Responses of the perfused liver of neonatal type 2 diabetic rats to gluconeogenic and ammoniogenic substrates

Abstract

The responses of livers from rats with type 2 diabetes to alanine (gluconeogenesis and ammonia detoxification) and other gluconeogenic substrates were investigated. The experimental system was the isolated perfused rat liver. Neonatal type 2 diabetes was induced with streptozotocin. Ammoniogenesis from endogenous substrates was 610% higher in livers from diabetic rats when compared to the control condition. Alanine (2.5 mM) ammoniogenesis was 285% higher in livers of diabetic rats. Gluconeogenesis from the following substrates was smaller in the liver of diabetic rats: Alanine (?43.5%), lactate (?28.3%) and glycerol (?30.5%). Pyruvate gluconeogenesis was normal. The high rate of ammoniogenesis explains the moderate hyperammonemia of type 2 diabetic rats. The enzymatic machinery of the gluconeogenic pathway of type 2 diabetic rats seems to be adapted to low rates of glucose removal by extrahepatic tissues. A significant contribution of gluconeogenesis to the fasting hyperglycemia can be expected only by short-term up-regulation mechanisms.

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Carvalho-Martini, M. , Suzuki-Kemmelmeier, F. , de Oliveira, D. , Comar, J. and Bracht, A. (2010) Responses of the perfused liver of neonatal type 2 diabetic rats to gluconeogenic and ammoniogenic substrates. Health, 2, 477-483. doi: 10.4236/health.2010.25071.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] Kraus-Friedmann, N. (1984) Hormonal regulation of hepatic gluconeogenesis. Physiology Reviews, 64, 170- 259.
[2] Pilks, S.J. and Granner, D.K. (1992). Molecular physiology of the regulation of hepatic gluconeogenesis and glycolysis. Annual Review of Physiology, 54, 885-909.
[3] Petersen, K.F., Price, T.B. and Bergeron, R. (1993) Regulation of net hepatic glycogenolysis and gluconeogenesis during exercise: Impact of type 1 diabetes. Journal of Clinical Endocrinology and Metabolism, 89(9), 4656- 4664.
[4] Boden, G., Chen, X. and Stein, T.P. (2001) Gluconeogenesis in moderately and severely hyperglycemic patients with type 2 diabetes mellitus. American Journal of Physiology, Endocrinology and Metabolism, 280(1), E23-E30.
[5] Diraison, F., Large, V., Brunengraber, H. and Beylot, M. (1998) Non-invasive tracing of liver intermediary metabolism in normal subjects and in moderately hyperglycaemic NIDDM subjects: Evidence against increased gluconeogenesis and hepatic fatty acid oxidation in NIDDM. Diabetologia, 41, 212-220.
[6] Andrikopoulos, S. and Proietto, J. (1995) The biochemical basis of increased hepatic glucose production in a mouse model of type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia, 38, 1389-1396.
[7] Puhakainen, I., Koivisto, V.A. and Yki-Jarvinen, H. (1992) Lipolysis and gluconeogenesis from glycerol are increased in patients with noninsulin-dependent diabetes mellitus. Journal of Clinical Endocrinology and Metabolism, 75, 789-794.
[8] Magnusson, I., Rothman, D.L., Katz, L.D., Shulman, R.G. and Shulman, G.I. (1992) Increased rate of gluconeogenesis in type II diabetes mellitus. Journal of Clinical Investigation, 90(4), 1323-1327.
[9] Basu, R., Schwenk, W.F. and Rizza, R.A. (2004) Both fasting glucose production and disappearance are abnormal in people with “mild” and “severe” type 2 diabetes. American Journal of Physiology-Endocrinology and Me- tabolism, 287(1), E55-E62.
[10] Söling, H.D., Koschel, R., Dragert, W., Kneer, P. and Creutzfeldt, W. (1966) The effect of insulin on the metabolism of isolated perfused livers of normal and alloxan-diabetic rats. I. The metabolism of isolated perfused livers in normal and alloxan-diabetic rats under various experimental conditions. Diabetologia, 2(1), 20- 31.
[11] Rudorff, K.H., Albrecht, G. and Staib, W. (1970) Über den Einflu von Insulin und Proinsulin auf die Gluco-neogenese aus alanin in der isoliert perfundierten leber normaler und alloxandiabetischer ratten. Hoppe-Seyler’s Zeitschrift für Physiologische Chemie, 351, 975-982.
