Skip to main content

Advertisement

SpringerLink
Log in

Deteriorated high-fat diet-induced diabetes caused by pancreatic β-cell-specific overexpression of Reg3β gene in mice

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Reg family proteins have long been implicated in islet β-cell proliferation, survival, and regeneration. In our previous study, we reported that Reg3β overexpression did not increase islet growth but prevented streptozotocin-induced islet damage by inducing specific genes. In order to explore its role in type 2 diabetes (T2D), we established high-fat diet (HFD)-induced obesity and diabetes in RIP-I/Reg3β mice. Glucose and insulin tolerance tests, immunofluorescence for insulin, eIF2α, and GLUT2 in islets, Western blots on phosphorylated AMPKα and hepatic histology were performed. Both RIP-I/Reg3β and wild-type mice gained weight rapidly and became hyperglycemic after 10 weeks on the HFD. However, the transgenic mice exhibited more significant acceleration in blood glucose levels, further deterioration of glucose intolerance and insulin resistance, and a lower intensity of insulin staining. Immunofluorescence revealed similar magnitude of islet compensation to a wild-type HFD. The normal GLUT2 distribution in the transgenic β-cells was disrupted and the staining was obviously diminished on the cell membrane. HFD feeding also caused a further decrease in the level of AMPKα phosphorylation in the transgenic islets. Our results suggest that unlike its protective effect against T1D, overexpressed Reg3β was unable to protect the β-cells against HFD-induced damage.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. K. Terazono, H. Yamamoto, S. Takasawa, K. Shiga, Y. Yonemura, Y. Tochino, H. Okamoto, A novel gene activated in regenerating islets. J. Biol. Chem. 263(5), 2111–2114 (1988)

    CAS  PubMed  Google Scholar 

  2. T. Watanabe, H. Yonekura, K. Terazono, H. Yamamoto, H. Okamoto, Complete nucleotide sequence of human reg gene and its expression in normal and tumoral tissues. The reg protein, pancreatic stone protein, and pancreatic thread protein are one and the same product of the gene. J. Biol. Chem. 265(13), 7432–7439 (1990)

    CAS  PubMed  Google Scholar 

  3. H. Miyashita, K. Nakagawara, M. Mori, Y. Narushima, N. Noguchi, S. Moriizumi, S. Takasawa, H. Yonekura, T. Takeuchi, H. Okamoto, Human REG family genes are tandemly ordered in a 95-kilobase region of chromosome 2p12. FEBS Lett. 377(3), 429–433 (1995)

    Article  CAS  PubMed  Google Scholar 

  4. Y. Narushima, M. Unno, K. Nakagawara, M. Mori, H. Miyashita, Y. Suzuki, N. Noguchi, S. Takasawa, T. Kumagai, H. Yonekura, H. Okamoto, Structure, chromosomal localization and expression of mouse genes encoding type III Reg, RegIII alpha, RegIII beta, RegIII γ. Gene 185(2), 159–168 (1997)

    Article  CAS  PubMed  Google Scholar 

  5. M. Abe, K. Nata, T. Akiyama, N.J. Shervani, S. Kobayashi, T. Tomioka-Kumagai, S. Ito, S. Takasawa, H. Okamoto, Identification of a novel Reg family gene, Reg IIIδ, and mapping of all three types of Reg family gene in a 75 kilobase mouse genomic region. Gene 246(1–2), 111–122 (2000)

    Article  CAS  PubMed  Google Scholar 

  6. H. Okamoto, The Reg gene family and Reg proteins: with special attention to the regeneration of pancreatic beta-cells. J. Hepatobiliary Pancreat. Surg. 6(3), 254–262 (1999)

    Article  CAS  PubMed  Google Scholar 

  7. Q. Li, X. Xiong, J.L. Liu, The contribution of Reg family proteins to cell growth and survival in pancreatic islets, in The Islets of Langerhans. Advances in Experimental Medicine and Biology, vol. 654, ed. by M.S. Islam (Springer, Berlin, 2014), pp. 955–988

    Google Scholar 

  8. J.L. Liu, W. Cui, B. Li, Y. Lu, Possible roles of reg family proteins in pancreatic islet cell growth. Endocr. Metab. Immune Disord. Drug Targets 8(1), 1–10 (2008)

    Article  CAS  PubMed  Google Scholar 

  9. L. Christa, F. Carnot, M.T. Simon, F. Levavasseur, M.G. Stinnakre, C. Lasserre, D. Thepot, B. Clement, E. Devinoy, C. Brechot, HIP/PAP is an adhesive protein expressed in hepatocarcinoma, normal Paneth, and pancreatic cells. Am. J. Physiol. 271(6 Pt 1), G993–G1002 (1996)

