Summary
We have previously demonstrated that in isolated hepatocytes from fasted rats, AICAriboside (5-amino 4-imidazolecarboxamide riboside), after its conversion into AICAribotide (AICAR or ZMP), exerts a dose-dependent inhibition on fructose-1,6-bisphosphatase and hence on gluconeogenesis. To assess the effect of AICAriboside in vivo, we measured plasma glucose and liver metabolites after intraperitoneal administration of AICAriboside in mice. In fasted animals, in which gluconeogenesis is activated, AICAriboside (250 mg/kg body weight) induced a 50% decrease of plasma glucose within 15 min, which lasted about 3 h. In fed mice, glucose decreased by 8% at 30 min, and normalized at 1 h. Under both conditions, ZMP accumulated to approximately 2 µmol/g of liver at 1 h. It decreased progressively thereafter, although much more slowly in the fasted state. Inhibition of fructose-1,6-bisphosphatase was evidenced by time-wise linear accumulations of fructose-1,6-bisphosphate, from 0.006 to 3.9 µmol/g of liver at 3 h in fasted mice, and from 0.010 to 0.114 µmol/g of liver at 1 h in fed animals. AICAriboside did not significantly influence plasma insulin or glucose utilization by muscle. We conclude that in vivo as in isolated hepatocytes, AICAriboside, owing to its conversion into ZMP, inhibits fructose-1,6-bisphosphatase and consequently gluconeogenesis.
Similar content being viewed by others
Abbreviations
- AICAriboside:
-
5-Amino 4-imidazolecarboxamide riboside
- AICAR (ZMP):
-
5-amino 4-imidazolecarboxamide riboside monophosphate
- HMG-CoA:
-
3-hydroxy-3-methylglutaryl-coenzyme A
- Pi:
-
inorganic phosphate
References
Vincent MF, Marangos PJ, Gruber HE, Van den Berghe G (1991) Inhibition by AICA riboside of gluconeogenesis in isolated rat hepatocytes. Diabetes 40: 1259–1266
Sabina RL, Holmes EW, Becker MA (1984) The enzymatic synthesis of 5-amino-4-imidazolecarboxamide riboside triphosphate (ZTP). Science 223:1193–1195
Sherratt HS (1981) Inhibition of gluconeogenesis by non-hormonal hypoglycaemic compounds. In: Hue L, van de Werve G (eds) Short-term regulation of liver metabolism. Elsevier/North-Holland, Amsterdam, pp 199–227
Wollenberger A, Ristau O, Schoffa G (1960) A simple technique for extremely rapid freezing of large pieces of tissue. Arch Ges Physiol 270:399–412
Hohorst HJ (1965) L-(+)-Lactate. Determination with lactic dehydrogenase and DPN. In: Bergmeyer HU (ed) Methods of enzymatic analysis. Academic Press, New York, pp 266–270
Lamprecht W, Heinz F (1985) D-Glycerate 2-phosphate and phosphoenol-pyruvate. In: Bergmeyer HU (ed) Methods of enzymatic analysis, 3rd edn, vol 6. Chemi, Weinheim, pp 555–561
Czok R (1985) D-Glycerate 3-phosphate. In: Bergmeyer HU (ed) Methods of enzymatic analysis, 3rd edn, vol 6. Chemie, Weinheim, pp 537–541
Michal G (1985) D-fructose-1,6-diphosphate, dihydroxyacetone phosphate and D-glyceraldehyde-3-phosphate. In: Bergmeyer HU (ed) Methods of enzymatic analysis, 3rd edn, vol 6. Chemie, Weinheim, pp 342–350
Huggett A St G, Nixon DA (1957) Enzymic determination of blood glucose. Biochem J 66:12P
Maes M, Ketelslegers JM, Underwood LE (1983) Low plasma somatomedin-C in streptozotocin-induced diabetes mellitus. Correlation with changes in somatogenic and lactogenic liver binding sites. Diabetes 32:1060–1069
Elliott J, Hems DA, Beloff-Chain A (1971) Carbohydrate metabolism of the isolated perfused liver of normal and genetically obese-hyperglycaemic (ob/ob) mice. Biochem J 125:773–780
Assimacopoulos-Jeannet F, Exton JH, Jeanrenaud B (1973) Control of gluconeogenesis and glycogenolysis in perfused livers of normal mice. Am J Physiol 225:25–32
Claus TH, El-Maghrabi MR, Pilkis SJ (1979) Modulation of the phosphorylation state of rat liver pyruvate kinase by allosteric effectors and insulin. J Biol Chem 254:7855–7864
