Reduced Insulin Secretion by Repeated Low Doses of STZ Impairs Glucose Effectiveness but Does Not Induce Insulin Resistance in Dogs

To investigate the longitudinal relationship between progressive beta-cell dysfunction and other parameters of glucose tolerance, we administered repeated low doses of STZ (10 mg/kg body wt) to dogs at 14-day intervals. STZ was discontinued after 10 doses (n = 4), the onset of fasting hyperglycemia (n = 1), or death (n = 1). Before the initial drug dose and 8 days after each treatment, an insulin-modified frequently sampled intravenous glucose tolerance test was performed to determine the integrated insulin response to glucose (0-19 min), insulin sensitivity, glucose effectiveness, and glucose tolerance. The integrated insulin response to glucose reached a nadir equal to 8% of pretreatment values by completion of the study. Despite this significant reduction in the insulin secretory response to glucose (P = 0.02), fasting plasma insulin, fasting plasma glucose, and insulin sensitivity remained constant throughout the study (P = 0.15, P = 0.71, and P = 0.5, respectively). SG, however, declined significantly below the pre-STZ treatment level in animals that received more than seven STZ doses (> 70 mg/kg STZ cumulatively, P < 0.03). In summary, when fasting normoglycemia is maintained, a 92% reduction in insulin secretory capacity and repeated low doses of STZ may alter glucose effectiveness but does not directly affect insulin sensitivity.