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mTORC1 pathway mediates beta cell compensatory proliferation in 60 % partial-pancreatectomy mice

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Abstract

Beta cell replication is the major component for maintenance of beta cell mass in adult rodents; however, little is known about what is the earliest signals that initiate rodent beta cell proliferation. The mTORC1 pathway integrates signals from growth factors and nutrients and regulates cell growth and survival. Here, we used normoglycemic 60 % partial-pancreatectomy (60 % Px) mouse model to determine whether mTORC1 pathway was required for compensatory beta cell proliferation. C57BL/6 J male mice were subjected to 60 % Px or sham operation, and subsequently treated with either rapamycin or vehicle for 7 days. Metabolic profile, pancreatic beta cell mass, and proliferation were examined, and expression levels of cell cycle regulators were determined. Beta cell proliferation was increased by 2.5-fold, and mTORC1 signaling was activated in islets post-Px. Rapamycin treatment impaired glucose tolerance and glucose stimulating insulin secretion in 60 % Px mice, but did not affect their insulin sensitivity in peripheral tissue. Rapamycin inhibited mTORC1 activity in beta cells, suppressed compensatory beta cell proliferation and growth, and reduced beta cell mass and insulin content in 60 % Px mice. Px caused an increase of the cyclin D2 at protein level and promoted cyclin D2 nuclear localization in an mTOR-dependent manner. Disrupting mTORC1 signaling suppressed cell proliferation and simultaneously diminished cyclin D2 protein abundance in RINm5F cells. Our data demonstrated that mTORC1 plays an essential role in beta cell adaption to significant beta cell mass loss in 60 % Px model and in early compensatory beta cell proliferation via cyclin D2 pathway.

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References

  1. M. Karaca, C. Magnan, C. Kargar, Functional pancreatic beta-cell mass: involvement in type 2 diabetes and therapeutic intervention. Diabetes Metab. 35(2), 77–84 (2009). doi:10.1016/j.diabet.2008.09.007

    Article  CAS  PubMed  Google Scholar 

  2. M.O. Larsen, Beta-cell function and mass in type 2 diabetes. Dan. Med. Bull. 56(3), 153–164 (2009)

    PubMed  Google Scholar 

  3. A.V. Matveyenko, P.C. Butler, Relationship between beta-cell mass and diabetes onset. Diabetes Obes. Metab. 10(Suppl 4), 23–31 (2008). doi:10.1111/j.1463-1326.2008.00939.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. J.J. Meier, R.C. Bonadonna, Role of reduced beta-cell mass versus impaired beta-cell function in the pathogenesis of type 2 diabetes. Diabetes Care 36(Suppl 2), S113–S119 (2013). doi:10.2337/dcS13-2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. G.C. Weir, S. Bonner-Weir, Islet beta cell mass in diabetes and how it relates to function, birth, and death. Ann. N. Y. Acad. Sci. 1281, 92–105 (2013). doi:10.1111/nyas.12031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. D. Pipeleers, M. Chintinne, B. Denys, G. Martens, B. Keymeulen, F. Gorus, Restoring a functional beta-cell mass in diabetes. Diabetes Obes. Metab. 10(Suppl 4), 54–62 (2008). doi:10.1111/j.1463-1326.2008.00941.x

    Article  PubMed  Google Scholar 

  7. C.J. Rhodes, Type 2 diabetes-a matter of beta-cell life and death? Science 307(5708), 380–384 (2005). doi:10.1126/science.1104345

    Article  CAS  PubMed  Google Scholar 

  8. Y. Dor, J. Brown, O.I. Martinez, D.A. Melton, Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature 429(6987), 41–46 (2004). doi:10.1038/nature02520

    Article  CAS  PubMed  Google Scholar 

  9. S. Georgia, A. Bhushan, Beta cell replication is the primary mechanism for maintaining postnatal beta cell mass. J. Clin. Invest. 114(7), 963–968 (2004). doi:10.1172/jci22098

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. M. Laplante, D.M. Sabatini, mTOR signaling at a glance. J. Cell Sci. 122(Pt 20), 3589–3594 (2009). doi:10.1242/jcs.051011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. J.J. Howell, B.D. Manning, mTOR couples cellular nutrient sensing to organismal metabolic homeostasis. Trends Endocrinol. Metab. 22(3), 94–102 (2011). doi:10.1016/j.tem.2010.12.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. S.C. Johnson, P.S. Rabinovitch, M. Kaeberlein, mTOR is a key modulator of ageing and age-related disease. Nature 493(7432), 338–345 (2013). doi:10.1038/nature11861

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. M. Shimobayashi, M.N. Hall, Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat. Rev. Mol. Cell Biol. 15(3), 155–162 (2014). doi:10.1038/nrm3757