[12] Cook, D.E. (1978) The effects of phenformin in normal vs. diabetic isolated perfused rat liver. Research Communications in Chemical Pathology and Pharmacology, 22, 119-134.
[13] Wagle, S.R., Ingebretsen, W.R. and Sampson, L. (1975) Studies on gluconeogenesis and stimulation of glycogen and protein synthesis in isolated hepatocytes in alloxan diabetic, normal fed and fasted animals. Acta Diabetologica Latina, 12, 185-198.
[14] Lombardo, Y.B., Hron, W.T. and Menahan, L.A. (1978) Effect of insulin in vitro on the isolated, perfused alloxan-diabetic rat liver. Diabetologia, 14(1), 47-51.
[15] Akimoto, L.S., Pedrinho, S.R., Lopes, G. and Bazotte, R.B. (2000) Rates of gluconeogenesis in perfused liver of alloxan-diabetic fed rats. Research Communications in Molecular Pathology and Pharmacology, 107(1-2), 65- 77.
[16] Barthel, A. and Schmoll, D. (2003) Novel concepts in insulin regulation of hepatic gluconeogenesis. American Journal of Physiology, Endocrinology and Metabolism, 285(4), E685-E692.
[17] Arulmozhi, D.K., Veeranjaneyulu, A. and Bodhankar, S.L. (2004) Neonatal streptozotocin-induced rat model of type 2 diabetes mellitus: A glance. Indian Journal of Pharmacology, 36(4), 217-221.
[18] Oliveira, D.S., Bersani-Amado, C.A., Martini, M.C., Suzuki-Kemmelmeier, F. and Bracht, A. (2007) Glycogen levels and energy status of the liver of fasting rats with diabetes types 1 and 2. Brazilian Archives of Biology and Technology, 50(5), 785-791.
[19] Portha, B., Levacher, C., Picon, L. and Rosselin, G. (1974) Diabetogenic effect of streptozotocin in the rat during the perinatal period. Diabetes, 23(11), 889-895.
[20] Cuman, R.K.N., Bersani-Amado, C. and Fortes, Z.B. (2001) Influence of type 2 diabetes upon the inflammatory response in rats. Inflammation, 50(9), 460-465.
[21] Scholz, R. and Bücher, T. (1965) Hemoglobin-free perfusion of rat liver. In: Changce, B., Estabrook, W. and Williamson, J.R., Eds., Control of Energy Metabolism, Academic Press, New York, 393-414.
[22] Bracht, A., Ishii-Iwamoto, E.L. and Kelmer-Bracht, A.M. (2003) O estudo do metabolismo no fígado em perfusão. In: Bracht, A. and Ishii-Iwamoto, E.L. Eds., Métodos de Laboratório em Bioquímica, Editora Manole, São Paulo, 275-289.
[23] Bergmeyer, H.U. (1974) Methods of Enzymatic Analysis, Verlag Chemie-Academic Press, Weinheim-London.
[24] Bazotte, R.B., Constantin, J., Hell, N.S. and Bracht, A. (1990) Hepatic metabolism of meal-fed rats: Studies in vivo and in the isolated perfused liver. Physiology and Behavior, 48(2), 247-253.
[25] Häussinger, D., Gerok, W. and Sies, S. (1983) Regulation of flux through glutaminase and glutamine synthetase in isolated perfused rat liver. Biochimica et Biophysica Acta, 755(2), 272-278.
[26] Beck-Nielsen, H., Hother-Nielsen, O. and Staehr, P. (2002) Is hepatic glucose production increased in type 2 diabetes mellitus? Current Diabetes Reports, 2, 231-236.
[27] Sies, H. (1982) Nicotinamide nucleotide compartmentation. In: Sies, H., Ed., Metabolic Compartmentation. Academic Press, New York, 205-231.
[28] Veiga, R.P., Silva, M.H., Teodoro, G.R., Yamamoto, N.S., Constantin, J. and Bracht, A. (2008) Metabolic fluxes in the liver of rats bearing the walker 256 tumor: Influence of the circulating levels of substrates and fatty acids. Cell Biochemistry and Function, 26(1), 51-63.
[29] Constantin, J., Ishii-Iwamoto, E.L., Suzuki Kemmelmeie, F. and Bracht, A. (1994) Zonation of the action of glucagon on gluconeogenesis studied in the bivascularly perfused rat liver. FEBS Letters, 352(1), 24-26.
[30] Marques da Silva, A.C., D’Ávila, R.B., Ferrari, A.G., Kelmer-Bracht, A.M., Constantin, J. and Bracht, A. (1997) Ca2+-dependence of gluconeogenesis stimulation by glucagon at different cytosolic NAD+-NADH redox potentials. Brazilian Journal of Medical and Biological Research, 30(7), 827-836.
[31] Nurjhan, N., Conoli, A. and Gerich, J. (1992) Increased lipolysis and its consequences on gluconeogenesis in non- insulin-dependent diabetes mellitus. Journal of Clinical Investigation, 89(1), 169-175.
[32] Argilés, J.M. and López-Soriano, F.J. (1991) The energy state of tumorbearing rats. Journal of Biological Chemistry, 266, 2978-2982.

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