Abstract
To elucidate gender-dependent protein regulation and molecular abnormalities in streptozotocin (STZ)-induced diabetes, we compared differentially expressed pancreatic proteins between male and female diabetic rats and their healthy controls using a 2-DE-based proteomic approach. In animal experiments, we found that females exposed to STZ displayed greater susceptibility towards diabetes development due to lower insulin secretion and severe β-cell damage. It was also accompanied with more impaired regulation of sex hormones, lower glucose tolerance, and higher blood glucose levels compared to male diabetic rats. Among 748 detected protein spots ranging in mass from 6 to 240 kDa between pH 3 and 10, a total of 42 proteins showed significant sexually-dimorphic regulation patterns between male and female diabetic rats. Proteomic data revealed that male and female rats displayed prominent gender-dimorphic differential regulation of pancreatic proteins involved in glycolysis, the citric acid cycle, amino acid synthesis, lipid metabolism, insulin biosynthesis, β-cell regeneration, cell signaling, as well as antioxidative and cellular stress defense. In conclusion, the current proteomic study revealed that severely impaired protein regulation in the pancreas, at least in part, is responsible for increased susceptibility of female rats to STZ-induced diabetes.
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Szalat, A. and I. Raz (2008) Gender-specific care of diabetes mellitus: Particular considerations in the management of diabetic women. Diabetes Obes. Metab. 10: 1135–1156.
King, H., R. E. Aubert, and W. H. Herman (1998) Global burden of diabetes 1995–2025: Prevalence, numerical estimates, and projections. Diabetes Care 21: 1414–1431.
Macedo, C. S., S. M. Capelletti, M. C. S. Mercadante, C. R. Padovani, and C. T. Spadella (2002) Role of metabolic control on diabetic nephropathy. Acta Cir. Bras. 17: 370–376.
Wandell, P. E. and A. C Carlsson (2013) Time trends and gender differences in incidence and prevalence of type 1 diabetes in Sweden. Curr. Diabetes. Rev. 9: 342–349.
Wells, C. C., S. Riazi, R. W. Mankhey, F. Bhatti, http://0-www.sciencedirect.com.precise.petronas.com.my/science/article/pii/S155085790580052X-aff1 C. Ecelbarger, and C. Maric (2005) Diabetic nephropathy is associated with decreased circulating estradiol levels and imbalance in the expression of renal estrogen receptors. Gend. Med. 2: 227–237.
Le May, C., K. Chu, M. Hu, C. S. Ortega, E. R. Simpson, K. S. Korach, M. J. Tsai, and F. Mauvais-Jarvis (2006) Estrogens protect pancreatic beta-cells from apoptosis and prevent insulin-deficient diabetes mellitus in mice. Proc. Natl. Acad. Sci. USA. 103: 9232–9237.
Vital, P., E. Larrieta, and M. Hiriart (2006) Sexual dimorphism in insulin sensitivity and susceptibility to develop diabetes in rats. J. Endocrinol. 190: 425–432.
Kim, S. W., H. J. Hwang, H. M. Kim, M. C. Lee, M. Shik Lee, J. W. Choi, and J. W. Yun (2006) Effect of fungal polysaccharides on the modulation of plasma proteins in streptozotocin-induced diabetic rats. Proteomics. 6: 5291–5302.
Kim, S. W., H. J. Hwang, E. J. Cho, J. Y. Oh, Y. M. Baek, J. W. Choi, and J. W. Yun (2006) Time-dependent plasma protein changes in streptozotocin-induced diabetic rats before and after fungal polysaccharide treatments. J. Proteome Res. 5: 2966–2976.
Kim, S. W., H. J. Hwang, Y. M. Baek, S. H. Lee, H. S. Hwang, and J. W. Yun (2008) Proteomic and transcriptomic analysis for streptozotocin-induced diabetic rat pancreas in response to fungal polysaccharide treatments. Proteomics. 8: 2344–2361.
Ahmed, M. (2010) Proteomics and islet research. Adv. Exp. Med. Biol. 654: 363–390.
Sparre, T., M. R. Larsen, P. E. Heding, A. E. Karlsen, O. N. Jensen, and F. Pociot (2005) Unraveling the pathogenesis of type 1 diabetes with proteomics: Present and future directions. Mol. Cell Proteomics. 4: 441–457.
Andersen, H. U., S. J. Fey, P. M. Larsen, A. Nawrocki, K. R. Hej naes, T. Mandrup-Poulsen, and J. Nerup (1997) Interleukin-1beta induced changes in the protein expression of rat islets: A computerized database. Electrophoresis. 18: 2091–2103.
