mTORC1 signaling and regulation of pancreatic β-cell mass

doi:10.4161/CC.20036

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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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Sung Hee Um, Francesca Frigerio, Mitsuhiro Watanabe, Frédéric Picard, Manel Joaquin, Melanie Sticker, Stefano Fumagalli, Peter R. Allegrini, Sara C. Kozma, Johan Auwerx - Show less +6 more

01 Jan 2004-Nature

TL;DR: In this article, S6K1-deficient mice are protected against obesity owing to enhanced β-oxidation, but on a high fat diet, levels of glucose and free fatty acids still rise in S6k1-dependent mice, resulting in insulin receptor desensitization.

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Abstract: Elucidating the signalling mechanisms by which obesity leads to impaired insulin action is critical in the development of therapeutic strategies for the treatment of diabetes. Recently, mice deficient for S6 Kinase 1 (S6K1), an effector of the mammalian target of rapamycin (mTOR) that acts to integrate nutrient and insulin signals, were shown to be hypoinsulinaemic, glucose intolerant and have reduced β-cell mass. However, S6K1-deficient mice maintain normal glucose levels during fasting, suggesting hypersensitivity to insulin, raising the question of their metabolic fate as a function of age and diet. Here, we report that S6K1-deficient mice are protected against obesity owing to enhanced β-oxidation. However on a high fat diet, levels of glucose and free fatty acids still rise in S6K1-deficient mice, resulting in insulin receptor desensitization. Nevertheless, S6K1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from S6K1 to insulin receptor substrate 1 (IRS1), which blunts S307 and S636/S639 phosphorylation; sites involved in insulin resistance. Moreover, wild-type mice on a high fat diet as well as K/K Ay and ob/ob (also known as Lep/Lep) micetwo genetic models of obesityhave markedly elevated S6K1 activity and, unlike S6K1-deficient mice, increased phosphorylation of IRS1 S307 and S636/S639. Thus under conditions of nutrient satiation S6K1 negatively regulates insulin signalling.

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1,408 citations

Journal Article•DOI•

The emerging multiple roles of nuclear Akt

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Alberto M. Martelli¹, Alberto M. Martelli², Giovanna Tabellini³, Daniela Bressanin¹, Andrea Ognibene, Kaoru Goto⁴, Lucio Cocco¹, Camilla Evangelisti² - Show less +4 more•Institutions (4)

University of Bologna¹, National Research Council², University of Brescia³, Yamagata University⁴

01 Dec 2012-Biochimica et Biophysica Acta

TL;DR: Evidence accumulated over the past 15 years has highlighted the presence of active Akt in the nucleus, where it acts as a fundamental component of key signaling pathways, and the most relevant findings about nuclear Akt are summarized.

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181 citations

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...As such, Akt isoforms play key roles in cell survival [17], proliferation [21], growth [22], migration [23], polarity [24], insulin-evoked...
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Journal Article•DOI•

Insulin demand regulates β cell number via the unfolded protein response

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Rohit Sharma¹, Amy C. O’Donnell², Rachel E. Stamateris¹, Binh Ha¹, Karen M. McCloskey², Paul R. Reynolds³, Peter Arvan, Laura C. Alonso¹ - Show less +4 more•Institutions (3)

University of Massachusetts Medical School¹, University of Pittsburgh², University of Colorado Denver³

01 Oct 2015-Journal of Clinical Investigation

TL;DR: A stem cell-independent model of tissue homeostasis is defined, in which differentiated secretory cells use the UPR sensor to adapt organ size to meet demand, suggesting that therapeutic UPR modulation has potential to expand β cell mass in people at risk for diabetes.

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Abstract: Although stem cell populations mediate regeneration of rapid turnover tissues, such as skin, blood, and gut, a stem cell reservoir has not been identified for some slower turnover tissues, such as the pancreatic islet. Despite lacking identifiable stem cells, murine pancreatic β cell number expands in response to an increase in insulin demand. Lineage tracing shows that new β cells are generated from proliferation of mature, differentiated β cells; however, the mechanism by which these mature cells sense systemic insulin demand and initiate a proliferative response remains unknown. Here, we identified the β cell unfolded protein response (UPR), which senses insulin production, as a regulator of β cell proliferation. Using genetic and physiologic models, we determined that among the population of β cells, those with an active UPR are more likely to proliferate. Moreover, subthreshold endoplasmic reticulum stress (ER stress) drove insulin demand-induced β cell proliferation, through activation of ATF6. We also confirmed that the UPR regulates proliferation of human β cells, suggesting that therapeutic UPR modulation has potential to expand β cell mass in people at risk for diabetes. Together, this work defines a stem cell-independent model of tissue homeostasis, in which differentiated secretory cells use the UPR sensor to adapt organ size to meet demand.

