Summary
An experimental model of phenformininduced lactic acidosis was established in rats. Following a subtotal nephrectomy, renal failure developed (serum creatinine 4.5±0.1mg/100ml and 2.8±0.1 mg/100 ml on the 1st and 8th postoperative days respectively). Immediately after nephrectomy intra-peritoneal phenformin treatment, 16 mg/day, was commenced. Lactic acidosis developed progressively within 8 days, or earlier in the rats with the most severe renal insufficiency. The metabolic pattern was very similar to that observed in diabetic patients with a biguanide-induced lactic acidosis: on the 8th day, 2 h after the last phenformin injection, blood lactate was 10.8±1.0 mmol/1 (controls: 1.50±0.03); pyruvate was 0.56±0.06 mmol/1 (controls: 0.10±0.01) and blood pH: 7.00 ± 0.02 (vs 7.34±0.02); 3-hydroxybutyrate was 1.41±0.37 mmol/1 (vs 0.32 ±0.03); acetoacetate: 0.51±0.15 mmol/1 (vs 0.17 ±0.01), and free glycerol: 0.63 ±0.07 mmol/1 (vs 0.14 ±0.02). Increased concentrations of alanine (1.66±0.26 mmol/1, vs 0.48 ± 0.04 in controls) and low blood glucose levels (23± 8 mg/ 100 ml vs 70 ± 2, after a 12 hours fast) accompanied the lactic acidosis in spite of high glucagon levels (2030±170 pg/ml vs 108±10 in controls) and low insulin/glucagon molar ratio (0.19 vs 6.9 in controls). Normal rats, treated with phenformin at same doses, and nephrectomized rats injected with saline served as controls and remained free of lactic acidosis. Hydroxyphenformin (16 mg/day) injected in nephrectomized rats, was biologically inactive. Glucose production from14C-lactate was 425 ±85 μmol/100 g body wt/h, vs 1050 ± 90 in control animals. Blood lactate specific activity declined more slowly in the lactic acidotic rats than in controls, suggesting that a decrease in lactate utilization contributed to hyperlactataemia more than an increased lactate production.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Bengtsson, K., Karlberg, B., Lindgren, S.: Lactic acidosis in phenformin-treated diabetics. Acta Med. Scand.191, 203–208 (1972)
Assan, R., Heuclin, Chr., Girard, J.R., Lemaire, F., Attail, J.R.: Phenformin-induced lactic acidosis in diabetic patients. Diabetes24, 791–800 (1975)
Heuclin, Chr., Attali, J.R., Girard, J.R., Assan, R.: Hyperphenforminaemia, renal failure, lactic acidosis: human clinical condition and experimental model in rats. Diabetologia10, 369 (1974)
Wick, A.N., Stewart, C.J., Serif, G.S.: Tissue distribution of14C-labelled beta-phenethylbiguanide. Diabetes9, 163–165 (1960)
Hall, H., Rachamander, G., Glassman, J.M.: Tissue distribution and excretion of phenformin in normal and diabetic animals. Ann. N. Y. Acad. Sci.148, 601–611 (1968)
Beckmann, R.: The fate of biguanides in man. Ann. N. Y. Acad. Sci.148, 820–832 (1968)
Murphy, P.J., Wick, A.N.: Metabolism of beta-phenethylbiguanide. J. Pharm. Sci.57, 1125–1127 (1968)
Hamburger, J., Donovski, L., Marche, Cl: Sur une technique de préparation d'une anse intestinale chez le rat pour l'étude de la dialyse du jéjunum comme traitement de l'urémie. Pathol. Biol. (Paris)18, 403–406 (1970)
Girard, J.R., Cuendet, G.J., Marliss, E.B., Kervran, A., Rieutort, M., Assan, R.: Fuels, hormones and liver metabolism at term and during the early post-natal period in the rat. J. Clin. Invest.52, 3190–3200 (1973)
Passoneau, J.V.: Lactate. In: H.U. Bergmeyer (Ed.): Methoden der Enzymatischen Analyse, 1430. Weinheim: Verlag-Chemie 1970
Passoneau, J.V., Lowry, O.H.: Pyruvate. In: H.U. Bergmeyer (Ed.): Methoden der Enzymatischen Analyse, 1412. Weinheim: Verlag-Chemie 1970
Mellanby, J., Williamson, D.H.: Beta-hydroxybutyrate. In: H.U. Bergmeyer (Ed.): Methoden der Enzymatischen Analyse, 1772. Weinheim: Verlag-Chemie 1970
Mellanby, J., Williamson, D.H.: Acetoacetate. In: H.U. Bergmeyer (Ed.): Methoden der Enzymatischen Analyse, 1776. Weinheim: Verlag-Chemie 1970
Williamson, D.H.: Alanine. In: H.U. Bergmeyer (Ed.): Methoden der Enzymatischen Analyse, 1634. Weinheim: Verlag-Chemie 1970
