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Differences in the Expression of Heat-Shock Proteins and Antioxidant Enzymes between Human and Rodent Pancreatic Islets: Implications for the Pathogenesis of Insulin-Dependent Diabetes Mellitus

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Abstract

Background

It has previously been observed that the insulin-producing cells of human pancreatic islets are more resistant to alloxan-, streptozotocin-, nitroprusside-, or cytokine-induced injury than those of mouse and rat islets.

Materials and Methods

Human pancreatic islets were obtained from heart-beating organ donors. The expression of the stress proteins heat shock protein 70 (hsp70) and heme oxygenase and the anti-apoptosis gene bcl-2 was determined in isolated rat, mouse, and human islets, either cultured in vitro or transplanted under the kidney capsule of nude mice, using immunoblot analysis. Rat and human islet sensitivity to hydrogen peroxide was assessed by glucose oxidation measurements. Isolated islets were also analyzed for their catalase and superoxide dismutase activities, and the islet cell levels of reduced glutathione were determined in response to hydrogen peroxide and nitroprusside. Programmed cell death in human and rat islets in response to streptozotocin was evaluated using TUNEL staining.

Results

Cultured human islets expressed higher contents of hsp70 than mouse and rat islets at basal conditions. Also after 4 weeks under the kidney capsule of normoglycemic mice, the hsp70 levels were higher in human islets than in rat islets. The expression of another stress protein, heme oxygenase (HO), was strongly increased in cultured rat islets, but was not affected in human islets. Expression of the bcl-2 gene could not be detected in human islets. In spite of this, 0.5 mM streptozotocin induced apotosis in rat but not in human islet cells. Hydrogen peroxide (0.1 and 0.4 mM) decreased glucose oxidation rates in rat but not in human islets. The levels of reduced glutathione were moderately decreased in human and rat islet cells and sharply decreased in mouse islet cells in response to hydrogen peroxide. Moreover, the activities of catalase and superoxide dismutase (SOD) were markedly lower in mouse islets than in human islets. The activity of catalase was lower in rat islets than in human islets.

Conclusions

Human islets differ clearly from mouse and rat islets in their increased expression of hsp70, catalase, and SOD, which may explain the increased resistance of human islets to β cell toxins.

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Acknowledgments

The excellent technical assistance of C. Göktürk, I.-B. Hallgren, E. Törnelius, E. Forsbeck, A. Nordin, and M. Engkvist is acknowledged. This study made use of human islets prepared by the Central Unit of the β Cell Transplant, with financial support of a concerted action in Medical and Health Research of the European Community. The study was also supported by the Swedish Medical Research Council (Grant 12X-9237, associated with the β Cell Transplant, European Concerted Action for the Treatment of Diabetes; and Grants 12X-109, 12X-9886, 12X-6538, 12P-10151, and 19P-8982), the Juvenile Diabetes Foundation International, the Swedish Diabetes Association, the Novo-Nordisk Insulin Foundation Committee, the Swedish CFN (Forskningsanlag för alternativa metoder), the Family Ernfors Fund, BIOMED concerted action, the Vlaamse Gemeenschap (Grant 9297-1807), and the Belgian Fonds voor Geneeskundig Wetenschappelijk Onderzoek (Grant 3.0057.94). Maria Alice R. de Mello is on leave from the Departamento de Educacao Fisica, UNESP, Rio Claro, SP, Brazil. She is the recipient of a postdoctoral fellowship from the Brazilian Research Agency CNPQ.

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Authors and Affiliations

  1. Department of Medical Cell Biology, Biomedical Center, Uppsala University, P.O. Box 571, S-751 23, Uppsala, Sweden

    Nils Welsh, Boris Margulis, L. A. Håkan Borg, Johan Saldeen, Malin Flodström, Maria Alice Mello, Arne Andersson, Claes Hellerström & Decio L. Eizirik

  2. Department of Pathology, University Hospital, Uppsala University, Uppsala, Sweden

    Helena Jernberg Wiklund

  3. Department of Metabolism and Endocrinology, Vrije Universiteit Brussels and B-cell Transplant, Brussels, Belgium

    Daniel G. Pipeleers

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  1. Nils Welsh
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Additional information

Contributed by D. F. Steiner on July 5, 1995.

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Welsh, N., Margulis, B., Borg, L.A.H. et al. Differences in the Expression of Heat-Shock Proteins and Antioxidant Enzymes between Human and Rodent Pancreatic Islets: Implications for the Pathogenesis of Insulin-Dependent Diabetes Mellitus. Mol Med 1, 806–820 (1995). https://doi.org/10.1007/BF03401895

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