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151 citations

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...Intriguingly, in HEK293T cells, the ISR preferentially reduces translation of MTOR-regulated genes (61); β cell proliferation is strictly dependent on MTOR activation (62)....
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Journal Article•DOI•

mTORC1 Signaling: A Double-Edged Sword in Diabetic β Cells.

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Amin Ardestani¹, Blaz Lupse¹, Yoshiaki Kido², Gil Leibowitz³, Kathrin Maedler¹ - Show less +1 more•Institutions (3)

University of Bremen¹, RMIT University², Hebrew University of Jerusalem³

21 Dec 2017-Cell Metabolism

TL;DR: It is suggested that mTORC1 may act as a "double edge sword" in the regulation of β cell mass and function in response to metabolic stress such as nutrient overload and insulin resistance.

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126 citations

Journal Article•DOI•

Roles for PI3K/AKT/PTEN Pathway in Cell Signaling of Nonalcoholic Fatty Liver Disease

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Satoru Matsuda¹, Mayumi Kobayashi¹, Yasuko Kitagishi¹•Institutions (1)

Nara Women's University¹

30 Jan 2013-International Scholarly Research Notices

TL;DR: Molecular studies in the NAFLD support a key role for PTEN in hepatic insulin sensitivity and the development of steatosis, steatohepatitis, and fibrosis, and review recent studies on the features of the PTEN and the PI3K/AKT pathway.

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Abstract: Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver pathologies and is associated with obesity and the metabolic syndrome, which represents a range of fatty liver diseases associated with an increased risk of type 2 diabetes. Molecular mechanisms underlying how to make transition from simple fatty liver to nonalcoholic steatohepatitis (NASH) are not well understood. However, accumulating evidence indicates that deregulation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway in hepatocytes is a common molecular event associated with metabolic dysfunctions including obesity, metabolic syndrome, and the NAFLD. A tumor suppressor PTEN negatively regulates the PI3K/AKT pathways through its lipid phosphatase activity. Molecular studies in the NAFLD support a key role for PTEN in hepatic insulin sensitivity and the development of steatosis, steatohepatitis, and fibrosis. We review recent studies on the features of the PTEN and the PI3K/AKT pathway and discuss the protein functions in the signaling pathways involved in the NAFLD. The molecular mechanisms contributing to the diseases are the subject of considerable investigation, as a better understanding of the pathogenesis will lead to novel therapies for a condition.

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125 citations

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...The oxidative stress can activate a series of stress pathways involving a family of serine/threonine kinases including AKT, which in turn have a negative effect on insulin signaling [21]....
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Increased ribosomal biogenesis induces pancreatic β cell failure in mice model of type 2 diabetes

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Shun-ichiro Asahara¹, Tomokazu Matsuda¹, Yoshiaki Kido¹, Masato Kasuga¹•Institutions (1)

Kobe University¹

10 Apr 2009-Biochemical and Biophysical Research Communications

TL;DR: In cases of pancreatic beta cell hyperplasia associated with insulin resistance, ribosomal biogenesis is increased, and ER stress is induced.

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17 citations

"mTORC1 signaling and regulation of ..." refers background in this paper

...The current evidence supports the concept that mTORC1 is active in states of increased insulin demand and plays a major role in β-cell expansion and proliferation induced by AKT and insulin resistance.(1,4,5,9,60,68) Most of our knowledge about the role of mTORC1 in β cells comes from in vitro experiments using insulinoma cells or isolated islets treated with rapamycin....
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...mTORC1 is overactive in many organs in animal models of obesity and insulin resistance.(1,4,5) Additionally, chronic mTORC1 activation plays an important role in the pathogenesis of insulin resistance in states of nutrient excess....
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...mTORC1 controls growth (cell size), proliferation (cell number) and metabolism directly, by modulating eukaryotic initiation factor 4E-binding proteins (4E-BP 1, 2 and 3) and ribosomal protein S6 kinases (S6K 1 and 2), and indirectly, by attenuating AKT signaling via an mTORC1/ S6K-mediated negative feedback loop.(1-10) How TSC/mTOR signaling regulates β-cell mass expansion is not completely understood....
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...(5) Rapamycin treatment results in reduced proliferation in β cells in pregnant mice and causes anti-proliferative effects in transplanted rat β cells in vivo....
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mTORC1 signaling and regulation of pancreatic β-cell mass

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