Context. During insulin-modified frequently sampled intravenous glucose tolerance tests (IM-FSIGT), which allows assessment of insulin action, plasma glucose can markedly decrease.

Objective. This study aimed to assess the counterregulatory impact of the insulin-induced fall of glucose on minimal model derived indices of insulin sensitivity (S_I) and glucose effectiveness (S_G).

Participants. Thirteen nondiabetic volunteers (7 male, 6 female, age: 26 ± 1 yr, body mass index: 22.1 ± 0.7 kg/m²) were studied.

Design. All participants were studied in random order during IM-FSIGT (0.3 g/kg glucose; 0.03 U/kg insulin at 20 min) and during identical conditions but with a variable glucose infusion preventing a decrease of plasma glucose concentration below euglycemia (IM-FSIGT-CLAMP). Five participants additionally underwent euglycemic-hyper-insulinemic (1 mU•kg^-1min^-1) clamp tests.

Results. Plasma glucose declined during IM-FSIGT to its nadir of 50 ± 3 mg/dl at 60 min in parallel to a rise (P < 0.05 vs. basal) of plasma glucagon, cortisol, epinephrine and growth hormone. Glucose infusion rates of 4.6 ± 0.5 mg•kg^-1•min^-1 between 30 and 180 min during IM-FSIGT-CLAMP prevented the decline of plasma glucose and the hypoglycemia counterregulatory hormone response.

S_I was 68% lower during IM-FSIGT (3.40 ± 0.36 vs. IM-FSIGT-CLAMP: 10.71 ± 1.06 10^-4•min^-1•µU^-1ml, P < 0.0001) whereas S_G did not differ between both protocols (0.024 ± 0.002 vs. 0.021 ± 0.003 min^-1, P=NS). Compared with the euglycemic hyperinsulinemic clamp test, insulin sensitivity expressed in identical units from IM-FSIGT was 66% (P < 0.001) lower but did not differ between the euglycemic hyperinsulinemic clamp test and the IM-FSIGT-CLAMP (P=NS).

Conclusions. The transient fall of plasma glucose during IM-FSIGT results in lower estimates of insulin sensitivity which can be explained by hormonal response to hypoglycemia.