To investigate the longitudinal relationship between progressive β-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.

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