mTOR Inhibition by Rapamycin Prevents β-Cell Adaptation to Hyperglycemia and Exacerbates the Metabolic State in Type 2 Diabetes
Tóm tắt
OBJECTIVE—Mammalian target of rapamycin (mTOR) and its downstream target S6 kinase 1 (S6K1) mediate nutrient-induced insulin resistance by downregulating insulin receptor substrate proteins with subsequent reduced Akt phosphorylation. Therefore, mTOR/S6K1 inhibition could become a therapeutic strategy in insulin-resistant states, including type 2 diabetes. We tested this hypothesis in the Psammomys obesus (P. obesus) model of nutrition-dependent type 2 diabetes, using the mTOR inhibitor rapamycin.
RESEARCH DESIGN AND METHODS—Normoglycemic and diabetic P. obesus were treated with 0.2 mg · kg−1 · day−1 i.p. rapamycin or vehicle, and the effects on insulin signaling in muscle, liver and islets, and on different metabolic parameters were analyzed.
RESULTS—Unexpectedly, rapamycin worsened hyperglycemia in diabetic P. obesus without affecting glycemia in normoglycemic controls. There was a 10-fold increase of serum insulin in diabetic P. obesus compared with controls; rapamycin completely abolished this increase. This was accompanied by weight loss and a robust increase of serum lipids and ketone bodies. Rapamycin decreased muscle insulin sensitivity paralleled by increased glycogen synthase kinase 3β activity. In diabetic animals, rapamycin reduced β-cell mass by 50% through increased apoptosis. Rapamycin increased the stress-responsive c-Jun NH2-terminal kinase pathway in muscle and islets, which could account for its effect on insulin resistance and β-cell apoptosis. Moreover, glucose-stimulated insulin secretion and biosynthesis were impaired in islets treated with rapamycin.
CONCLUSIONS—Rapamycin induces fulminant diabetes by increasing insulin resistance and reducing β-cell function and mass. These findings emphasize the essential role of mTOR/S6K1 in orchestrating β-cell adaptation to hyperglycemia in type 2 diabetes. It is likely that treatments based on mTOR inhibition will cause exacerbation of diabetes.
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Tài liệu tham khảo
Manning BD: Balancing Akt with S6K: implications for both metabolic diseases and tumorigenesis. J Cell Biol 167:399–403,2004
Um SH, D'Alessio D, Thomas G: Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1. Cell Metab 3:393–402,2006
Hara K, Maruki Y, Long X, Yoshino K, Oshiro N, Hidayat S, Tokunaga C, Avruch J, Yonezawa K: Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110:177–189,2002
Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM: mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110:163–175,2002
Loewith R, Jacinto E, Wullschleger S, Lorberg A, Crespo JL, Bonenfant D, Oppliger W, Jenoe P, Hall MN: Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell 10:457–468,2002
Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM: Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 14:1296–1302,2004
Wang X, Beugnet A, Murakami M, Yamanaka S, Proud CG: Distinct signaling events downstream of mTOR cooperate to mediate the effects of amino acids and insulin on initiation factor 4E-binding proteins. Mol Cell Biol 25:2558–2572,2005
Sekulic A, Hudson CC, Homme JL, Yin P, Otterness DM, Karnitz LM, Abraham RT: A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. Cancer Res 60:3504–3513,2000
Werner ED, Lee J, Hansen L, Yuan M, Shoelson SE: Insulin resistance due to phosphorylation of insulin receptor substrate-1 at serine 302. J Biol Chem 279:35298–35305,2004
Tzatsos A, Kandror KV: Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation. Mol Cell Biol 26:63–76,2006
