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

Tracer methodology has been applied extensively to the estimation of endogenous glucose production (Ra) during euglycemic glucose clamps. The accuracy of this approach has been questioned due to the observation of significantly negative estimates for Ra 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, Ra, 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, Ra 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 Ra 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 Ra during euglycemic glucose clamps. Two new strategies for estimating Ra from the one-compartment model, the hot GINF protocol and the regression method calculation, yielded more accurate and physiologically plausible estimates of Ra than currently used methodology.

[1]  R. Wolfe,et al.  The realiability of rates of glucose appearance in vivo calculated from constant tracer infusions. , 1978, The Biochemical journal.

[2]  R. Steele,et al.  INHIBITION BY INSULIN OF HEPATIC GLUCOSE PRODUCTION IN THE NORMAL DOG. , 1965, The American journal of physiology.

[3]  R N Bergman,et al.  PACBERG: an adaptive program for controlling the blood sugar. , 1983, Computer programs in biomedicine.

[4]  R. Steele,et al.  Measurement of size and turnover rate of body glucose pool by the isotope dilution method. , 1956, The American journal of physiology.

[5]  C. Park,et al.  The action of insulin on the transport of glucose through the cell membrane. , 1959, The American journal of medicine.

[6]  R. DeFronzo,et al.  Influence of Plasma Glucose and Insulin Concentration on Plasma Glucose Clearance in Man , 1982, Diabetes.

[7]  R. Steele,et al.  ON THE HORMONAL REGULATION OF CARBOHYDRATE METABOLISM; STUDIES WITH C14 GLUCOSE. , 1963, Recent progress in hormone research.

[8]  G. Hetényi,et al.  Glucoregulatory responses in normal and diabetic dogs recorded by a new tracer method. , 1971, Metabolism: clinical and experimental.

[9]  K.,et al.  Experimental validation of measurements of glucose turnover in nonsteady state. , 1978, The American journal of physiology.

[10]  M. Vranic,et al.  Effect of D-glucose or D-ribose on the Turnover of Glucose in Pancreatectomized Dogs Maintained on a Matched Intraportal Infusion of Insulin , 1969, Diabetes.

[11]  K. Norwich Measuring rates of appearance in systems which are not in steady state. , 1973, Canadian journal of physiology and pharmacology.

[12]  A. Tiengo,et al.  Insulin resistance in Cushing's syndrome. , 1983, The Journal of clinical endocrinology and metabolism.

[13]  R N Bergman,et al.  Assessment of insulin sensitivity in vivo. , 1985, Endocrine reviews.

[14]  V. Herbert,et al.  Coated charcoal immunoassay of insulin. , 1965, The Journal of clinical endocrinology and metabolism.

[15]  J. A. Scarlett,et al.  Receptor and postreceptor defects contribute to the insulin resistance in noninsulin-dependent diabetes mellitus. , 1981, The Journal of clinical investigation.

[16]  E. Kinney Primer of Biostatistics , 1987 .

[17]  L. Mandarino,et al.  Cortisol-induced insulin resistance in man: impaired suppression of glucose production and stimulation of glucose utilization due to a postreceptor detect of insulin action. , 1982, The Journal of clinical endocrinology and metabolism.

[18]  R. Rizza,et al.  Assessment of insulin action in insulin-dependent diabetes mellitus using [6(14)C]glucose, [3(3)H]glucose, and [2(3)H]glucose. Differences in the apparent pattern of insulin resistance depending on the isotope used. , 1986, The Journal of clinical investigation.

[19]  H. Marques [Determination of the blood sugar]. , 1951, Revista de quimica e farmacia.

[20]  J. Wright,et al.  Effect of insulin on transport of several hexoses and pentoses into cells of muscle and brain. , 1957, The American journal of physiology.

[21]  G. Reaven,et al.  Comparison of Insulin Secretion and In Vivo Insulin Action in Nonobese and Moderately Obese Individuals with Non-insulin-dependent Diabetes Mellitus , 1982, Diabetes.

[22]  G. Reaven,et al.  Quantification of Insulin Secretion and In Vivo Insulin Action in Nonobese and Moderately Obese Individuals with Normal Glucose Tolerance , 1983, Diabetes.

[23]  R. DeFronzo,et al.  Regulation of Splanchnic and Peripheral Glucose Uptake by Insulin and Hyperglycemia in Man , 1983, Diabetes.

[24]  B. Issekutz,et al.  Estimation of hepatic glucose output in non-steady state. The simultaneous use of 2-3H-glucose and 14C-glucose in the dog. , 1974, Canadian journal of physiology and pharmacology.

[25]  C. Park,et al.  Stereospecific transport of glucose in the perfused rat liver. , 1968, The American journal of physiology.

[26]  R. Steele,et al.  INFLUENCES OF GLUCOSE LOADING AND OF INJECTED INSULIN ON HEPATIC GLUCOSE OUTPUT * , 1959, Annals of the New York Academy of Sciences.

[27]  H. Rush,et al.  Management of septicemia in rhesus monkeys with chronic indwelling venous catheters. , 1983, Laboratory animal science.

[28]  R. Bergman,et al.  Optimal segments: a method for smoothing tracer data to calculate metabolic fluxes. , 1983, The American journal of physiology.

[29]  K. Sussman,et al.  Insulin Immunoassay by Back-titration Using Alcohol Precipitation of Insulin-Antibody Complexes , 1969, Diabetes.

[30]  Abdelmonem A. Afifi,et al.  Statistical Analysis: A Computer Oriented Approach. , 1973 .

[31]  H. Yki-Järvinen,et al.  Insulin Resistance in Type 2 Diabetes , 2010 .

[32]  M. Vranic,et al.  Turnover and precursor-product relationships of nonlipid metabolites. , 1983, Physiological reviews.

[33]  C. Cobelli,et al.  Insulin-mediated glucose disposal in type I diabetes: evidence for insulin resistance. , 1983, Journal of Clinical Endocrinology and Metabolism.

[34]  C Cobelli,et al.  Effect of insulin on the distribution and disposition of glucose in man. , 1985, The Journal of clinical investigation.

[35]  J. Olefsky,et al.  Mechanisms of insulin resistance in human obesity: evidence for receptor and postreceptor defects. , 1980, The Journal of clinical investigation.

[36]  K. Norwich,et al.  Measurement and validation of nonsteady turnover rates with applications to the inulin and glucose systems. , 1974, Federation proceedings.

[37]  L. Mandarino,et al.  Dose-response characteristics for effects of insulin on production and utilization of glucose in man. , 1981, The American journal of physiology.