BETA-CELL APOPTOSIS IS RESPONSIBLE FOR THE DEVELOPMENT OF IDDM IN THEMULTIPLE LOW-DOSE STREPTOZOTOCIN MODEL

Although insulin-dependent diabetes mellitus (IDDM) results from irrev ersible loss of beta cells, the mode of cell death responsible for thi s loss has not previously been categorized. In this study, the multipl e low-dose streptozotocin (stz) model (intraperitoneal injection of st z at a concentration of 40 mg/kg body weight per day for five consecut ive days) was used to investigate beta-cell death during the developme nt of IDDM in male C57B1/6 mice. Apoptotic cells mere evident by light microscopy within the islets of Langerhans of treated animals from da y 2 (the day of the second stz injection) until day 17. Immunohistoche mical localization of insulin to the dying cells confirmed the beta-ce ll origin of the apoptosis. Two peaks in the incidence of beta-cell ap optosis occurred: the first at day 5, which corresponded to an increas e in blood glucose concentration, and the second at day 11, when lymph ocytic infiltration of the islets (insulitis) was maximal. Insulitis d id not begin until day 9, by which time treated animals had developed overt diabetes as revealed by blood glucose and pancreatic immunoreact ive insulin (IRI) measurements. Beta-cell apoptosis preceded the appea rance of T-cells in the islets and continued throughout the period of insulitis. Thus, whether induced by stz or a subsequent immune respons e, apoptosis is the mode of cell death responsible for beta-cell loss in the multiple low-dose stz model of IDDM.