results There exists intercellular heterogeneity of mTORC1 activities in human islets. Islet mTORC1 activity was independently and positively correlated with FBG in ND, but not in IFG and T2D. Moreover, we did not detect significant change in mTORC1 activities between T2D and ND. Of note, the islet mTORC1 activities were significantly higher in IFG than in ND. We further stratified IFG individuals according to their islet PS6 levels and found that IFG-PS6(high) exhibited remarkably higher urocortin3 and glucose transporter 2 expression in their beta cells compared to IFG-PS6(low). Consistently, we also detected a significant increase in mTORC1 activities in prediabetic db/db mice compared to nondiabetic littermates. Interestingly, mTORC1 activities determined beta-cell adaptation or failure in db/db mice: A strong negative correlation was found between islet mTORC1 activities and fasting glucose levels in db/db mice during their diabetes progression. Conclusions Our finding highlights a dynamic islet mTORC1 response in beta-cell adaption/failure in human T2D.

Automated summary

The study reveals intercellular heterogeneity of mTORC1 activities in human islets. Islet mTORC1 activity is independently correlated with fasting blood glucose levels in nondiabetic individuals, but not in impaired fasting glucose and type 2 diabetic individuals. Interestingly, mTORC1 activity is significantly higher in impaired fasting glucose individuals compared to nondiabetic individuals, and it plays a role in beta-cell adaptation or failure in diabetes progression.