    Article  CAS  PubMed  Google Scholar 

  14. M. Blandino-Rosano, A.Y. Chen, J.O. Scheys, E.U. Alejandro, A.P. Gould, T. Taranukha, L. Elghazi, C. Cras-Meneur, E. Bernal-Mizrachi, mTORC1 signaling and regulation of pancreatic beta-cell mass. Cell Cycle 11(10), 1892–1902 (2012). doi:10.4161/cc.20036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. A.D. Barlow, M.L. Nicholson, T.P. Herbert, Evidence for rapamycin toxicity in pancreatic beta-cells and a review of the underlying molecular mechanisms. Diabetes 62(8), 2674–2682 (2013). doi:10.2337/db13-0106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. B.W. Paty, J.S. Harmon, C.L. Marsh, R.P. Robertson, Inhibitory effects of immunosuppressive drugs on insulin secretion from HIT-T15 cells and Wistar rat islets. Transplantation 73(3), 353–357 (2002)

    Article  CAS  PubMed  Google Scholar 

  17. E. Bell, X. Cao, J.A. Moibi, S.R. Greene, R. Young, M. Trucco, Z. Gao, F.M. Matschinsky, S. Deng, J.F. Markman, A. Naji, B.A. Wolf, Rapamycin has a deleterious effect on MIN-6 cells and rat and human islets. Diabetes 52(11), 2731–2739 (2003)

    Article  CAS  PubMed  Google Scholar 

  18. L. Rachdi, N. Balcazar, F. Osorio-Duque, L. Elghazi, A. Weiss, A. Gould, K.J. Chang-Chen, M.J. Gambello, E. Bernal-Mizrachi, Disruption of Tsc2 in pancreatic beta cells induces beta cell mass expansion and improved glucose tolerance in a TORC1-dependent manner. Proc. Natl. Acad. Sci. USA 105(27), 9250–9255 (2008). doi:10.1073/pnas.0803047105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. H. Mori, K. Inoki, D. Opland, H. Munzberg, E.C. Villanueva, M. Faouzi, T. Ikenoue, D.J. Kwiatkowski, O.A. Macdougald, M.G. Myers Jr, K.L. Guan, Critical roles for the TSC-mTOR pathway in beta-cell function. Am. J. Physiol. Endocrinol. Metab. 297(5), E1013–E1022 (2009). doi:10.1152/ajpendo.00262.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. S. Hamada, K. Hara, T. Hamada, H. Yasuda, H. Moriyama, R. Nakayama, M. Nagata, K. Yokono, Upregulation of the mammalian target of rapamycin complex 1 pathway by Ras homolog enriched in brain in pancreatic beta-cells leads to increased beta-cell mass and prevention of hyperglycemia. Diabetes 58(6), 1321–1332 (2009). doi:10.2337/db08-0519

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. M. Pende, S.H. Um, V. Mieulet, M. Sticker, V.L. Goss, J. Mestan, M. Mueller, S. Fumagalli, S.C. Kozma, G. Thomas, S6K1(-/-)/S6K2(-/-) mice exhibit perinatal lethality and rapamycin-sensitive 5’-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway. Mol. Cell. Biol. 24(8), 3112–3124 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. I. Ruvinsky, N. Sharon, T. Lerer, H. Cohen, M. Stolovich-Rain, T. Nir, Y. Dor, P. Zisman, O. Meyuhas, Ribosomal protein S6 phosphorylation is a determinant of cell size and glucose homeostasis. Genes Dev. 19(18), 2199–2211 (2005). doi:10.1101/gad.351605

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. M. Pende, S.C. Kozma, M. Jaquet, V. Oorschot, R. Burcelin, Y. Le Marchand-Brustel, J. Klumperman, B. Thorens, G. Thomas, Hypoinsulinaemia, glucose intolerance and diminished beta-cell size in S6K1-deficient mice. Nature 408(6815), 994–997 (2000). doi:10.1038/35050135

    Article  CAS  PubMed  Google Scholar 

  24. N. Niclauss, D. Bosco, P. Morel, L. Giovannoni, T. Berney, G. Parnaud, Rapamycin impairs proliferation of transplanted islet beta cells. Transplantation 91(7), 714–722 (2011). doi:10.1097/TP.0b013e31820c10c8

    CAS  PubMed  Google Scholar 

  25. C.T. Bussiere, J.R. Lakey, A.M. Shapiro, G.S. Korbutt, The impact of the mTOR inhibitor sirolimus on the proliferation and function of pancreatic islets and ductal cells. Diabetologia 49(10), 2341–2349 (2006). doi:10.1007/s00125-006-0374-5

