Proper mTORC1 activity is required for glucose sensing and early adaptation in human pancreatic beta cell.

Context The mTORC1 is crucial for beta cell identity and function in rodents. However, its possible relevance to physiopathology of diabetes in human remains unclear. Objective 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 non-diabetic (ND), 11 impaired fasting glucose (IFG) and 11 glycemic-controlled type 2 diabetic (T2D) subjects. We also assessed the dynamic change of mTORC1 activity in beta cells of db/db mice with newly onset of diabetes. Results There exists inter-cellular heterogeneity of mTORC1 activities in human islet. 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 according to their islet PS6 levels and found that IFG-PS6 high exhibited remarkably higher Ucn3 and Glut2 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 non-diabetic 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 progression to diabetes. Conclusions Our finding highlights a dynamic islet mTORC1 response in beta cell adaption/failure in human T2D.