TSC1-mTOR signaling determines the differentiation of islet cells

    1. Weizhen Zhang1,2
    1. 1Department of Physiology and Pathophysiology, Peking University Health Science Center, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
    2. 2Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan, USA
    1. Correspondence should be addressed to W Zhang; Email: weizhenzhang{at}bjmu.edu.cn

    Abstract

    Neurogenin3-driven deletion of tuberous sclerosis complex 1 (Tsc1) activated mechanistic target of rapamycin complex 1 (mTORC1) measured by the upregulation of mTOR and S6 phosphorylation in islet cells. Neurogenin3-Tsc1−/− mice demonstrated a significant increase in average islet size and mean area of individual islet cell. Insulin mRNA and plasma insulin levels increased significantly after weaning. Glucagon mRNA and plasma levels increased in neonate followed by modest reduction in adult. Somatostatin mRNA and plasma levels markedly increased. Neurogenin3-Tsc1−/− mice fed standard chow demonstrated a significant improvement in glucose tolerance and no alteration in insulin sensitivity. In Neurogenin3-Tsc1−/− mice fed 45% high-fat diets, both glucose tolerance and insulin sensitivity were significantly impaired. Rapamycin reversed the activation of mTORC1, attenuated β cells hypertrophy and abolished the improvement of glucose tolerance. TSC1-mTORC1 signaling plays an important role in the development of pancreatic endocrine cells and in the regulation of glucose metabolism.

    Keywords
    • Received 7 October 2016
    • Accepted 17 October 2016
    • Made available online as an Accepted Preprint 17 October 2016
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