Christensen, U. B., P. M. Larsen, S. J. Fey, H. U. Andersen, A. Nawrocki, T. Sparre, T. Mandrup-Poulsen, and J. Nerup (2000) Islet protein expression changes during diabetes development in islet syngrafts in BB-DP rats and during rejection of BB-DP islet allografts. Autoimmunity. 32: 1–15.
Larsen, P. M., S. J. Fey, M. R. Larsen, A. Nawrocki, H. U. Andersen, H. Kahler, C. Heilmann, M. C. Voss, P. Roepstorff, F. Pociot, A. E. Karlsen, and J. Nerup (2001) Proteome analysis of interleukin-1 beta-induced changes in protein expression in rat islets of Langerhans. Diabetes. 50: 105610–105663.
Sparre, T., U. B. Christensen, P. Mose Larsen, S. J. Fey, K. Wrzesinski, P. Roepstorff, T. Mandrup-Poulsen, F. Pociot, A. E. Karlsen, and J. Nerup (2002) IL-1beta induced protein changes in diabetes prone BB rat islets of Langerhans identified by proteome analysis. Diabetol. 45: 1550–1561.
Xie, X., S. Li, S. Liu, Y. Lu, P. Shen, and J. Ji (2008) Proteomic analysis of mouse islets after multiple low-dose streptozotocin injection. Biochim. Biophys. Acta 1784: 276–284.
Zhi, W., S. Purohit, C. Carey, M. Wang, and J. X. She (2010) Proteomic technologiesfor the discovery of type 1 diabetes biomarkers. J. Diabetes Sci. Technol. 4: 993–1002.
Jiang, Y. L., Y. Ning, X. L. Ma, Y. Y. Liu, Y. Wang, Z. Zhang, C. X. Shan, Y. D. Xu, L. M. Yin, and Y. Q. Yang (2011) Alteration of the proteome profile of the pancreas in diabetic rats induced by streptozotocin. Int. J. Mol. Med. 28: 153–160.
Yang, M., W. Liu, C. Y. Wang, T. Liu, F. Zhou, J. Tao, Y. Wang, and M. T. Li (2006) Proteomic analysis of differential protein expression in early process of pancreatic regeneration in pancreatectomized rats. Acta Pharmacol. Sin. 27: 568–578.
Resjo, S., K. Berger, M. Fex, and O. Hansson (2008) Proteomic studies in animal models of diabetes. Proteomics Clin. Appl. 2: 654–669.
Bradford, M. M. (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72: 248–254.
Choi, J. W., X. Wang, J. I. Joo, D. H. Kim, T. S. Oh, D. K. Choi, and J. W. Yun (2010) Plasma proteome analysis in diet-induced obesity-prone and obesity-resistant rats. Proteomics. 10: 4386–4400.
Shevchenko, A., M. Wilm, O. Vorm, and M. Mann (1996) Mass spectrometric sequencing of proteins silver-stained polyacrylamide gels. Anal. Chem. 68: 850–858.
Rodriguez-Cuenca, S., E. Pujol, R. Justo, M. Frontera, J. Oliver, M. Gianotti, and P. Roca (2002) Sex-dependent thermogenesis, differences in mitochondrial morphology and function, and adrenergic response in brown adipose tissue. J. Biol. Chem. 277: 42958–42963.
Justo, R., J. Boada, M. Frontera, J. Oliver, J. Bermudez, and M. Gianotti (2005) Gender dimorphism in rat liver mitochondrial oxidative metabolism and biogenesis. Am. J. Physiol. Cell Physiol. 289: 372–378.
Zhang, D., J. Christianson, Z. X. Liu, L. Tian, C. S. Choi, S. Neschen, J. Dong, P. A. Wood, and G. I. Shulman (2010) Resistance to high-fat diet-induced obesity and insulin resistance in mice with very long-chain acyl CoA dehydrogenase deficiency. Cell. Metab. 11: 402–411.
Ashmarina, L. I., N. Rusnak, H. M. Miziorko, and G. A. Mitchell (1994) 3-Hydroxy-3-methylglutaryl-CoA lyase is present in mouse and human liver peroxisomes. J. Biol. Chem. 269: 31929–31932.
Sowers, M., C. Gonzalez Villalpando, M. P Stern, C. Fox, and B. D. Mitchell (1995) Relationships between physical activity, insulin levels and lipids in non-diabetic low income residents of Mexico City: The Mexico city diabetes study. Arch. Med. Res. 26: 133–140.
Adrogue, H. J., H. Wilson, A. E. III. Boyd, W. N. Suki, and knoyan (1982) Plasma acid base patterns in diabetic ketoacidosis. N. Engl. J. Med. 307: 1603–1610.
