We previously demonstrated that minimal model-derived estimates of glucose effectiveness (SG), based on the frequently sampled intravenous glucose tolerance test (SGFSIGT), were reduced in islet-transplanted or streptozotocin-treated dogs and in patients with insulin-dependent diabetes mellitus. To ascertain the validity of our observations, we compared SGFSIGT with estimates based on a basal hormone replacement glucose clamp (SGBRCLAMP) and a basal hormone replacement glucose tolerance test (SGBRGTT) in normal control (CNTL, n = 12) and streptozotocin-treated dogs with normal fasting plasma glucose (STZ-Rx, n = 9). SGFSIGT was reduced in STZ-Rx compared with CNTL (P < 0.05). However, neither SGBRCLAMP nor SGBRGTT was reduced in the STZ-Rx group (P > 0.05). Comparison of protocols for each subject indicated that SGFSIGT was greater than either SGBRCLAMP or SGBRGTT in control (P < 0.002) but not in STZ-Rx dogs (P > 0.1). The relationship of SGFSIGT to insulin secretory function suggests that our previous conclusion that SGFSIGT was reduced in subjects with limited insulin release may be an artifact of the minimal-model method. Our results suggest that caution must be exercised in the interpretation of differences in minimal-model estimates of SG between subject groups with significantly different levels of insulin secretory function.