Effects of free fatty acids on hepatic glycogenolysis and gluconeogenesis in conscious dogs.

The aim of this study was to determine the effect of high levels of free fatty acids (FFA) and/or hyperglycemia on hepatic glycogenolysis and gluconeogenesis. Intralipid was infused peripherally in 18-h-fasted conscious dogs maintained on a pancreatic clamp in the presence (FFA + HG) or absence (FFA + EuG) of hyperglycemia. In the control studies, Intralipid was not infused, and euglycemia (EuG) or hyperglycemia (HG) was maintained. Insulin and glucagon were clamped at basal levels in all four groups. The arterial blood glucose level increased by 50% in the HG and FFA + HG groups. It did not change in the EuG and FFA + EuG groups. Arterial plasma FFA increased by approximately 140% in the FFA + EuG and FFA + HG groups but did not change significantly either in the EuG or HG groups. Arterial glycerol levels increased by approximately 150% in both groups. Overall (3-h) net hepatic glycogenolysis was 196 +/- 26 mg/kg in the EuG group. It decreased by 96 +/- 20, 82 +/- 16, and 177 +/- 22 mg/kg in the HG, FFA + EuG, and FFA + HG groups, respectively. Overall (3-h) hepatic gluconeogenic flux was 128 +/- 22 mg/kg in the EuG group, but it was suppressed by 30 +/- 9 mg/kg in response to hyperglycemia. It was increased by 59 +/- 12 and 56 +/- 10 mg/kg in the FFA + EuG and FFA + HG groups, respectively. In conclusion, an increase in plasma FFA and glycerol significantly inhibited hepatic glycogenolysis and markedly stimulated hepatic gluconeogenesis.

[1]  L. Groop,et al.  Modulation of hepatic glucose production by non-esterified fatty acids in Type 2 (non-insulin-dependent) diabetes mellitus , 1991, Diabetologia.

[2]  M. Mozzoli,et al.  Effects of free fatty acids on gluconeogenesis and autoregulation of glucose production in type 2 diabetes. , 2001, Diabetes.

[3]  G. Shulman,et al.  Lipid-dependent control of hepatic glycogen stores in healthy humans , 2001, Diabetologia.

[4]  R. Gomis,et al.  Shared control of hepatic glycogen synthesis by glycogen synthase and glucokinase. , 2000, The Biochemical journal.

[5]  G. Shulman,et al.  Effects of free fatty acid elevation on postabsorptive endogenous glucose production and gluconeogenesis in humans. , 2000, Diabetes.

[6]  D W Neal,et al.  Basal hepatic glucose production is regulated by the portal vein insulin concentration. , 1998, Diabetes.

[7]  K. Petersen,et al.  Mechanism by which glucose and insulin inhibit net hepatic glycogenolysis in humans. , 1998, The Journal of clinical investigation.

[8]  E. Donahue,et al.  Effect of a selective rise in sinusoidal norepinephrine on HGP is due to an increase in glycogenolysis. , 1998, American journal of physiology. Endocrinology and metabolism.

[9]  E. Donahue,et al.  Comparison of the direct and indirect effects of epinephrine on hepatic glucose production. , 1997, The Journal of clinical investigation.

[10]  C. Chu,et al.  The Role of Fatty Acids in Mediating the Effects of Peripheral Insulin on Hepatic Glucose Production in the Conscious Dog , 1997, Diabetes.

[11]  R. DeFronzo,et al.  In vitro and in vivo suppression of gluconeogenesis by inhibition of pyruvate carboxylase. , 1997, Biochemical pharmacology.

[12]  S. Turner,et al.  Altered fluxes responsible for reduced hepatic glucose production and gluconeogenesis by exogenous glucose in rats. , 1997, The American journal of physiology.

[13]  C. Newgard,et al.  Evidence for a Role of Glucose-induced Translocation of Glucokinase in the Control of Hepatic Glycogen Synthesis* , 1996, The Journal of Biological Chemistry.