    Article  CAS  PubMed  Google Scholar 

  26. M. Fraenkel, M. Ketzinel-Gilad, Y. Ariav, O. Pappo, M. Karaca, J. Castel, M.F. Berthault, C. Magnan, E. Cerasi, N. Kaiser, G. Leibowitz, mTOR inhibition by rapamycin prevents beta-cell adaptation to hyperglycemia and exacerbates the metabolic state in type 2 diabetes. Diabetes 57(4), 945–957 (2008). doi:10.2337/db07-0922

    Article  CAS  PubMed  Google Scholar 

  27. E. Zahr, R.D. Molano, A. Pileggi, H. Ichii, S.S. Jose, N. Bocca, W. An, J. Gonzalez-Quintana, C. Fraker, C. Ricordi, L. Inverardi, Rapamycin impairs in vivo proliferation of islet beta-cells. Transplantation 84(12), 1576–1583 (2007). doi:10.1097/01.tp.0000296035.48728.28

    Article  CAS  PubMed  Google Scholar 

  28. V.P. Houde, S. Brule, W.T. Festuccia, P.G. Blanchard, K. Bellmann, Y. Deshaies, A. Marette, Chronic rapamycin treatment causes glucose intolerance and hyperlipidemia by upregulating hepatic gluconeogenesis and impairing lipid deposition in adipose tissue. Diabetes 59(6), 1338–1348 (2010). doi:10.2337/db09-1324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. S.B. Yang, H.Y. Lee, D.M. Young, A.C. Tien, A. Rowson-Baldwin, Y.Y. Shu, Y.N. Jan, L.Y. Jan, Rapamycin induces glucose intolerance in mice by reducing islet mass, insulin content, and insulin sensitivity. J. Mol. Med. (Berl) 90(5), 575–585 (2012). doi:10.1007/s00109-011-0834-3

    Article  CAS  Google Scholar 

  30. A.A. Misfeldt, R.H. Costa, M. Gannon, Beta-cell proliferation, but not neogenesis, following 60 % partial pancreatectomy is impaired in the absence of FoxM1. Diabetes 57(11), 3069–3077 (2008). doi:10.2337/db08-0878

    Article  CAS  Google Scholar 

  31. M. Peshavaria, B.L. Larmie, J. Lausier, B. Satish, A. Habibovic, V. Roskens, K. Larock, B. Everill, J.L. Leahy, T.L. Jetton, Regulation of pancreatic beta-cell regeneration in the normoglycemic 60 % partial-pancreatectomy mouse. Diabetes 55(12), 3289–3298 (2006). doi:10.2337/db06-0017

    Article  CAS  PubMed  Google Scholar 

  32. D.D. De Leon, S. Deng, R. Madani, R.S. Ahima, D.J. Drucker, D.A. Stoffers, Role of endogenous glucagon-like peptide-1 in islet regeneration after partial pancreatectomy. Diabetes 52(2), 365–371 (2003)

    Article  PubMed  Google Scholar 

  33. Y. Gu, J. Lindner, A. Kumar, W. Yuan, M.A. Magnuson, Rictor/mTORC2 is essential for maintaining a balance between beta-cell proliferation and cell size. Diabetes 60(3), 827–837 (2011). doi:10.2337/db10-1194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. S.H. Um, M. Sticker-Jantscheff, G.C. Chau, K. Vintersten, M. Mueller, Y.G. Gangloff, R.H. Adams, J.F. Spetz, L. Elghazi, P.T. Pfluger, M. Pende, E. Bernal-Mizrachi, A. Tauler, M.H. Tschop, G. Thomas, S.C. Kozma, S6K1 controls pancreatic beta cell size independently of intrauterine growth restriction. J. Clin. Invest. 125(7), 2736–2747 (2015). doi:10.1172/jci77030

    Article  PubMed  PubMed Central  Google Scholar 

  35. D. Baetens, F. Malaisse-Lagae, A. Perrelet, L. Orci, Endocrine pancreas: three-dimensional reconstruction shows two types of islets of langerhans. Science 206(4424), 1323–1325 (1979)

    Article  CAS  PubMed  Google Scholar 

  36. E.R. Trimble, P.A. Halban, C.B. Wollheim, A.E. Renold, Functional differences between rat islets of ventral and dorsal pancreatic origin. J. Clin. Invest. 69(2), 405–413 (1982)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. G. Kilimnik, J. Jo, V. Periwal, M.C. Zielinski, M. Hara, Quantification of islet size and architecture. Islets 4(2), 167–172 (2012). doi:10.4161/isl.19256

