Effect of 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside infusion on in vivo glucose and lipid metabolism in lean and obese Zucker rats.

Activation of AMP-activated protein kinase (AMPK) with 5-aminoimidazole-4-carboxamide-1-beta-D-ribofurano-side (AICAR) increases glucose transport in skeletal muscle via an insulin-independent pathway. To examine the effects of AMPK activation on skeletal muscle glucose transport activity and whole-body carbohydrate and lipid metabolism in an insulin-resistant rat model, awake obese Zuckerfa/fa rats (n = 26) and their lean (n = 23) littermates were infused for 90 min with AICAR, insulin, or saline. The insulin infusion rate (4 mU.kg(-1).min(-1)) was selected to match the glucose requirements during AICAR (bolus, 100 mg/kg; constant, 10 mg.kg(-1).min(-1)) isoglycemic clamps in the lean rats. The effects of these identical AICAR and insulin infusion rates were then examined in the obese Zucker rats. AICAR infusion increased muscle AMPK activity more than fivefold (P < 0.01 vs. control and insulin) in both lean and obese rats. Plasma triglycerides, fatty acid concentrations, and glycerol turnover, as assessed by [2-13C]glycerol, were all decreased in both lean and obese rats infused with AICAR (P < 0.05 vs. basal), whereas insulin had no effect on these parameters in the obese rats. Endogenous glucose production rates, measured by [U-13C]glucose, were suppressed by >50% during AICAR and insulin infusions in both lean and obese rats (P < 0.05 vs. basal). In lean rats, rates of whole-body glucose disposal increased by more than two-fold (P < 0.05 vs. basal) during both AICAR and insulin infusion; [3H]2-deoxy-D-glucose transport activity increased to a similar extent, by >2.2-fold (both P < 0.05 vs. control), in both soleus and red gastrocnemius muscles of lean rats infused with either AICAR or insulin. In the obese Zucker rats, neither AICAR nor insulin stimulated whole-body glucose disposal or soleus muscle glucose transport activity. However, AICAR increased glucose transport activity by approximately 2.4-fold (P < 0.05 vs. control) in the red gastrocnemius from obese rats, whereas insulin had no effect. In summary, acute infusion of AICAR in an insulin-resistant rat model activates skeletal muscle AMPK and increases glucose transport activity in red gastrocnemius muscle while suppressing endogenous glucose production and lipolysis. Because type 2 diabetes is characterized by diminished rates of insulin-stimulated glucose uptake as well as increased basal rates of endogenous glucose production and lipolysis, these results suggest that AICAR-related compounds may represent a new class of antidiabetic agents.

[1]  P. Gardiner Neuromuscular Aspects of Physical Activity , 2001 .

[2]  G. Shulman,et al.  Translocation of myocardial GLUT-4 and increased glucose uptake through activation of AMPK by AICAR. , 1999, The American journal of physiology.

[3]  Z Trajanoski,et al.  Impaired glucose transport as a cause of decreased insulin-stimulated muscle glycogen synthesis in type 2 diabetes. , 1999, The New England journal of medicine.

[4]  G. Shulman,et al.  Effect of AMPK activation on muscle glucose metabolism in conscious rats. , 1999, American journal of physiology. Endocrinology and metabolism.

[5]  E. Horton,et al.  Acute exercise induces GLUT4 translocation in skeletal muscle of normal human subjects and subjects with type 2 diabetes. , 1999, Diabetes.

[6]  R. Coleman,et al.  AMP-activated kinase reciprocally regulates triacylglycerol synthesis and fatty acid oxidation in liver and muscle: evidence that sn-glycerol-3-phosphate acyltransferase is a novel target. , 1999, The Biochemical journal.

[7]  W. Kraemer,et al.  Fiber type composition of four hindlimb muscles of adult Fisher 344 rats , 1999, Histochemistry and Cell Biology.

[8]  D L Rothman,et al.  Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. , 1999, The Journal of clinical investigation.

[9]  Tatsuya Hayashi,et al.  Evidence for 5′AMP-Activated Protein Kinase Mediation of the Effect of Muscle Contraction on Glucose Transport , 1998, Diabetes.

[10]  T. Buchanan,et al.  Metabolic Effects of Troglitazone Monotherapy in Type 2 Diabetes Mellitus , 1998, Annals of Internal Medicine.

[11]  D. Hardie,et al.  AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle. , 1997, American journal of physiology. Endocrinology and metabolism.

[12]  R. Bergman,et al.  Causal linkage between insulin suppression of lipolysis and suppression of liver glucose output in dogs. , 1996, The Journal of clinical investigation.

[13]  C. Wilson,et al.  Glucose transport and cell surface GLUT-4 protein in skeletal muscle of the obese Zucker rat. , 1996, The American journal of physiology.

[14]  K. Petersen,et al.  Mechanism of free fatty acid-induced insulin resistance in humans. , 1996, The Journal of clinical investigation.

[15]  R. Shulman,et al.  NMR studies of muscle glycogen synthesis in insulin-resistant offspring of parents with non-insulin-dependent diabetes mellitus immediately after glycogen-depleting exercise. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[16]  D. Hardie,et al.  Inactivation of acetyl-CoA carboxylase and activation of AMP-activated protein kinase in muscle during exercise. , 1996, The American journal of physiology.