    CAS  PubMed  Google Scholar 

  10. H.T. Lieu, F. Batteux, M.T. Simon, A. Cortes, C. Nicco, F. Zavala, A. Pauloin, J.G. Tralhao, O. Soubrane, B. Weill, C. Brechot, L. Christa, HIP/PAP accelerates liver regeneration and protects against acetaminophen injury in mice. Hepatology 42(3), 618–626 (2005)

    Article  CAS  PubMed  Google Scholar 

  11. S. Takasawa, T. Ikeda, T. Akiyama, K. Nata, K. Nakagawa, N.J. Shervani, N. Noguchi, S. Murakami-Kawaguchi, A. Yamauchi, I. Takahashi, T. Tomioka-Kumagai, H. Okamoto, Cyclin D1 activation through ATF-2 in Reg-induced pancreatic beta-cell regeneration. FEBS Lett. 580(2), 585–591 (2006)

    Article  CAS  PubMed  Google Scholar 

  12. L. Rosenberg, M. Lipsett, J.W. Yoon, M. Prentki, R. Wang, H.S. Jun, G.L. Pittenger, D. Taylor-Fishwick, A.I. Vinik, A pentadecapeptide fragment of islet neogenesis-associated protein increases beta-cell mass and reverses diabetes in C57BL/6 J mice. Ann. Surg. 240(5), 875–884 (2004)

    Article  PubMed  PubMed Central  Google Scholar 

  13. D.A. Taylor-Fishwick, A. Bowman, N. Hamblet, P. Bernard, D.M. Harlan, A.I. Vinik, Islet neogenesis associated protein transgenic mice are resistant to hyperglycemia induced by streptozotocin. J. Endocrinol. 190(3), 729–737 (2006). doi:10.1677/joe.1.06698

    Article  CAS  PubMed  Google Scholar 

  14. T.J. Chang, J.R. Weaver, A. Bowman, K. Leone, R. Raab, A.I. Vinik, G.L. Pittenger, D.A. Taylor-Fishwick, Targeted expression of INGAP to beta cells enhances glucose tolerance and confers resistance to streptozotocin-induced hyperglycemia. Mol. Cell. Endocrinol. 335(2), 104–109 (2011). doi:10.1016/j.mce.2010.12.026

    Article  CAS  PubMed  Google Scholar 

  15. L. Liu, J.L. Liu, C.B. Srikant, Reg2 protects mouse insulinoma cells from streptozotocin-induced mitochondrial disruption and apoptosis. Growth Factors 28(5), 370–378 (2010). doi:10.3109/08977194.2010.504721

    Article  CAS  PubMed  Google Scholar 

  16. L. Liu, S. Chowdhury, X. Fang, J.L. Liu, C.B. Srikant, Attenuation of unfolded protein response and apoptosis by mReg2 induced GRP78 in mouse insulinoma cells. FEBS Lett. 588(11), 2016–2024 (2014). doi:10.1016/j.febslet.2014.04.030

    Article  CAS  PubMed  Google Scholar 

  17. W. Cui, K. De Jesus, H. Zhao, S. Takasawa, B. Shi, C.B. Srikant, J.L. Liu, Overexpression of Reg3alpha increases cell growth and the levels of cyclin D1 and CDK4 in insulinoma cells. Growth Factors 27(3), 195–202 (2009). doi:10.1080/08977190902863548

    Article  CAS  PubMed  Google Scholar 

  18. C. Lasserre, M.T. Simon, H. Ishikawa, S. Diriong, V.C. Nguyen, L. Christa, P. Vernier, C. Brechot, Structural organization and chromosomal localization of a human gene (HIP/PAP) encoding a C-type lectin overexpressed in primary liver cancer. Eur. J. Biochem. 224(1), 29–38 (1994)

    Article  CAS  PubMed  Google Scholar 

  19. J.C. Hartupee, H. Zhang, M.F. Bonaldo, M.B. Soares, B.K. Dieckgraefe, Isolation and characterization of a cDNA encoding a novel member of the human regenerating protein family: reg IV. Biochim. Biophys. Acta 1518(3), 287–293 (2001)

    Article  CAS  PubMed  Google Scholar 

  20. R. Graf, M. Schiesser, A. Lussi, P. Went, G.A. Scheele, D. Bimmler, Coordinate regulation of secretory stress proteins (PSP/reg, PAP I, PAP II, and PAP III) in the rat exocrine pancreas during experimental acute pancreatitis. J. Surg. Res. 105(2), 136–144 (2002)