Wieland, O.: Glycerol. In: H.U. Bergmeyer (Ed.): Methoden der Enzymatischen Analyse, 1367. Weinheim: Verlag-Chemie 1970
Huggett, A.S. G., Nixon, D.A.: Use of glucose-oxidase, peroxidase and O-dianisidine in the determination of blood and urine glucose. Lancet1957 II, 368–370
Yalow, R.S., Berson, S.A.: Immunologic aspects of insulin. Am. J. Med.31, 882–891 (1961)
Assan, R., Tchobroutsky, G., Derot, M.: Glucagon radioimmunoassay: technical problems and recent data. Horm. Metab. Res.5 (suppl. 1) 82–90 (1971)
Rosselin, G., Assan, R., Yalow, R.S., Berson, S.A.: Separation of antibody bound and unbound peptide hormones labelled with iodine 131 by talcum powder and precipitated silica. Nature212, 355–357 (1966)
Exton, J.H., Park, C.R.: Control of gluconeogenesis in liver. 1) General features of gluconeogenesis in the perfused livers of rats. J. Biol. Chem.242, 2622–2636 (1967)
Bray, G.A.: A simple, efficient liquid scintillation for counting aqueous solutions in a liquid scintillation counter. Anal. Biochem.1, 279–285 (1960)
Cook, D.E., Blair, J.B., Gilfillan, C., Lardy, H.A.: Mode of action of hypoglycemic agents. IV) Control of the hypoglycemic activity of phenylethylbiguanide in rats and guinea-pigs. Biochem. Pharmacol.22, 2121–2128 (1973)
Marliss, E.B., Aoki, T.T., Toews, C.J., Felig, P., Connon, J.J., Kyner, J., Huckabee, W.E., Cahill, G.F., Jr.: Aminoacid metabolism in lactic acidosis. Am. J. Med.52, 474–481 (1972)
Ball, S., Woods, H.F., Alberti, K.G.M.M.: Lactic acidosis, keto-acidosis and hyperalaninaemia in a phenformin-treated diabetic patient. Br. Med. J.1974 IV, 699–700
Wise, P.J., Chapman, M., Thomas, T.W., Clarkson, A.R., Harding, P.E., Edwards, J.B.: Phenformin and lactic acidosis. Br. Med. J.1976 I, 70–72
Holloway, P.H., Alberti, K.G.M.M.: Phenformin-induced lactic acidosis: prevention by dichloro-acetate. Clin. Sci. Mol. Med.50, 33 (1976)
Arieff, A.I., Guisado, R., Lazarowitz, V.C., Leach, W.: Phenformin and lactic acidosis: pathophysiology in an experimental model. Clin. Res.83, 1361 (1976)
Meyer, R., Ipaktchi, M., Clauser, H.: Specific inhibition of gluconeogenesis by biguanides. Nature213, 203–204 (1967)
Häckel, R., Häckel, H.: Inhibition of gluconeogenesis from lactate by phenylethylbiguanide in the perfused guinea-pig liver. Diabetologia8, 117–124 (1972)
Toews, C.J., Kyner, J.L., Connon, J.J., Cahill, G.F., Jr.: The effects of phenformin on gluconeogenesis in isolated perfused rat liver. Diabetes19, 368 (1970)
Cook, D.E., Blair, J.B., Lardy, H.A.: Mode of action of hypoglycemic agents. V) Studies with phenethyl-biguanide in isolated perfused rat liver. J. Biol. Chem.248, 5272–5277 (1973)
Assan, R., Heuclin, Chr., Ganeval, D., Bismuth, C., George, J., Girard, J.R.: Metformin-induced lactic acidosis in the presence of acute renal failure. Diabetologia13, 211–218 (1977)
Cowley, L.A., Karam, J.H., Matin, S.D., Löwensein, J.E.: Serum phenformin concentrations in patients with phenformin-associated lactic acidosis. Diabetes26, 628–631 (1977)
Yudkin, J., Cohen, R.D., Slack, B.: The haemodynamic effect of metabolic acidosis in the rat. Clin. Sci. Mol. Med.50, 177–184 (1976)
Krebs, H.A., Hems, R., Weideman, M.J., Speaker, N.: The fate of isotopic carbon in kidney cortex synthetizing glucose from lactate. Biochem. J.101, 242–246 (1966)
Cohen, R.D., Woods, H.F.: Clinical and biochemical aspects of lactic acidosis, pp. 234–236. Oxford: Blackwell Scientific Publications 1976
Nattrass, M., Todd, P.G., Hinks, L., Lloyd, B., Alberti, K.G.M.M.: Comparative effects of phenformin, metformin and glibenclamide on metabolic rhythms in maturity-onset diabetics. Diabetologia13, 145–152 (1977)
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Assan, R., Heuclin, C. & Girard, J.R. An Experimental model of phenformin-induced lactic acidosis in rats. Diabetologia 14, 261–267 (1978). https://doi.org/10.1007/BF01219426
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF01219426