mTORC1 signaling and regulation of pancreatic β-cell mass
Manuel Blandino-Rosano,Angela Y. Chen,Joshua O. Scheys,Emilyn U. Alejandro,Aaron P. Gould,Tatyana Taranukha,Lynda Elghazi,Corentin Cras-Méneur,Ernesto Bernal-Mizrachi +8 more
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TLDR
It is demonstrated that deletion of Tsc1 in pancreatic β cells results in improved glucose tolerance, hyperinsulinemia and expansion of β-cell mass that persists with aging.Abstract:
The capacity of β cells to expand in response to insulin resistance is a critical factor in the development of type 2 diabetes. Proliferation of β cells is a major component for these adaptive responses in animal models. The extracellular signals responsible for β-cell expansion include growth factors, such as insulin, and nutrients, such as glucose and amino acids. AKT activation is one of the important components linking growth signals to the regulation of β-cell expansion. Downstream of AKT, tuberous sclerosis complex 1 and 2 (TSC1/2) and mechanistic target of rapamycin complex 1 (mTORC1) signaling have emerged as prime candidates in this process, because they integrate signals from growth factors and nutrients. Recent studies demonstrate the importance of mTORC1 signaling in β cells. This review will discuss recent advances in the understanding of how this pathway regulates β-cell mass and present data on the role of TSC1 in modulation of β-cell mass. Herein, we also demonstrate that deletion of Tsc1 ...read more
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Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. [Erratum: 2004 Sept. 23, v. 431, no. 7007, p. 485.]
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References
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Journal ArticleDOI
The tuberous sclerosis complex (TSC) pathway and mechanism of size control
TL;DR: It is shown further that S6 kinase (S6K) is a downstream component of the PI3K/Akt/TSC pathway and reduction of S6K activity can block TSC defects, and drugs that antagonize S 6K activities, such as rapamycin, diminish tumours in TSC-deficient mice and rats.
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Rapamycin impairs proliferation of transplanted islet β cells.
Nadja Niclauss,Domenico Bosco,Philippe Morel,Laurianne Giovannoni,Thierry Berney,Géraldine Parnaud +5 more
TL;DR: Rapamycin, at concentration usually used to prevent islet graft rejection, is able to reduce the rate of cell proliferation in transplanted rat islets but also in host murine islets.
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Tuberous sclerosis causing mutants of the TSC2 gene product affect proliferation and p27 expression.
Thomas Soucek,Margit Rosner,Angelina Miloloza,Marion Kubista,Jeremy Peter Cheadle,Julian R. Sampson,Markus Hengstschläger +6 more
TL;DR: Three different naturally occurring and TSC causing mutations within the TSC2 gene elliminate neither the anti-proliferative capacity of tuberin nor tuberin's effects on p27 expression provide strong evidence that deregulation of proliferation and/or upregulation of p27 are not likely to be the primary/only mechanisms of hamartoma development in TSC.
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Rapamycin impairs metabolism-secretion coupling in rat pancreatic islets by suppressing carbohydrate metabolism
Makiko Shimodahira,Shimpei Fujimoto,Eri Mukai,Yasuhiko Nakamura,Yuichi Nishi,Mayumi Sasaki,Yuichi Sato,Hiroki Sato,Masaya Hosokawa,Kazuaki Nagashima,Yutaka Seino,Nobuya Inagaki +11 more
TL;DR: Findings indicate that rapamycin suppresses high glucose-induced insulin secretion from pancreatic islets by reducing mitochondrial ATP production through suppression of carbohydrate metabolism in the Krebs cycle, together with reduced KGDH activity.
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Evidence for separable functions of tuberous sclerosis gene products in mammalian cell cycle regulation.
TL;DR: It is shown for the first time that TSC proteins possess separable functions, and it is demonstrated that hamartin can affect proliferation control independent of the presence of functional tuberin and that binding to Hamartin is not essential for tuberin to affect proliferation.