Wang, Z., L. Jiang, C. Huang, Z. Li, L. Chen, L. Gou, P. Chen, A. Tong, M. Tang, F. Gao, J. Shen, Y. Zhang, J. Bai, M. Zhou, D. Miao, and Q. Chen (2008) Comparative proteomics approach to screening of potential diagnostic and therapeutic targets for oral squamous cell carcinoma. Mol. Cell Proteomics. 7: 1639–1650.
Qiu, Y., T. Mao, Y. Zhang, M. Shao, J. You, Q. Ding, Y. Chen, D. Wu, D. Xie, X. Lin, X. Gao, R. J. Kaufman, W. Li, and Y. Liu (2010) A crucial role for RACK1 in the regulation of glucosestimulated IRE1alpha activation in pancreatic beta cells. Sci. Signal. 3: ra7.
Lipson, K. L., S. G. Fonseca, S. Ishigaki, L. X. Nguyen, E. Foss, R. Bortell, A. A. Rossini, and F. Urano (2006) Regulation of insulin biosynthesis in pancreatic beta cells by an endoplasmic reticulum-resident protein kinase IRE1. Cell Metab. 4: 245–254.
Anastasi, E., E. Ponte, R. Gradini, A. Bulotta, P. Sale, C. Tiberti, H. Okamoto, F. Dotta, and U. Di Mario (1999) Expression of Reg and cytokeratin 20 during ductal cell differentiation and proliferation in a mouse model of autoimmune diabetes. Eur. J. Endocrinol. 141: 644–652.
De Reggi, M. and B. Gharib (2001) Protein-X, pancreatic stone-, pancreatic thread-, reg-protein, P19, lithostathine, and now what? Characterization, structural analysis and putative function(s) of the major nonenzymatic protein of pancreatic secretions. Curr. Protein Pept. Sci. 2: 19–42.
Okamoto, H. (1999) The Reg gene family and Reg proteins: With special attention to the regeneration of pancreatic beta-cells. J. Hepatobiliary Pancreat. Surg. 6: 254–262.
Ohno, T., C. Ishii, N. Kato, Y. Ito, M. Shimizu, S. Tomono, K. Murata, and S. Kawazu (1995) Increased expression of a regenerating (reg) gene protein in neonatal rat pancreas treated with streptozotocin. Endocr. J. 42: 649–653.
Christofilis, M. A., J. Carrere, C. Atlan-Gepner, C. Zevaco-Mattei, C. Thivolet, N. Baeza, C. Figarella, and B. Vialettes (1999) Serum reg protein level is not related to the beta cell destruction/regeneration process during early phases of diabetogenesis in type I diabetes. Eur. J. Endocrinol. 141: 368–373.
Qiu, L., E. O. List, and J. J. Kopchick (2005) Differentially expressed proteins in the pancreas of diet-induced diabetic mice. Mol. Cell Proteomics. 4: 1311–1318.
Watanabe, T., Y. Yonemura, H. Yonekura, Y. Suzuki, H. Miyashita, K. Sugiyama, S. Moriizumi, M. Unno, O. Tanaka, and H. Kondo (1994) Pancreatic beta-cell replication and amelioration of surgical diabetes by Reg protein. Proc. Natl. Acad. Sci. U S A. 91: 3589–3592.
Kakkar, R., S. V. Mantha, J. Radhi, K. Prasad, and J. Kalra (1998) Increased oxidative stress in rat liver and pancreas during progression of streptozotocin-induced diabetes. Clin. Sci. 94: 623–632.
Kaneto, H., N. Katakami, M. Matsuhisa, and T. A. Matsuoka (2010) Role of reactive oxygen species in the progression of type 2 diabetes and atherosclerosis. Mediators Inflamm. 2010: 453892.
Strehlow, K., S. Rotter, S. Wassmann, O. Adam, C. Grohe, K. Laufs, M. Bohm, and G. Nickenig (2003) Modulation of antioxidant enzyme expression and function by estrogen. Circ Res. 93: 170–177.
Halliwell, B. (1994) Free radicals, antioxidants, and human disease: Curiosity, cause, or consequence? Lancet. 344: 721–724.
Liochev, S. I. and I. Fridovich (1994) The role of O2. — in the production of HO.:In vitro and in vivo. Free Radic. Biol. Med. 16: 29–33.
Lenzen, S., J. Drinkgern, and M. Tiedge (1996) Low antioxidant enzyme gene expression in pancreatic islets compared with various other mouse tissues. Free Radic. Biol. Med. 20: 463–466.
Ketterer, B. (1998) Glutathione S-transferases and prevention of cellular free radical damage. Free Radic. Res. 28: 647–658.
Kim, S. K., K. J. Woodcroft, and R. F. Novak (2003) Insulin and glucagon regulation of glutathione S-transferase expression in primary cultured rat hepatocytes. J. Pharmacol. Exp. Ther. 305: 353–361.
