Anti-diabetic effects of mildronate alone or in combination with metformin in obese Zucker rats

European Journal of Pharmacology

Volumn 658, Issue 2-3, 2011, Pages 277-283

  Liepinsh, Edgars ^a   Skapare, Elina ^a,b   Svalbe, Baiba ^a,c   Makrecka, Marina ^a,b   Cirule, Helena ^a   Dambrova, Maija ^a  

^a LATVIAN INSTITUTE OF ORGANIC SYNTHESIS   (Latvia)

^b RIGA STRADINS UNIVERSITY   (Latvia)

^c UNIVERSITY OF LATVIA   (Latvia)

Author keywords

Diabetes; Dyslipidemia; Hyperglycemia; Metformin; Mildronate; Zucker rat

Indexed keywords

INSULIN; LACTIC ACID; MESSENGER RNA; METFORMIN; MILDRONATE; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA;

ACUTE DRUG ADMINISTRATION; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CHRONIC DRUG ADMINISTRATION; CONTROLLED STUDY; DIABETES MELLITUS; DRUG EFFECT; DRUG MECHANISM; FOOD INTAKE; GENE EXPRESSION PROFILING; GENE TARGETING; GLUCOSE BLOOD LEVEL; GLUCOSE METABOLISM; HYPERGLYCEMIA; HYPERLIPIDEMIA; INSULIN BLOOD LEVEL; LACTATE BLOOD LEVEL; LIPID ANALYSIS; MALE; METABOLITE; MONOTHERAPY; NONHUMAN; OBESITY; PRIORITY JOURNAL; PROTEIN EXPRESSION; RAT; WEIGHT GAIN;

ANIMALS; BLOOD GLUCOSE; BODY WEIGHT; CELL NUCLEUS; DRUG COMBINATIONS; EATING; GENE EXPRESSION REGULATION; HYPOGLYCEMIC AGENTS; INSULIN; LACTIC ACID; LIPID METABOLISM; MALE; METFORMIN; METHYLHYDRAZINES; MYOCARDIUM; OBESITY; PPAR ALPHA; PPAR GAMMA; RATS; RATS, ZUCKER; RNA, MESSENGER;

EID: 79953775086     PISSN: 00142999     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.ejphar.2011.02.019     Document Type: Article

References (32)

