Multiple low-dose streptozotocin-induced hyperglycemia and insulitis in C57BL mice: Influence of inbred background, sex, and thymus

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Abstract
Insulin-dependent diabetes induced in susceptible strains of mice by multiple, low-dose streptozotocin treatment was proposed to entail a thymus-dependent, autoimmune destruction of .beta. cells. Thymectomized and genetically athymic mice were tested for susceptibility to streptozotocin. Thymectomy was performed on newborn (day 1) to 3-day-old C57BL/KsJ mice. At 8 wk of age, thymectomized and sham-operated mice of both sexes were tested for susceptibility to diabetes induction by multiple, low-dose streptozotocin treatment (35 mg/kg of body wt per day for 6 consecutive days). Thymectomy failed to block susceptibility of males to induction of severe hyperglycemia. .beta. cell necrosis and inflammatory cell infiltrates (insulitis) were consistent histopathological features. In general, females (both thymus-intact and thymectomized) were less susceptible than males to streptozotocin-induced hyperglycemia, and females exhibited an equally severe insulitis by experimental day 14; thus, the detection of an underlying insulitis did not predict the development of a more severe hyperglycemia because most streptozotocin-treated females at experimental day 35 continued to show only a modest hyperglycemia (.apprx. 200 mg/dl) compared to males (> 400 mg/dl). That streptozotocin-induced hyperglycemia could occur in the absence of an intact thymus was further demonstrated in genetically athymic C57BL/6J NIcrOu nu/nu males and thymus-intact +/? littermate controls. C57BL/6J mice were resistant to streptozotocin-induced insulitis. The presence of insulitis does not necessarily presage onset of severe hyperglycemia (e.g., C57BL/Ks females), and conversely, the presence of severe hyperglycemia after low-dose streptozotocin treatment is not necessarily diagnostic of an underlying insulitis (e.g., C57BL/6J +/? and nu/nu males). These data stress the need for caution in the interpretation of studies of streptozotocin-insulitis sensitivities of nude mice.