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

Background: It has previously been observed that the insulin-producing cells of human pancreatic islets are more resistant to alloxan-, stre ptozotocin-, nitroprusside-, or cytokine-induced injury than those of mouse and rat islets. Materials and Methods: Human pancreatic islets w ere obtained from heart-heating organ donors. The expression of the st ress 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 kidne y capsule of nude mice, using immunoblot analysis. Rat and human islet sensitivity to hydrogen peroxide was assessed by glucose oxidation me asurements. Isolated islets were also analyzed for their catalase and superoxide dismutase activities, and the islet eel levels of reduced g lutathione were determined in response to hydrogen peroxide and nitrop russide. Programmed cell death in human and rat islets in response to streptozotocin was evaluated using TUNEL staining. Results: Cultured h uman islets expressed higher contents of hsp70 than mouse and rat isle ts at basal, conditions. Also after 4 weeks under the kidney capsule o f normoglycemic mice, the hsp70 levels were higher in human islets tha n in rat islets. The expression of another stress protein, heme oxygen ase (HO), was strongly increased in cultured rat islets, but was not a ffected in human islets. Expression of the bcl-2 gene could not be det ected 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 th an in human islets, The activity of catalase was lower in rat islets t han in human islets. Conclusion: Human islets differ clearly from mous e and rat islets in their increased expression of hsp70, catalase, and SOD, which may explain the increased resistance of human islets to be ta cell toxins.