Van Schaftingen E, Hue L, Hers HG (1980) Study of the fructose 6-phosphate/fructose 1,6-bisphosphate cycle in the liver in vivo. Biochem J 192:263–271
Dixon R, Gourzis J, McDermott D, Fujitaki J, Dewland P, Gruber H (1991) AICA-riboside: safety, tolerance and pharmacokinetics of a novel adenosine-regulating agent. J Clin Pharmacol 31:342–347
Menasché P, Jamieson WRE, Flameng W, Davies MK (1995) Acadesine: a new drug that may improve myocardial protection in coronary artery bypass grafting. Results of the first international multicenter study. J Thorac Cardiovasc Surg 110:1096–1106
Akkan AG, Malaisse WJ (1994) Insulinotropic action of AICAriboside. I. Insulin release by isolated islets and the perfused pancreas. Diabetes Res 25:13–23
Vincent MF, Bontemps F, Van den Berghe G (1992) Inhibition of glycolysis by 5-amino-4-imidazolecarboxamide riboside in isolated rat hepatocytes. Biochem J 281:267–272
Henin N, Vincent MF, Gruber HE, Van den Berghe G (1995) Inhibition of fatty acid and cholesterol synthesis by stimulation of AMP-activated protein kinase. FASEB J 9:541–546
Salmon DMW, Bowen NL, Hems DA (1974) Synthesis of fatty acids in the perfused mouse liver. Biochem J 142:611–618
Buchalter SE, Crain MR, Kreisberg R (1989) Regulation of lactate metabolism in vivo. Diabet Metab Rev 5:379–391
Rothman DL, Magnusson I, Katz LD, Shulman RG, Shulman GI (1991) Quantitation of hepatic glycogenolysis and gluconeogenesis in fasting humans with13C NMR. Science 254:573–576
Yki-Järvinen H, Helve E, Sane T, Nurjhan N, Taskinen MR (1989) Insulin inhibition of overnight glucose production and gluconeogenesis from lactate in NIDDM. Am J Physiol 256:E732-E739
Blackshear PJ, Holloway PAH, Alberti KGMM (1975) Metabolic interactions of dichloroacetate and insulin in experimental diabetic ketoacidosis. Studies on whole animals and after functional hepatectomy. Biochem J 146:447–456
Pagliara AS, Karl IE, Keating JP, Brown BI, Kipnis DM (1972) Hepatic fructose-1,6-diphosphatase deficiency. A cause of lactic acidosis in infancy. J Clin Invest 51:2115–2123
Morris AAM, Deshpande S, Ward-Platt MP et al. (1995) Impaired ketogenesis in fructose-1,6-bisphosphatase deficiency: a pitfall in the investigation of hypoglycaemia. J Inher Metab Dis 18:28–32
Gitzelmann R, Steinmann B, Van den Berghe G (1995) Disorders of fructose metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease, 7th edn. McGraw-Hill, New York, pp 905–934
Sabina RL, Patterson D, Holmes EW (1985) 5-Amino-4-imidazolecarboxamide riboside (Z-riboside) metabolism in eukaryotic cells. J Biol Chem 260:6107–6114
Shafrir E, Berman M, Felig P (1986) The endocrine pancreas: diabetes mellitus. In: Felig P, Baxter JD, Broadus AE, Frohman LA (eds) Endocrinology and metabolism, 2nd edn. McGraw-Hill, New York, pp 1043–1178
Consoli A, Nurjhan N, Capani F, Gerich J (1989) Predominant role of gluconeogenesis in increased hepatic glucose production in NIDDM. Diabetes 38:550–557
Mitrakou A, Kelley D, Mokan M et al. (1992) Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance. New Engl J Med 326:22–29
Nurjhan N, Consoli A, Gerich J (1992) Increased lipolysis and its consequences on gluconeogenesis in non-insulin-dependent diabetes mellitus. J Clin Invest 89:169–175
Magnusson I, Rothman DL, Katz LD, Shulman RG, Shulman GI (1992) Increased rate of gluconeogenesis in type II diabetes mellitus. A13C nuclear magnetic resonance study. J Clin Invest 90:1323–1327
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Vincent, M.F., Erion, M.D., Gruber, H.E. et al. Hypoglycaemic effect of AICAriboside in mice. Diabetologia 39, 1148–1155 (1996). https://doi.org/10.1007/BF02658500
Received:
Revised:
Published:
Issue Date:
DOI: https://doi.org/10.1007/BF02658500