The role of endocrine counterregulation for estimating insulin sensitivity from intravenous glucose tolerance tests

Context: During insulin-modified frequently sampled iv glucose tol- erance tests (IM-FSIGT), which allow 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 in- dices of insulin sensitivity (SI) and glucose effectiveness. Participants: Thirteen nondiabetic volunteers (seven males, six fe- males, aged 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 euglyce- mic-hyperinsulinemic (1 mU kg-1 min-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 GH. 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. SI was approxi- mately 68% lower during IM-FSIGT (3.40 +- 0.36 vs. IM-FSIGT- CLAMP: 10.71 +- 1.06 10-4 min-1 per µU/ml, P < 0.0001), whereas glucose effectiveness did not differ between both protocols (0.024 +- 0.002 vs. 0.021 +- 0.003 min-1, P = NS). Compared with the eugly- cemic hyperinsulinemic clamp test, SI expressed in identical units from IM-FSIGT was approximately 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 SI, which can be explained by hormonal response to hypoglycemia.