[17]  G. Dohm,et al.  Differential effect of maturation on insulin- vs. contraction-stimulated glucose transport in Zucker rats. , 1995, The American journal of physiology.

[18]  D. Hardie,et al.  5-aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells? , 1995, European journal of biochemistry.

[19]  A. Edelman,et al.  Similar substrate recognition motifs for mammalian AMP‐activated protein kinase, higher plant HMG‐CoA reductase kinase‐A, yeast SNF1, and mammalian calmodulin‐dependent protein kinase I , 1995, FEBS letters.

[20]  D. Carling,et al.  Inhibition of lipolysis and lipogenesis in isolated rat adipocytes with AICAR, a cell‐permeable activator of AMP‐activated protein kinase , 1994, FEBS letters.

[21]  R. Dixon,et al.  Spectrophotometric determination of acadesine (AICA-riboside) in plasma using a diazotization coupling technique with N-(1-naphthyl)ethylenediamine. , 1994, Journal of biochemical and biophysical methods.

[22]  J. Ivy,et al.  Glucose uptake and GLUT-4 protein distribution in skeletal muscle of the obese Zucker rat. , 1994, The American journal of physiology.

[23]  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.

[24]  M. Walker,et al.  Metabolic Effects of Suppression of Nonesterified Fatty Acid Levels With Acipimox in Obese NIDDM Subjects , 1992, Diabetes.

[25]  J. Ivy,et al.  Contraction-activated glucose uptake is normal in insulin-resistant muscle of the obese Zucker rat. , 1992, Journal of applied physiology.

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

[27]  M. Vincent,et al.  Inhibition by AICA Riboside of Gluconeogenesis in Isolated Rat Hepatocytes , 1991, Diabetes.

[28]  M. Mozzoli,et al.  Effects of fat on insulin-stimulated carbohydrate metabolism in normal men. , 1991, The Journal of clinical investigation.

[29]  H. Taegtmeyer,et al.  Temporal analysis of myocardial glucose metabolism by 2-[18F]fluoro-2-deoxy-D-glucose. , 1990, The American journal of physiology.

[30]  B. Jeanrenaud,et al.  Contribution of glycerol and alanine to basal hepatic glucose production in the genetically obese (fa/fa) rat. , 1990, The Biochemical journal.

[31]  R G Shulman,et al.  Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy. , 1990, The New England journal of medicine.

[32]  G. Dohm,et al.  An in vitro human muscle preparation suitable for metabolic studies. Decreased insulin stimulation of glucose transport in muscle from morbidly obese and diabetic subjects. , 1988, The Journal of clinical investigation.

[33]  R. Rizza,et al.  Insulin action in non-insulin-dependent diabetes mellitus: the relationship between hepatic and extrahepatic insulin resistance and obesity. , 1987, Metabolism: clinical and experimental.

[34]  R. DeFronzo,et al.  Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats. , 1987, The Journal of clinical investigation.

[35]  R. DeFronzo,et al.  Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus. , 1985, The Journal of clinical investigation.

[36]  D. James,et al.  Dose-response curves for in vivo insulin sensitivity in individual tissues in rats. , 1985, The American journal of physiology.

[37]  R. Armstrong,et al.  Muscle fiber type composition of the rat hindlimb. , 1984, The American journal of anatomy.

[38]  B V Howard,et al.  Relationships between insulin secretion, insulin action, and fasting plasma glucose concentration in nondiabetic and noninsulin-dependent diabetic subjects. , 1984, The Journal of clinical investigation.

[39]  E. Jéquier,et al.  Study on lipid metabolism in obesity diabetes. , 1984, Metabolism: clinical and experimental.

[40]  B. Jeanrenaud,et al.  In vivo hepatic and peripheral insulin resistance in genetically obese (fa/fa) rats. , 1983, Endocrinology.

[41]  J. L. Swain,et al.  Metabolism of 5-amino-4-imidazolecarboxamide riboside in cardiac and skeletal muscle. Effects on purine nucleotide synthesis. , 1982, The Journal of biological chemistry.

[42]  G. Shulman,et al.  Glucose disposal during insulinopenia in somatostatin-treated dogs. The roles of glucose and glucagon. , 1978, The Journal of clinical investigation.

[43]  J. Passonneau,et al.  A comparison of three methods of glycogen measurement in tissues. , 1974, Analytical biochemistry.

[44]  G. Shulman,et al.  A critical evaluation of mass isotopomer distribution analysis of gluconeogenesis in vivo. , 1999, The American journal of physiology.

[45]  R. DeFronzo PATHOGENESIS OF TYPE 2 DIABETES: METABOLIC AND MOLECULAR IMPLICATIONS FOR IDENTIFYING DIABETES GENES , 1997 .

[46]  M. Delp,et al.  Composition and size of type I, IIA, IID/X, and IIB fibers and citrate synthase activity of rat muscle. , 1996, Journal of applied physiology.

[47]  L. Mandarino,et al.  Quantification of the relative impairment in actions of insulin on hepatic glucose production and peripheral glucose uptake in non-insulin-dependent diabetes mellitus. , 1988, Metabolism: clinical and experimental.

[48]  A. Golay,et al.  Resistance to insulin suppression of plasma free fatty acid concentrations and insulin stimulation of glucose uptake in noninsulin-dependent diabetes mellitus. , 1987, The Journal of clinical endocrinology and metabolism.