    Article  CAS  PubMed  Google Scholar 

  21. B. Zhong, P. Strnad, D.M. Toivola, G.Z. Tao, X. Ji, H.B. Greenberg, M.B. Omary, Reg-II is an exocrine pancreas injury-response product that is up-regulated by keratin absence or mutation. Mol. Biol. Cell 18(12), 4969–4978 (2007). doi:10.1091/mbc.E07-02-0180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Y. Lu, A. Ponton, H. Okamoto, S. Takasawa, P.L. Herrera, J.L. Liu, Activation of the Reg family genes by pancreatic-specific IGF-I gene deficiency and after streptozotocin-induced diabetes in mouse pancreas. Am. J. Physiol. Endocrinol. Metab. 291(1), E50–E58 (2006). doi:10.1152/ajpendo.00596.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Y. Wang, C. Jacovetti, B. Li, T. Siddique, X. Xiong, H. Yin, M. Wang, H. Zhao, J.L. Liu, Coordinated age-dependent and pancreatic-specific expression of mouse Reg2Reg3alpha, and Reg3beta genes. Growth Factors 29(2–3), 72–81 (2011). doi:10.3109/08977194.2011.562866

    Article  CAS  PubMed  Google Scholar 

  24. M. Gironella, E. Folch-Puy, A. LeGoffic, S. Garcia, L. Christa, A. Smith, L. Tebar, S.P. Hunt, R. Bayne, A.J. Smith, J.C. Dagorn, D. Closa, J.L. Iovanna, Experimental acute pancreatitis in PAP/HIP knock-out mice. Gut 56(8), 1091–1097 (2007). doi:10.1136/gut.2006.116087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. N. Baeza, D. Sanchez, L. Christa, O. Guy-Crotte, B. Vialettes, C. Figarella, Pancreatitis-associated protein (HIP/PAP) gene expression is upregulated in NOD mice pancreas and localized in exocrine tissue during diabetes. Digestion 64(4), 233–239 (2001)

    Article  CAS  PubMed  Google Scholar 

  26. X. Xiong, X. Wang, B. Li, S. Chowdhury, Y. Lu, C.B. Srikant, G. Ning, J.L. Liu, Pancreatic islet-specific overexpression of Reg3β protein induced the expression of pro-islet genes and protected mice against streptozotocin-induced diabetes. Am. J. Physiol. Endocrinol. Metab. 300, E669–E680 (2011)

    Article  CAS  PubMed  Google Scholar 

  27. Y. Lu, P.L. Herrera, Y. Guo, D. Sun, Z. Tang, D. LeRoith, J.L. Liu, Pancreatic-specific inactivation of IGF-I gene causes enlarged pancreatic islets and significant resistance to diabetes. Diabetes 53(12), 3131–3141 (2004)

    Article  CAS  PubMed  Google Scholar 

  28. S.H. Back, R.J. Kaufman, Endoplasmic reticulum stress and type 2 diabetes. Annu. Rev. Biochem. 81, 767–793 (2012). doi:10.1146/annurev-biochem-072909-095555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. D.R. Clemmons, A.C. Moses, A. Sommer, W. Jacobson, A.D. Rogol, M.R. Sleevi, G. Allan, Rh/IGF-I/rhIGFBP-3 administration to patients with type 2 diabetes mellitus reduces insulin requirements while also lowering fasting glucose. Growth Horm. IGF Res. 15(4), 265–274 (2005)

    Article  CAS  PubMed  Google Scholar 

  30. P. Zhang, B. McGrath, S. Li, A. Frank, F. Zambito, J. Reinert, M. Gannon, K. Ma, K. McNaughton, D.R. Cavener, The PERK eukaryotic initiation factor 2 alpha kinase is required for the development of the skeletal system, postnatal growth, and the function and viability of the pancreas. Mol. Cell. Biol. 22(11), 3864–3874 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. C.R. Lindholm, R.L. Ertel, J.D. Bauwens, E.G. Schmuck, J.D. Mulligan, K.W. Saupe, A high-fat diet decreases AMPK activity in multiple tissues in the absence of hyperglycemia or systemic inflammation in rats. J. Physiol. Biochem. 69(2), 165–175 (2013). doi:10.1007/s13105-012-0199-2

    Article  CAS  PubMed  Google Scholar 

  32. F. Schuit, D. Flamez, A. De Vos, D. Pipeleers, Glucose-regulated gene expression maintaining the glucose-responsive state of beta-cells. Diabetes 51(suppl 3), S326–S332 (2002). doi:10.2337/diabetes.51.2007.S326

    Article  CAS  PubMed  Google Scholar 

  33. R. Jacob, E. Barrett, G. Plewe, K.D. Fagin, R.S. Sherwin, Acute effects of insulin-like growth factor I on glucose and amino acid metabolism in the awake fasted rat. Comparison with insulin. J. Clin. Invest. 83(5), 1717–1723 (1989)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. K. Ohtsubo, S. Takamatsu, M.T. Minowa, A. Yoshida, M. Takeuchi, J.D. Marth, Dietary and genetic control of glucose transporter 2 glycosylation promotes insulin secretion in suppressing diabetes. Cell 123(7), 1307–1321 (2005). doi:10.1016/j.cell.2005.09.041

