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

Author:

Ni Qicheng12ORCID,Song Jiaxi12,Wang Yichen12,Sun Jiajun12,Xie Jing3,Zhang Jun4,Ning Guang12,Wang Weiqing12ORCID,Wang Qidi125ORCID

Affiliation:

1. Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

2. Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

3. Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

4. Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

5. Sino-French Research Center for Life Sciences and Genomics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

Abstract

Abstract Context The mechanistic target of rapamycin complex I (mTORC1) is crucial for β-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 β 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 β 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-PS6high exhibited remarkably higher urocortin3 and glucose transporter 2 expression in their β cells compared to IFG-PS6low. Consistently, we also detected a significant increase in mTORC1 activities in prediabetic db/db mice compared to nondiabetic littermates. Interestingly, mTORC1 activities determined β-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 β-cell adaption/failure in human T2D.

Funder

National Key R&D Program of China

National Natural Sciences Foundation of China

Shanghai Municipal Education Commission—Gaofeng Clinical Medicine

Publisher

The Endocrine Society

Subject

Biochemistry (medical),Clinical Biochemistry,Endocrinology,Biochemistry,Endocrinology, Diabetes and Metabolism

Reference62 articles.

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