Effects of physiological hyperinsulinemia on systemic, renal, and hepatic substrate metabolism.

To determine the effect of physiological hyperinsulinemia on renal and hepatic substrate metabolism, we assessed systemic and renal glucose release and uptake, systemic and renal gluconeogenesis from glutamine, and certain aspects of systemic and renal glutamine and free fatty acid (FFA) metabolism. These were assessed under basal postabsorptive conditions and during 4-h hyperinsulinemic euglycemic clamp experiments in nine normal volunteers using a combination of isotopic techniques and renal balance measurements. Hepatic glucose release (HGR) and glutamine gluconeogenesis were calculated as the difference between systemic and renal measurements. Infusion of insulin suppressed systemic glucose release and glutamine gluconeogenesis by approximately 50% during the last hour of the insulin infusion (P < 0.001). Renal glucose release and glutamine gluconeogenesis decreased from 2.3 +/- 0.4 to 0.9 +/- 0.2 (P < 0.002) and from 0.52 +/- 0.07 to 0.14 +/- 0.03 micromol. kg-1. min-1 (P < 0.001), respectively. HGR and glutamine gluconeogenesis decreased from 8.7 +/- 0.4 to 4.5 +/- 0.5 (P < 0.001) and from 0.35 +/- 0.02 to 0.27 +/- 0.03 micromol. kg-1. min-1 (P < 0.002), respectively. Renal glucose uptake (RGU) increased from 1.61 +/- 0.19 to 2.18 +/- 0.25 micromol. kg-1. min-1 (P = 0.029) but accounted for only approximately 5% of systemic glucose disposal (40.6 +/- 4.3 micromol. kg-1. min-1). Both systemic and renal FFA clearance increased approximately fourfold (P < 0.001 for both). Nevertheless, renal FFA uptake decreased (P = 0.024) and was inversely correlated with RGU (r = -0.582, P = 0.011). Finally, insulin increased systemic glutamine release (P = 0.007), uptake (P < 0.005), and clearance (P < 0.001) but left renal glutamine uptake and release unaffected (P > 0.4 for both).

[1]  C Meyer,et al.  Human kidney free fatty acid and glucose uptake: evidence for a renal glucose-fatty acid cycle. , 1997, The American journal of physiology.

[2]  W. Guder,et al.  Renal lipid metabolism. , 1983, Mineral and electrolyte metabolism.

[3]  L. Mandarino,et al.  Skeletal muscle is a major site of lactate uptake and release during hyperinsulinemia. , 1992, Metabolism: clinical and experimental.

[4]  J. Exton.  Mechanisms of hormonal regulation of hepatic glucose metabolism. , 1987, Diabetes/metabolism reviews.

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

[6]  M. Stumvoll,et al.  Human kidney and liver gluconeogenesis: evidence for organ substrate selectivity. , 1998, American journal of physiology. Endocrinology and metabolism.

[7]  H. Krebs,et al.  ACCELERATION OF RENAL GLUCONEOGENESIS BY KETONE BODIES AND FATTY ACIDS. , 1965, The Biochemical journal.

[8]  C. Bogardus,et al.  Regulation of plasma lactate concentration in resting human subjects. , 1990, Metabolism: clinical and experimental.

[9]  R. Sherwin,et al.  Role of gluconeogenesis in epinephrine-stimulated hepatic glucose production in humans. , 1983, The American journal of physiology.

[10]  P. Kelly,et al.  Studies of insulin, growth hormone and prolactin binding: tissue distribution, species variation and characterization. , 1974, Endocrinology.

[11]  C. Brun.  A rapid method for the determination of para-aminohippuric acid in kidney function tests. , 1951, The Journal of laboratory and clinical medicine.

[12]  M. Stumvoll,et al.  Uptake and release of glucose by the human kidney. Postabsorptive rates and responses to epinephrine. , 1995, The Journal of clinical investigation.

[13]  B. Landau,et al.  Effect of glucocorticoids on metabolism of carbohydrate by kidney cortex. , 1966, The American journal of physiology.

[14]  M. Jensen,et al.  Preservation of insulin effects on glucose production and proteolysis during fasting. , 1988, The American journal of physiology.

[15]  R N Bergman,et al.  Estimation of Endogenous Glucose Production During Hyperinsulinemic-Euglycemic Glucose Clamps: Comparison of Unlabeled and Labeled Exogenous Glucose Infusates , 1987, Diabetes.

[16]  Robert R. Wolfe,et al.  Radioactive and Stable Isotope Tracers in Biomedicine: Principles and Practice of Kinetic Analysis , 1992 .

