Estimation of Endogenous Glucose Production During Hyperinsulinemic-Euglycemic Glucose Clamps: Comparison of Unlabeled and Labeled Exogenous Glucose Infusates

Diane T Finegood; Richard N Bergman; Mladen Vranic

doi:10.2337/diab.36.8.914

Original Articles

Estimation of Endogenous Glucose Production During Hyperinsulinemic-Euglycemic Glucose Clamps: Comparison of Unlabeled and Labeled Exogenous Glucose Infusates

Diane T Finegood,
Richard N Bergman and
Mladen Vranic

Departments of Physiology and Medicine, University of Toronto Toronto, Canada
Department of Physiology and Biophysics, University of Southern California Los Angeles, California

Address correspondence to Diane T. Finegood, PhD, 7-117 Clinical Sciences Bldg., Division of Endocrinology and Metabolism, University of Alberta, Edmonton, Alberta, Canada T6G 2G3.
Address reprint requests to Mladen Vranie, MD, DSc, Department of Physiology, University of Toronto, Medical Sciences Bldg., Rm. 3358, Toronto, Canada M5S 1A8.

Diabetes 1987 Aug; 36(8): 914-924. https://doi.org/10.2337/diab.36.8.914

Abstract

Tracer methodology has been applied extensively to the estimation of endogenous glucose production (R_a) during euglycemic glucose clamps. The accuracy of this approach has been questioned due to the observation of significantly negative estimates for R_a when insulin levels are high. We performed hyperinsulinemic (300 μU/ml)-euglycemic glucose clamps for 180 min in normal dogs and compared the standard approach, an unlabeled exogenous glucose infusate (cold GINF protocol, n = 12), to a new approach in which a tracer (D-[3-³H]glucose) was added to the exogenous glucose used for clamping (hot GINF protocol, n = 10). Plasma glucose, insulin and glucagon concentrations, and glucose infusion rates were similar for the two protocols. Plasma glucose specific activity was 20 ± 1% of basal (at 120–180 min) in the cold GINF studies, and 44 ± 3 to 187 ± 5% of basal in the hot GINF studies. With the one-compartment, fixed pool volume model of Steele, R_a, for the cold GINF studies was –2.4 ± 0.7 mg · min⁻¹ · kg⁻¹ at 25 min and remained significantly negative until 110 min (P < .05). For the hot GINF studies, R_a was never significantly less than zero (P > .05) and was greater than in the cold GINF studies at 20–90 min (P < .05). There was substantially less between-(78%) and within- (40%) experiment variation for the hot GINF studies compared with the cold GINF studies. An alternate approach (regression method) to the application of the one-compartment model, which allows for a variable and estimable effective distribution volume, yielded R_a estimates that were suppressed 60–100% from basal.

In conclusion, the one-compartment, fixed pool volume model of glucose kinetics is inadequate for the estimation of R_a during euglycemic glucose clamps. Two new strategies for estimating R_a from the one-compartment model, the hot GINF protocol and the regression method calculation, yielded more accurate and physiologically plausible estimates of R_a than currently used methodology.