Deteriorated high-fat diet-induced diabetes caused by pancreatic β-cell-specific overexpression of Reg3β gene in mice
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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.
KeywordsInsulin resistance GLUT2 AMPKα Aging Hepatic steatosis eIF2α
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.
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Conflicts of interest
All authors declared there were no conflicts of interest.
- 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)PubMedGoogle 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)PubMedCrossRefGoogle 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)PubMedCrossRefGoogle 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. 955–988Google 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)PubMedCrossRefGoogle 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)PubMedPubMedCentralCrossRefGoogle 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 PubMedCrossRefGoogle 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)PubMedCrossRefGoogle 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 PubMedPubMedCentralCrossRefGoogle 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 PubMedPubMedCentralCrossRefGoogle 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 PubMedPubMedCentralCrossRefGoogle 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)PubMedCrossRefGoogle 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)PubMedPubMedCentralCrossRefGoogle 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 PubMedCrossRefGoogle 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)CrossRefGoogle Scholar