Fatma, N., P. Singh, B. Chhunchha., E. Kubo, T. Shinohara, B. Bhargavan, and D. P. Singh (2011) Deficiency of Prdx6 in lens epithelial cells induces ER stress response-mediated impaired homeostasis and apoptosis. Am. J. Physiol. Cell Physiol. 301: 954–967.
Nair, S., D. Yadav, and C. S. Pitchumoni (2000) Association of diabetic ketoacidosis and acute pancreatitis: Observations in 100 consecutive episodes of DKA. Am. J. Gastroenterol. 95: 2795–2800.
Hardt, P. D., A. Killinger, J. Nalop, H. Schnell-Kretschmer, T. Zekorn, and H. U. Klor (2002) Chronic pancreatitis and diabetes mellitus. A retrospective analysis of 156 ERCP investigations in patients with insulin-dependent and non-insulin-dependent diabetes mellitus. Pancreatol. 2: 30–33.
Vantyghem, M. C., S. Haye, M. Balduyck, C. Hober, P. M. Degand, and J. Lefebvre (1999) Changes in serum amylase, lipase and leukocyte elastase during diabetic ketoacidosis and poorly controlled diabetes. Acta Diabetol. 36: 39–44.
Jennens, M. L. and M. E. Lowe (1995) Rat GP-3 is a pancreatic lipase with kinetic properties that differ from colipase-dependent pancreatic lipase. J. Lipid Res. 36: 2374–2382.
Lowe, M. E., M. H. Kaplan, L. Jackson-Grusby, D. D’Agostino, and M. J. Grusby (1998) Decreased neonatal dietary fat absorption and T cell cytotoxicity in pancreatic lipase-related protein 2-deficient mice. J. Biol. Chem. 273: 31215–31221.
Rippe, C., K. Berger, J. Mei, M. E. Lowe, and C. Erlanson-Albertsson (2003) Effect of long-term high-fat feeding on the expression of pancreatic lipases and adipose tissue uncoupling proteins in mice. Pancreas. 26: e36–42.
Rosendahl, J., H. Witt, R. Szmola, E. Bhatia, B. Ozsvari, O. Landt, H. U. Schulz, T. M. Gress, R. Pfutzer, M. Lohr, P. Kovacs, M. Bluher, M. Stumvoll, G. Choudhuri, P. Hegyi, R. H. te Morsche, J. P. Drenth, K. Truninger, M. Macek, G. Puhl, U. Witt, H. Schmidt, C. Buning, J. Ockenga, A. Kage, D. A. Groneberg, R. Nickel, T. Berg, B. Wiedenmann, H. Bodeker, V. Keim, J. Mossner, N. Teich, and M. Sahin-Toth (2008) Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis. Nat. Genet. 40: 78–82.
Szabo, A. and M. Sahin-Toth (2012) Increased activation of hereditary pancreatitis-associated human cationic trypsinogen mutants in presence of chymotrypsin C. J. Biol. Chem. 287: 20701–20710.
Rebours, V., P. Levy, and P. Ruszniewski (2012) An overview of hereditary pancreatitis. Dig. Liver Dis. 44: 8–15.
Saluja, A. K., L. Bhagat, H. S. Lee, M. Bhatia, J. L. Frossard, and M. L. Steer (1999) Secretagogue-induced digestive enzyme activation and cell injury in rat pancreatic acini. Am. J. Physiol. 276: 835–842.
Hartl, F. U. (1996) Molecular chaperones in cellular protein folding. Nature 381: 571–579.
Quintana, F. J., A. Rotem, P. Carmi, and I. R Cohen (2000) Vaccination with empty plasmid DNA or CpG oligonucleotide inhibits diabetes in non-obese diabetic mice: Modulation of spontaneous 60-kDa heat shock protein autoimmunity. J. Immunol. 165: 6148–6155.
Tessari, P., L. Puricelli, E. Iori, G. Arrigoni, M. Vedovato, P. James, A. Coracina, and R. Millioni (2007) Altered chaperone and protein turnover regulators expression in cultured skin fibroblasts from type 1 diabetes mellitus with nephropathy. J. Proteome Res. 6: 976–986.
Pullen, T. J., A. M. Khan, G. Barton, S. A. Butcher, G. Sun, and G. A. Rutter (2010) Identification of genes selectively disallowed in the pancreatic islet. Islets. 2: 89–95.
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Aseer, K.R., Yun, J.W. Gender-dependent expression of pancreatic proteins in streptozotocin-induced diabetic rats. Biotechnol Bioproc E 18, 1122–1134 (2013). https://doi.org/10.1007/s12257-013-0324-2
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DOI: https://doi.org/10.1007/s12257-013-0324-2