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The Role of Endocrine Counterregulation for Estimating Insulin Sensitivity from Intravenous Glucose Tolerance Tests

Division of Endocrinology and Metabolism (A.B., E.B., P.N., W.W., M.R.), Department of Internal Medicine III, Medical University of Vienna, A-1090 Vienna, Austria; Metabolic Unit (K.T., G.P.), Institute of Biomedical Engineering, I-35127 Padova, Italy; and First Medical Department (A.B., M.R.), Hanusch Hospital, A-1140 Vienna, Austria

Address all correspondence and requests for reprints to: Michael Roden, M.D., Division of Endocrinology and Metabolism, Department of Internal Medicine 3, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria, c/o 1. Medical Department, Hanusch Hospital, Heinrich Collin Strasse 30, A-1140 Vienna, Austria. E-mail: michael.roden{at}meduniwien.ac.at.

Context: During insulin-modified frequently sampled iv glucose tolerance 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 indices of insulin sensitivity (S_I) and glucose effectiveness.

Participants: Thirteen nondiabetic volunteers (seven males, six females, 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 euglycemic-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. S_I was approximately 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 euglycemic hyperinsulinemic clamp test, S_I 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 S_I, which can be explained by hormonal response to hypoglycemia.

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