Harrington LS, Findlay GM, Gray A, Tolkacheva T, Wigfield S, Rebholz H, Barnett J, Leslie NR, Cheng S, Shepherd PR, Gout I, Downes CP, Lamb RF: The TSC1–2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J Cell Biol 166:213–223,2004
Shah OJ, Wang Z, Hunter T: Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr Biol 14:1650–1656,2004
Um SH, Frigerio F, Watanabe M, Picard F, Joaquin M, Sticker M, Fumagalli S, Allegrini PR, Kozma SC, Auwerx J, Thomas G: Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 431:200–205,2004
Ruvinsky I, Sharon N, Lerer T, Cohen H, Stolovich-Rain M, Nir T, Dor Y, Zisman P, Meyuhas O: Ribosomal protein S6 phosphorylation is a determinant of cell size and glucose homeostasis. Genes Dev 19:2199–2211,2005
Khamzina L, Veilleux A, Bergeron S, Marette A: Increased activation of the mammalian target of rapamycin pathway in liver and skeletal muscle of obese rats: possible involvement in obesity-linked insulin resistance. Endocrinology 146:1473–1481,2005
Tremblay F, Krebs M, Dombrowski L, Brehm A, Bernroider E, Roth E, Nowotny P, Waldhausl W, Marette A, Roden M: Overactivation of S6 kinase 1 as a cause of human insulin resistance during increased amino acid availability. Diabetes 54:2674–2684,2005
Krebs M, Brunmair B, Brehm A, Artwohl M, Szendroedi J, Nowotny P, Roth E, Furnsinn C, Promintzer M, Anderwald C, Bischof M, Roden M: The mTOR-pathway regulates nutrient sensitive glucose uptake in man. Diabetes 56:1600–1607,2007
Rhodes CJ, White MF: Molecular insights into insulin action and secretion. Eur J Clin Invest 32(Suppl. 3):3–13,2002
Lingohr MK, Dickson LM, McCuaig JF, Hugl SR, Twardzik DR, Rhodes CJ: Activation of IRS-2-mediated signal transduction by IGF-1, but not TGF-α or EGF, augments pancreatic β-cell proliferation. Diabetes 51:966–976,2002
Hennige AM, Burks DJ, Ozcan U, Kulkarni RN, Ye J, Park S, Schubert M, Fisher TL, Dow MA, Leshan R, Zakaria M, Mossa-Basha M, White MF: Upregulation of insulin receptor substrate-2 in pancreatic beta cells prevents diabetes. J Clin Invest 112:1521–1532,2003
Briaud I, Dickson LM, Lingohr MK, McCuaig JF, Lawrence JC, Rhodes CJ: Insulin receptor substrate-2 proteasomal degradation mediated by a mammalian target of rapamycin (mTOR)-induced negative feedback down-regulates protein kinase B-mediated signaling pathway in beta-cells. J Biol Chem 280:2282–2293,2005
Lingohr MK, Dickson LM, Wrede CE, McCuaig JF, Myers MGJ, Rhodes CJ: IRS-3 inhibits IRS-2-mediated signaling in pancreatic beta-cells. Mol Cell Endocrinol 30:85–99,2003
Kaiser N, Nesher R, Donath MY, Fraenkel M, Behar V, Magnan C, Ktorza A, Cerasi E, Leibowitz G: Psammomys obesus, a model for environment-gene interactions in type 2 diabetes. Diabetes 54 (Suppl. 2):S137–S144,2005
Nesher R, Gross DJ, Donath MY, Cerasi E, Kaiser N: Interaction between genetic and dietary factors determines β-cell function in Psammomys obesus, an animal model of type 2 diabetes. Diabetes 48:731–737,1999
Gadot M, Leibowitz G, Shafrir E, Cerasi E, Gross DJ, Kaiser N: Hyperproinsulinemia and insulin deficiency in the diabetic Psammomys obesus. Endocrinology 135:610–616,1994
Hansen JL, Freier EF: Direct assays of lactate, pyruvate, beta-hydroxybutyrate, and acetoacetate with a centrifugal analyzer. Clin Chem475–479,1978
Kaiser N, Corcos AP, Tur-Sinai A, Ariav Y, Cerasi E: Monolayer culture of adult rat pancreatic islets on extracellular matrix: long term maintenance of differentiated B-cell function. Endocrinology 123:834–840,1988
Attali V, Parnes M, Ariav Y, Cerasi E, Kaiser N, Leibowitz G: Regulation of insulin secretion and proinsulin biosynthesis by succinate. Endocrinology 147:5110–5118,2006
Alarcon C, Lincoln B, Rhodes CJ: The biosynthesis of the subtilisin-related proprotein convertase PC3, but no that of the PC2 convertase, is regulated by glucose in parallel to proinsulin biosynthesis in rat pancreatic islets. J Biol Chem 268:4276–4280,1993