1. Asaka, N., Muranaka, Y., Kirimoto, T., Miyake, H., 1998. Cardioprotective profile of MET-88, an inhibitor of carnitine synthesis, and insulin during hypoxia in isolated perfused rat hearts. Fundam. Clin. Pharmacol. 12, 158-163.
2. Bailey, C.J., Turner, R.C., 1996. Metformin. N. Engl. J. Med. 334, 574-579.
3. Bray, G.A., 1977. The Zucker-fatty rat: a review. Fed. Proc. 36, 148-153.
4. Brunton, S., 2009. Beyond glycemic control: treating the entire type 2 diabetes disorder. Postgrad. Med. 121, 68-81.
5. Dambrova, M., Liepinsh, E., Kalvinsh, I., 2002. Mildronate: cardioprotective action through carnitine-lowering effect. Trends Cardiovasc. Med. 12, 275-279.
6. Degrace, P., Demizieux, L., Du, Z.Y., Gresti, J., Caverot, L., Djaouti, L., Jourdan, T., Moindrot, B., Guilland, J.C., Hocquette, J.F., Clouet, P., 2007. Regulation of lipid flux between liver and adipose tissue during transient hepatic steatosis in carnitine-depleted rats. J. Biol. Chem. 282, 20816-20826.
7. Grimaldi, P.A., 2007. Peroxisome proliferator-activated receptors as sensors of fatty acids and derivatives. Cell. Mol. Life Sci. 64, 2459-2464.
8. Hayashi, Y., Tajima, K., Kirimoto, T., Miyake, H., Matsuura, N., 2000. Cardioprotective effects of MET-88, a gamma-butyrobetaine hydroxylase inhibitor, on cardiac dysfunction induced by ischemia/reperfusion in isolated rat hearts. Pharmacology 61, 238-243.
9. Khan, M.A., St Peter, J.V., Xue, J.L., 2002. A prospective, randomized comparison of the metabolic effects of pioglitazone or rosiglitazone in patients with type 2 diabetes who were previously treated with troglitazone. Diab. Care 25, 708-711. (Pubitemid 41071191)
10. Kirimoto, T., Nobori, K., Asaka, N., Muranaka, Y., Tajima, K., Miyake, H., 1996. Beneficial effect of MET-88, a gamma-butyrobetaine hydroxylase inhibitor, on energy metabolism in ischemic dog hearts. Arch. Int. Pharmacodyn. Thér. 331, 163-178.
11. Koves, T.R., Ussher, J.R., Noland, R.C., Slentz, D., Mosedale, M., Ilkayeva, O., Bain, J., Stevens, R., Dyck, J.R., Newgard, C.B., Lopaschuk, G.D., Muoio, D.M., 2008. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab. 7, 45-56.
12. Kuhlmann, J., Neumann-Haefelin, C., Belz, U., Kalisch, J., Juretschke, H.P., Stein, M., Kleinschmidt, E., Kramer, W., Herling, A.W., 2003. Intramyocellular lipid and insulin resistance: a longitudinal in vivo 1H-spectroscopic study in Zucker diabetic fatty rats. Diabetes 52, 138-144. (Pubitemid 36042118)
13. Larsen, T.S., Aasum, E., 2008. Metabolic (in)flexibility of the diabetic heart. Cardiovasc. Drugs Ther. 22, 91-95.
14. Lau, D.C., 2009. Metabolic syndrome: perception or reality? Curr. Atheroscler. Rep. 11, 264-271.
15. Liepinsh, E., Vilskersts, R., Loca, D., Kirjanova, O., Pugovichs, O., Kalvinsh, I., Dambrova, M., 2006. Mildronate, an inhibitor of carnitine biosynthesis, induces an increase in gamma-butyrobetaine contents and cardioprotection in isolated rat heart infarction. J. Cardiovasc. Pharmacol. 48, 314-319.
16. Liepinsh, E., Vilskersts, R., Skapare, E., Svalbe, B., Kuka, J., Cirule, H., Pugovics, O., Kalvinsh, I., Dambrova, M., 2008. Mildronate decreases carnitine availability and up-regulates glucose uptake and related gene expression in the mouse heart. Life Sci. 83, 613-619.
17. Liepinsh, E., Kuka, J., Svalbe, B., Vilskersts, R., Skapare, E., Cirule, H., Pugovics, O., Kalvinsh, I., Dambrova, M., 2009a. Effects of long-term mildronate treatment on cardiac and liver functions in rats. Basic Clin. Pharmacol. Toxicol. 105, 387-394.
18. Liepinsh, E., Vilskersts, R., Zvejniece, L., Svalbe, B., Skapare, E., Kuka, J., Cirule, H., Grinberga, S., Kalvinsh, I., Dambrova, M., 2009b. Protective effects of mildronate in an experimental model of type 2 diabetes in Goto-Kakizaki rats. Br. J. Pharmacol. 157, 1549-1556.
19. Matthaei, S., Reibold, J.P., Hamann, A., Benecke, H., Haring, H.U., Greten, H., Klein, H.H., 1993. In vivo metformin treatment ameliorates insulin resistance: evidence for potentiation of insulin-induced translocation and increased functional activity of glucose transporters in obese (fa/fa) Zucker rat adipocytes. Endocrinology 133, 304-311.
20. McGarry, J.D., Mills, S.E., Long, C.S., Foster, D.W., 1983. Observations on the affinity for carnitine, and malonyl-CoA sensitivity, of carnitine palmitoyltransferase I in animal and human tissues. Demonstration of the presence of malonyl-CoA in non-hepatic tissues of the rat. Biochem. J. 214, 21-28.
21. Satapati, S., He, T., Inagaki, T., Potthoff, M., Merritt, M.E., Esser, V., Mangelsdorf, D.J., Kliewer, S.A., Browning, J.D., Burgess, S.C., 2008. Partial resistance to peroxisome proliferator-activated receptor-alpha agonists in ZDF rats is associated with defective hepatic mitochondrial metabolism. Diabetes 57, 2012-2021.
22. Sesti, C., Simkhovich, B.Z., Kalvinsh, I., Kloner, R.A., 2006. Mildronate, a novel fatty acid oxidation inhibitor and antianginal agent, reduces myocardial infarct size without affecting hemodynamics. J. Cardiovasc. Pharmacol. 47, 493-499.
23. Shulman, G.I., 2000. Cellular mechanisms of insulin resistance. J. Clin. Invest. 106, 171-176.
24. Spaniol, M., Kaufmann, P., Beier, K., Wuthrich, J., Torok, M., Scharnagl, H., Marz, W., Krahenbuhl, S., 2003. Mechanisms of liver steatosis in rats with systemic carnitine deficiency due to treatment with trimethylhydraziniumpropionate. J. Lipid Res. 44, 144-153. (Pubitemid 36114780)
25. Sugden, M.C., Zariwala, M.G., Holness, M.J., 2009. PPARs and the orchestration of metabolic fuel selection. Pharmacol. Res. 60, 141-150.
26. U.K. Prospective Diabetes Study Group, 1998. UKPDS 28: a randomized trial of efficacy of early addition of metformin in sulfonylurea-treated type 2 diabetes. Diab. Care 21, 87-92.
27. Vilskersts, R., Liepinsh, E., Kuka, J., Cirule, H., Veveris, M., Kalvinsh, I., Dambrova, M., 2009a. Myocardial infarct size-limiting and anti-arrhythmic effects of mildronate orotate in the rat heart. Cardiovasc. Drugs Ther. 23, 281-288.
28. Vilskersts, R., Liepinsh, E., Mateuszuk, L., Grinberga, S., Kalvinsh, I., Chlopicki, S., Dambrova, M., 2009b. Mildronate, a regulator of energy metabolism, reduces atherosclerosis in apoE/LDLR-/- mice. Pharmacology 83, 287-293.
29. Wang, W., Lopaschuk, G.D., 2007. Metabolic therapy for the treatment of ischemic heart disease: reality and expectations. Expert Rev. Cardiovasc. Ther. 5, 1123-1134.
30. Wiernsperger, N.F., Bailey, C.J., 1999. The antihyperglycaemic effect of metformin: therapeutic and cellular mechanisms. Drugs 58 (Suppl 1), 31-39. (Pubitemid 129758579)
31. Williams, S.D., Hsu, F.F., Ford, D.A., 2000. Electrospray ionization mass spectrometry analyses of nuclear membrane phospholipid loss after reperfusion of ischemic myocardium. J. Lipid Res. 41, 1585-1595.
32. Yasuda, N., Inoue, T., Nagakura, T., Yamazaki, K., Kira, K., Saeki, T., Tanaka, I., 2004. Metformin causes reduction of food intake and body weight gain and improvement of glucose intolerance in combination with dipeptidyl peptidase IV inhibitor in Zucker fa/fa rats. J. Pharmacol. Exp. Ther. 310, 614-619.