[17]  P. Fournel,et al.  Renal enzymes during experimental diabetes mellitus in the rat. Role of insulin, carbohydrate metabolism, and ketoacidosis. , 1984, Canadian journal of physiology and pharmacology.

[18]  M. Kilberg,et al.  The regulation of neutral amino acid transport in mammalian cells. , 1983, Biochimica et biophysica acta.

[19]  T. Jenssen,et al.  Failure of substrate-induced gluconeogenesis to increase overall glucose appearance in normal humans. Demonstration of hepatic autoregulation without a change in plasma glucose concentration. , 1990, The Journal of clinical investigation.

[20]  A. Consoli,et al.  Mechanism for Underestimation of Isotopically Determined Glucose Disposal , 1989, Diabetes.

[21]  R. Judd,et al.  Insulin regulation of renal glucose metabolism in conscious dogs. , 1994, The Journal of clinical investigation.

[22]  C. Teng.  Studies on carbohydrate metabolism in rat kidney slices. II. Effect of alloxan diabetes and insulin administration on glucose uptake and glucose formation. , 1954, Archives of biochemistry and biophysics.

[23]  A. Cherrington,et al.  Gluconeogenesis: methodological approaches in vivo. , 1977, Federation proceedings.

[24]  T. Nishio,et al.  Renal net glucose release in vivo and its contribution to blood glucose in rats. , 1978, The Journal of clinical investigation.

[25]  B. Landau.  Gluconeogenesis and pyruvate metabolism in rat kidney, in vitro. , 1960, Endocrinology.

[26]  B. Beaufrère,et al.  Protein degradation and synthesis measured with multiple amino acid tracers in vivo. , 1996, The American journal of physiology.

[27]  M. Stumvoll,et al.  Estimation of glucose-alanine-lactate-glutamine cycles in postabsorptive humans: role of skeletal muscle. , 1995, The American journal of physiology.

[28]  M. Jensen,et al.  Validation of a new method for determination of free fatty acid turnover. , 1987, The American journal of physiology.

[29]  T. Jenssen,et al.  Determination of [14C] Glutamine Specific Activity in Plasma , 1994 .

[30]  P. Felig,et al.  The Contrasting Responses of Splanchnic and Renal Glucose Output to Gluconeogenic Substrates and to Hypoglucagonemia in 60-h-fasted Humans , 1980, Diabetes.

[31]  D. Kelley,et al.  Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance. , 1992, The New England journal of medicine.

[32]  I. Macdonald,et al.  Effects of fasting on fatty acid kinetics and on the cardiovascular, thermogenic and metabolic responses to the glucose clamp. , 1994, Clinical science.

[33]  H. Krebs,et al.  The fate of isotopic carbon in kidney cortex synthesizing glucose from lactate. , 1966, The Biochemical journal.

[34]  H. Yki-Järvinen,et al.  Measurement of lactate formation from glucose using [6-3H]- and [6-14C]glucose in humans. , 1990, The American journal of physiology.

[35]  J. Chiasson,et al.  Differential Sensitivity of Glycogenolysis and Gluconeogenesis to Insulin Infusions in Dogs , 1976, Diabetes.

[36]  A. Consoli,et al.  Quantification of the glycolytic origin of plasma glycerol: implications for the use of the rate of appearance of plasma glycerol as an index of lipolysis in vivo. , 1988, Metabolism: clinical and experimental.

[37]  M. Vranic,et al.  Fatty Acids Mediate the Acute Extrahepatic Effects of Insulin on Hepatic Glucose Production in Humans , 1997, Diabetes.

[38]  D. Matthews,et al.  Glucose and amino acid metabolism in aging man: differential effects of insulin. , 1988, Metabolism: clinical and experimental.

[39]  R. Kreisberg,et al.  Mechanism for the stimulation of gluconeogenesis by fatty acids in perfused rat liver. , 1966, Proceedings of the National Academy of Sciences of the United States of America.

[40]  J. Katz,et al.  Determination of gluconeogenesis in vivo with 14C-labeled substrates. , 1985, The American journal of physiology.

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

[42]  W. Guder,et al.  Renal substrate metabolism. , 1986, Physiological reviews.

[43]  J. Hill,et al.  Regulation of free fatty acid metabolism by insulin in humans: role of lipolysis and reesterification. , 1992, The American journal of physiology.

[44]  L. Groop,et al.  Role of free fatty acids and insulin in determining free fatty acid and lipid oxidation in man. , 1991, The Journal of clinical investigation.

[45]  R. Bergman,et al.  Peripheral effects of insulin dominate suppression of fasting hepatic glucose production. , 1990, The American journal of physiology.

[46]  R. DeFronzo,et al.  Splanchnic and renal metabolism of insulin in human subjects: a dose-response study. , 1983, The American journal of physiology.