    Article  PubMed  PubMed Central  Google Scholar 

  38. N. Balcazar, A. Sathyamurthy, L. Elghazi, A. Gould, A. Weiss, I. Shiojima, K. Walsh, E. Bernal-Mizrachi, mTORC1 activation regulates beta-cell mass and proliferation by modulation of cyclin D2 synthesis and stability. J. Biol. Chem. 284(12), 7832–7842 (2009). doi:10.1074/jbc.M807458200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. M. Prentki, C.J. Nolan, Islet beta cell failure in type 2 diabetes. J. Clin. Invest. 116(7), 1802–1812 (2006). doi:10.1172/jci29103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. E.U. Alejandro, B. Gregg, M. Blandino-Rosano, C. Cras-Meneur, E. Bernal-Mizrachi, Natural history of beta-cell adaptation and failure in type 2 diabetes. Mol. Aspects Med. (2014). doi:10.1016/j.mam.2014.12.002

    PubMed  PubMed Central  Google Scholar 

  41. S. Rieck, K.H. Kaestner, Expansion of beta-cell mass in response to pregnancy. Trends Endocrinol. Metab. 21(3), 151–158 (2010). doi:10.1016/j.tem.2009.11.001

    Article  CAS  PubMed  Google Scholar 

  42. S. Chen, M. Shimoda, J. Chen, S. Matsumoto, P.A. Grayburn, Transient overexpression of cyclin D2/CDK4/GLP1 genes induces proliferation and differentiation of adult pancreatic progenitors and mediates islet regeneration. Cell Cycle 11(4), 695–705 (2012). doi:10.4161/cc.11.4.19120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. S.J. Salpeter, A. Klochendler, N. Weinberg-Corem, S. Porat, Z. Granot, A.M. Shapiro, M.A. Magnuson, A. Eden, J. Grimsby, B. Glaser, Y. Dor, Glucose regulates cyclin D2 expression in quiescent and replicating pancreatic beta-cells through glycolysis and calcium channels. Endocrinology 152(7), 2589–2598 (2011). doi:10.1210/en.2010-1372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. J.A. Kushner, M.A. Ciemerych, E. Sicinska, L.M. Wartschow, M. Teta, S.Y. Long, P. Sicinski, M.F. White, Cyclins D2 and D1 are essential for postnatal pancreatic beta-cell growth. Mol. Cell. Biol. 25(9), 3752–3762 (2005). doi:10.1128/mcb.25.9.3752-3762.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. R.E. Stamateris, R.B. Sharma, D.A. Hollern, L.C. Alonso, Adaptive beta-cell proliferation increases early in high-fat feeding in mice, concurrent with metabolic changes, with induction of islet cyclin D2 expression. Am. J. Physiol. Endocrinol. Metab. 305(1), E149–E159 (2013). doi:10.1152/ajpendo.00040.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. M.C. Fabian, J.R. Lakey, R.V. Rajotte, N.M. Kneteman, The efficacy and toxicity of rapamycin in murine islet transplantation. In vitro and in vivo studies. Transplantation 56(5), 1137–1142 (1993)

    Article  CAS  PubMed  Google Scholar 

  47. N. Zhang, D. Su, S. Qu, T. Tse, R. Bottino, A.N. Balamurugan, J. Xu, J.S. Bromberg, H.H. Dong, Sirolimus is associated with reduced islet engraftment and impaired beta-cell function. Diabetes 55(9), 2429–2436 (2006). doi:10.2337/db06-0173

    Article  CAS  PubMed  Google Scholar 

  48. S. Di Paolo, A. Teutonico, D. Leogrande, C. Capobianco, P.F. Schena, 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(8), 2236–2244 (2006). doi:10.1681/asn.2006030196

    Article  PubMed  Google Scholar 

  49. A.Y. Choo, J. Blenis, Not all substrates are treated equally: implications for mTOR, rapamycin-resistance and cancer therapy. Cell Cycle 8(4), 567–572 (2009)

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We are grateful to Mrs Yun Liu, Dr Qinglei Yin, Dr Yun Xie, Dr Binbing Guan, and Dr Xiu Luo for theirs help during islet isolation. This work was supported by National Natural Sciences Foundation of China Grants (81200565, 81270860, 81370875, 81200563, 81390350).

Author contribution

W.L and Q.W researched data, wrote the manuscript, contributed to discussion, and reviewed/edited the manuscript. Y.G researched data and reviewed/edited the manuscript. H.Z, F.L, Q.N, and A.N researched data and contributed to discussion. G.N and X.L contributed to discussion and reviewed/edited the manuscript.

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    1. Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, 197 Rui-Jin 2nd Road, Shanghai, 200025, China

      Wenyi li, Hongli Zhang, Aifang Nie, Qicheng Ni, Fengying Li, Guang Ning, Xiaoying Li, Yanyun Gu & Qidi Wang

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    li, W., Zhang, H., Nie, A. et al. mTORC1 pathway mediates beta cell compensatory proliferation in 60 % partial-pancreatectomy mice. Endocrine 53, 117–128 (2016). https://doi.org/10.1007/s12020-016-0861-5

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