    Article  CAS  PubMed  Google Scholar 

  35. M.S. Lipkowitz, E. Leal-Pinto, B.E. Cohen, R.G. Abramson, Galectin 9 is the sugar-regulated urate transporter/channel UAT. Glycoconj. J. 19(7–9), 491–498 (2004). doi:10.1023/B:GLYC.0000014078.65610.2f

    PubMed  Google Scholar 

  36. D.R. Clemmons, Involvement of insulin-like growth factor-I in the control of glucose homeostasis. Curr. Opin. Pharmacol. 6(6), 620–625 (2006). doi:10.1016/j.coph.2006.08.006

    Article  CAS  PubMed  Google Scholar 

  37. S.G. Laychock, J. Duzen, C.O. Simpkins, Metallothionein induction in islets of Langerhans and insulinoma cells. Mol. Cell. Endocrinol. 165(1–2), 179–187 (2000)

    Article  CAS  PubMed  Google Scholar 

  38. X. Li, H. Chen, P.N. Epstein, Metallothionein and catalase sensitize to diabetes in nonobese diabetic mice: reactive oxygen species may have a protective role in pancreatic {beta}-cells. Diabetes 55(6), 1592–1604 (2006)

    Article  CAS  PubMed  Google Scholar 

  39. C.L. Acerini, C.M. Patton, M.O. Savage, A. Kernell, O. Westphal, D.B. Dunger, Randomised placebo-controlled trial of human recombinant insulin-like growth factor I plus intensive insulin therapy in adolescents with insulin-dependent diabetes mellitus. The Lancet 350(9086), 1199–1204 (1997)

    Article  CAS  Google Scholar 

  40. B. Viollet, L. Lantier, J. Devin-Leclerc, S. Hebrard, C. Amouyal, R. Mounier, M. Foretz, F. Andreelli, Targeting the AMPK pathway for the treatment of type 2 diabetes. Front. Biosci. J. Virtual Libr. 14, 3380–3400 (2009)

    Article  CAS  Google Scholar 

  41. G.R. Steinberg, B.E. Kemp, AMPK in health and disease. Physiol. Rev. 89(3), 1025–1078 (2009). doi:10.1152/physrev.00011.2008

    Article  CAS  PubMed  Google Scholar 

  42. K.M. Utzschneider, S.E. Kahn, Review: the role of insulin resistance in nonalcoholic fatty liver disease. J. Clin. Endocrinol. Metab. 91(12), 4753–4761 (2006). doi:10.1210/jc.2006-0587

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to thank Dr. Louise Larose for her instructions on ER stress tests and Carolynna Olha for the English revision and editing of this manuscript. This work was supported by the Canadian Institutes of Health Research (Grant MOP-84389), Canadian Diabetes Association (OG-3-11-3469-JL) and a bridge fund from the Research Institute of the McGill University Health Centre (RI-MUHC) to JLL. QL received support from the China Scholarship Council (201208370055). ZHG was supported by the RI-MUHC.

Author information

Author notes

    Authors and Affiliations

    1. Fraser Laboratories for Diabetes Research, Department of Medicine, RI-McGill University Health Centre, Room E02.7220, 1001 Décarie Blvd, Montreal, QC, H4A 3J1, Canada

      Xiaoquan Xiong, Qing Li & Jun-Li Liu

    2. Department of Endocrinology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China

      Wei Cui

    3. Department of Pathology, RI-McGill University Health Centre, Room E04.1820, 1001 Decarie Boulevard, Montreal, QC, H4A 3J1, Canada

      Zu-Hua Gao

    4. Montreal Diabetes Research Centre, Montreal, Canada

      Jun-Li Liu

    Authors
    1. Xiaoquan Xiong
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Qing Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Wei Cui
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Zu-Hua Gao
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Jun-Li Liu
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Zu-Hua Gao or Jun-Li Liu.

    Ethics declarations

    Conflicts of interest

    All authors declared there were no conflicts of interest.

    Additional information

    Xiaoquan Xiong and Qing Li have contributed equally to this work.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    12020_2016_998_MOESM1_ESM.tif

    Supplemental Figure 1. Interlobular fat deposition within the pancreatic tissues of HFD- but not Chow-fed mice. At the end of the 10-week HFD feeding, pancreatic sections were stained with HE, the brown arrows indicate fat deposition in the form of bubbles. Representative images of N=5. Supplementary material 1 (TIFF 1345 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Xiong, X., Li, Q., Cui, W. et al. Deteriorated high-fat diet-induced diabetes caused by pancreatic β-cell-specific overexpression of Reg3β gene in mice. Endocrine 54, 360–370 (2016). https://doi.org/10.1007/s12020-016-0998-2

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s12020-016-0998-2

    Keywords

    Search

    Navigation