Abstract
Diabetes is associated with beta cell mass loss and islet dysfunctions. mTORC1 regulates beta cell survival, proliferation and function in physiological and pathological conditions, such as pregnancy and pancreatectomy. Here we show that deletion of Raptor, which is an essential component of mTORC1, in insulin-expressing cells promotes hypoinsulinemia and glucose intolerance. Raptor-deficient beta cells display reduced glucose responsiveness and exhibit a glucose metabolic profile resembling fetal beta cells. Knockout islets have decreased expression of key factors of functional maturation and upregulation of neonatal markers and beta cell disallowed genes, resulting in loss of functional maturity. Mechanistically, Raptor-deficient beta cells show reduced expression of DNA-methyltransferase 3a and altered patterns of DNA methylation at loci that are involved in the repression of disallowed genes. The present findings highlight a novel role of mTORC1 as a core mechanism governing postnatal beta cell maturation and physiologic beta cell mass during adulthood.
Highlights
Diabetes is associated with beta cell mass loss and islet dysfunctions. mTOR complex 1 (mTORC1) regulates beta cell survival, proliferation and function in physiological and pathological conditions, such as pregnancy and pancreatectomy
MTOR signalling is composed of a number of highly conserved Ser/Thr protein kinases, functioning in the form of at least two large protein complexes, mTOR complex 1 and mTOR complex 216. mTORC1 consists of RAPTOR, mLST8, PRAS40, DEPTOR and mTOR, which is sensitive to rapamycin17. mTORC1 pathway is recognized as a key factor to integrate signals from nutrients, growth factors and hormones, and controls cellular processes, including protein synthesis, ribosome biogenesis and lipogenesis by modulating eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1)
Expression of PS6 coincides with the transition from ‘immature’ to ‘mature’ glucose-stimulated insulin secretion (GSIS) response between 2 and 8 postnatal days, raising the possibility that the mTORC1 pathway plays a role in beta cell functional maturation
Summary
Diabetes is associated with beta cell mass loss and islet dysfunctions. mTORC1 regulates beta cell survival, proliferation and function in physiological and pathological conditions, such as pregnancy and pancreatectomy. Functional beta cell mass is determined by the number of beta cells, and by their functional maturation status, including the ability to produce and secrete mature insulin in response to elevated blood glucose level[2,3]. 12) have been reported to be crucial for maintaining beta cell identity and functional maturation It remains unclear which signalling pathway determines beta cell functional maturation and mass expansion after birth. In vitro studies using rapamycin demonstrated that mTORC1 regulates beta cell function and survival in beta cell lines and murine/human islets[19]. We use beta cell specific Raptor knockout mice and report a direct link between mTORC1 signalling and beta cell functional maturation, which is an important and novel field of beta cell research. Raptorinduced beta cell functional immaturity precedes the onset of hyperglycaemia, which leads to beta cell failure
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