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.
Tobin
B L
BL
Department of Physiology, University of Alberta, Edmonton, Canada.
Finegood
D T
DT
D000704:Analysis of Variance; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000503:physiopathology; D004195:Disease Models, Animal; D004285:Dogs; D005947:Glucose / Q000494:pharmacology*; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D000078790:Insulin Secretion; D008297:Male; D013311:Streptozocin / Q000008:administration & dosage
D007328:Insulin; D013311:Streptozocin; D005947:Glucose