[14]  Chulhyun Kim,et al.  Effect of decreasing plasma free fatty acids by acipimox on hepatic glucose metabolism in normal rats. , 1996, Metabolism: clinical and experimental.

[15]  C. Chu,et al.  Direct effects of catecholamines on hepatic glucose production in conscious dog are due to glycogenolysis. , 1996, The American journal of physiology.

[16]  D. Wasserman,et al.  Effect of prior exercise on the partitioning of an intestinal glucose load between splanchnic bed and skeletal muscle. , 1996, The Journal of clinical investigation.

[17]  C. Lechuga,et al.  Impairment of the modulation by glucose of hepatic gluconeogenesis in the genetically obese (fa/fa) Zucker rat. , 1995, Endocrinology.

[18]  P. J. Randle,et al.  Glucose fatty acid interactions and the regulation of glucose disposal , 1994, Journal of cellular biochemistry.

[19]  L. Agius,et al.  Intracellular binding of glucokinase in hepatocytes and translocation by glucose, fructose and insulin. , 1993, The Biochemical journal.

[20]  H. Yki-Järvinen,et al.  Inhibition of Lipolysis Decreases Lipid Oxidation and Gluconeogenesis From Lactate But Not Fasting Hyperglycemia or Total Hepatic Glucose Production in NIDDM , 1993, Diabetes.

[21]  N. Barzilai,et al.  Mechanism by which hyperglycemia inhibits hepatic glucose production in conscious rats. Implications for the pathophysiology of fasting hyperglycemia in diabetes. , 1993, The Journal of clinical investigation.

[22]  O. McGuinness,et al.  Impact of chronic stress hormone infusion on hepatic carbohydrate metabolism in the conscious dog. , 1993, The American journal of physiology.

[23]  J. Clore,et al.  In vivo evidence for hepatic autoregulation during FFA-stimulated gluconeogenesis in normal humans. , 1991, The American journal of physiology.

[24]  H. Yki-Järvinen,et al.  No Reduction in Total Hepatic Glucose Output by Inhibition of Gluconeogenesis With Ethanol in NIDDM Patients , 1991, Diabetes.

[25]  G. Boden,et al.  Effects of Lipid on Basal Carbohydrate Metabolism in Normal Men , 1991, Diabetes.

[26]  W. Sheu,et al.  Acute Changes in Plasma Non‐esterified Fatty Acid Concentration do not Change Hepatic Glucose Production in People with Type 2 Diabetes , 1990, Diabetic medicine : a journal of the British Diabetic Association.

[27]  R. DeFronzo,et al.  Effect of fatty acids on glucose production and utilization in man. , 1983, The Journal of clinical investigation.

[28]  B. Trimarco,et al.  The glucoregulatory response to intravenous glucose infusion in normal man: roles of insulin and glucose. , 1981, Metabolism: clinical and experimental.

[29]  M. Davidson.  Autoregulation by glucose of hepatic glucose balance: permissive effect of insulin. , 1981, Metabolism: clinical and experimental.

[30]  G. Shulman,et al.  Effect of glucose, independent of changes in insulin and glucagon secretion, on alanine metabolism in the conscious dog. , 1980, The Journal of clinical investigation.

[31]  P. Sugden,et al.  Effect of citrate on the activities of 6-phosphofructokinase from nervous and muscle tissues from different animals and its relationships to the regulation of glycolysis. , 1977, The Biochemical journal.

[32]  A. Girotti,et al.  Interaction of inhibitors with muscle phosphofructokinase. , 1975, The Journal of biological chemistry.

[33]  J. Williamson,et al.  Control mechanisms of gluconeogenesis and ketogenesis. I. Effects of oleate on gluconeogenesis in perfused rat liver. , 1969, The Journal of biological chemistry.

[34]  S. Weinhouse,et al.  Effects of insulin and fatty acids on gluconeogenesis in the rat. , 1967, The Journal of biological chemistry.

[35]  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.