Kaiser N, Yuli M, Uckaya G, Oprescu AI, Berthault MF, Kargar C, Donath MY, Cerasi E, Ktorza A: Dynamic changes in β-cell mass and pancreatic insulin during the evolution of nutrition-dependent diabetes in Psammomys obesus: impact of glycemic control. Diabetes 54:138–145,2005
Kanety H, Moshe S, Shafrir E, Lunenfeld B, Karasik A: Hyperinsulinemia induces a reversible impairment in insulin receptor function leading to diabetes in the sand rat model of non-insulin-dependent diabetes mellitus. Proc Natl Acad Sci U S A 91:1853–1857,1994
Lee J, Kim MS: The role of GSK3 in glucose homeostasis and the development of insulin resistance. Diabetes Res Clin Pract 77 (Suppl. 1):S49–S57,2007
Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS: A central role for JNK in obesity and insulin resistance. Nature 420:333–336,2002
Huang S, Shu L, Dilling MB, Easton J, Harwood FC, Ichijo H, Houghton PJ: Sustained activation of the JNK cascade and rapamycin-induced apoptosis are suppressed by p53/p21(Cip1). Mol Cell 11:1491–1501,2003
Di Paolo S, Teutonico A, Leogrande D, Capobianco C, Schena PF: Chronic inhibition of mammalian target of rapamycin signaling downregulates insulin receptor substrates 1 and 2 and AKT activation: a crossroad between cancer and diabetes?J Am Soc Nephrol 17:2236–2244,2006
Sarbassov DD, Guertin DA, Ali SM, Sabatini DM: Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307:1098–1101,2005
Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, Markhard AL, Sabatini DM: Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22:159–168,2006
Eldar-Finkelman H, Krebs EG: Phosphorylation of insulin receptor substrate 1 by glycogen synthase kinase 3 impairs insulin action. Proc Natl Acad Sci U S A 94:9660–9664,1997
Lingohr MK, Briaud I, Dickson LM, McCuaig JF, Alarcon C, Wicksteed BL, Rhodes CJ: Specific regulation of IRS-2 expression by glucose in rat primary pancreatic islet beta-cells. J Biol Chem 281:15884–15992,2006
Park S, Dong X, Fisher TL, Dunn S, Omer AK, Weir G, White MF: Exendin-4 uses Irs2 signaling to mediate pancreatic beta cell growth and function. J Biol Chem 281:1159–1168,2006
Dickson LM, Rhodes CJ: Pancreatic beta-cell growth and survival in the onset of type 2 diabetes: a role for protein kinase B in the Akt?Am J Physiol Endocrinol Metab 287:E192–E198,2004
Pende M, Kozma SC, Jaquet M, Oorschot V, Burcelin R, Le Marchand-Brustel Y, Klumperman J, Thorens B, Thomas G: Hypoinsulinaemia, glucose intolerance and diminished beta-cell size in S6K1-deficient mice. Nature 408:994–997,2000
Shapiro AM, Ricordi C, Hering BJ, Auchincloss H, Lindblad R, Robertson RP, Secchi A, Brendel MD, Berney T, Brennan DC, Cagliero E, Alejandro R, Ryan EA, DiMercurio B, Morel P, Polonsky KS, Reems JA, Bretzel RG, Bertuzzi F, Froud T, Kandaswamy R, Sutherland DE, Eisenbarth G, Segal M, Preiksaitis J, Korbutt GS, Barton FB, Viviano L, Seyfert-Margolis V, Bluestone J, Lakey JR: International trial of the Edmonton protocol for islet transplantation. N Engl J Med 355:1318–1330,2006
Marchetti P: New-onset diabetes after transplantation. J Heart Lung Transplant 23 (Suppl. 5):S194–S201,2004
Bussiere CT, Lakey JR, Shapiro AM, Korbutt GS: The impact of the mTOR inhibitor sirolimus on the proliferation and function of pancreatic islets and ductal cells. Diabetologia 49:2341–2349,2006
Zhang N, Su D, Qu S, Tse T, Bottino R, Balamurugan AN, Xu J, Bromberg JS, Dong HH: Sirolimus is associated with reduced islet engraftment and impaired β-cell function. Diabetes 55:2429–2436,2006
Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ, the Global ARCC Trial: Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356:2271–2281,2007