Ukr.Biochem.J. 2020; Volume 92, Issue 5, Sep-Oct, pp. 33-40

doi: https://doi.org/10.15407/ubj92.05.033

L-carnitine administration effects on AMPK, APPL1 and PPARγ genes expression in the liver and serum adiponectin levels and HOMA-IR in type 2 diabetes rat model induced by STZ and nicotinamide

B. Shahouzehi1,2, H. Fallah3, Y. Masoumi-Ardakani4*

1Student Research Committee, Kerman University of Medical Sciences, Kerman, Iran;
2Cardiovascular Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran;
3Department of Biochemistry, Afzalipour School of Medicine,
Kerman University of Medical Sciences, Kerman, Iran;
4Physiology Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran;
*e-mail: ymab125@gmail.com

Received: 18 January 2020; Accepted: 25 June 2020

Diabetes is a chronic disease and a public health problem globally. L-Carnitine is synthesized in the liver, promotes fatty acids oxidation and currently is used as a supplement against weight gain. Carnitine level is found to be reduced in diabetic patients and to be beneficial as a supplement at diabetes, but the mechanisms­ of this effect is not fully understood. Therefore, we evaluated the oral L-carnitine supplementation on expression of AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma (PPARγ), adaptor protein APPL1 genes in the liver and insulin and adiponectin levels  in the serum of diabetic rats. Rats were randomly divided into three groups (n = 8) as follow: group 1 – control without any treatment, group 2 – diabetic control rats which received STZ (45 mg/kg) and nicotinamide (200 mg/kg) by i.p. injection, group 3 – diabetic rats which received 600 mg/kg/day carnitine orally for 35 days. It was found that L-carnitine supplementation reduced the level of fasting glucose compared to that in control and diabetic groups (P = 0.001,  P = 0.0001 respectively) and increased adiponectin level compared to diabetic nontreated rats (P = 0.0001). Homeostasis model assessment of insulin resistance (HOMA-IR) was significantly increased in the diabetic group and reduced in the group that received L-carnitine. These promising beneficial effect of L-carnitine on the type 2 diabetes in rats’ model was shown to be conducted through the up-regulation of AMPK, PPARγ and APPL1 genes expression in the liver and elevation of serum adiponectin level.

Keywords: , , , , , ,


References:

  1. Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract. 2014;103(2):137-149. PubMed, CrossRef
  2. Wang J, Wang H. Oxidative Stress in Pancreatic Beta Cell Regeneration. Oxid Med Cell Longev. 2017;2017:1930261. PubMed, PubMedCentral, CrossRef
  3. Flanagan JL, Simmons PA, Vehige J, Willcox MD, Garrett Q.   Role of carnitine in disease. Nutr Metab (Lond). 201;7:30.    PubMed, PubMedCentral, CrossRef
  4. Shahouzehi B. 1, Barkhordari K Aminizadeh S, Masoumi-Ardakani Y. Effect of L-carnitine administration on serum insulin and adiponectin levels, and AMPK, APPL1 and PPARγ gene expression in STZ-induced diabetic rat liver. Ukr Biochem J. 2017;89(6): 48-55. CrossRef
  5. Poorabbas A, Fallah F, Bagdadchi J, Mahdavi R, Aliasgarzadeh A, Asadi Y, Koushavar H, Vahed Jabbari M. Determination of free L-carnitine levels in type II diabetic women with and without complications. Eur J Clin Nutr. 2007;61(7):892-895. PubMed, CrossRef
  6. Argani H, Rahbaninoubar M, Ghorbanihagjo A, Golmohammadi Z, Rashtchizadeh N. Effect of L-carnitine on the serum lipoproteins and HDL-C subclasses in hemodialysis patients. Nephron Clin Pract. 2005;101(4):c174-c179. PubMed, CrossRef
  7. Bazotte RB, Lopes-Bertolini G.  Effects of oral L-carnitine and DL-carnitine supplementation on alloxan-diabetic rats. Braz Arch Biol Technol. 2012;55(1):81-88.  CrossRef
  8. D’Antona G, Nabavi SM, Micheletti P, Di Lorenzo A, Aquilani R, Nisoli E, Rondanelli M, Daglia M. Creatine, L-carnitine, and ω3 polyunsaturated fatty acid supplementation from healthy to diseased skeletal muscle. Biomed Res Int. 2014;2014:613890. PubMed, PubMedCentralCrossRef
  9. Mynatt RL. Carnitine and type 2 diabetes. Diabetes Metab Res Rev. 2009;25(Suppl 1):S45–S49. CrossRef
  10. Mihaylova MM, Shaw RJ. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol. 2011;13(9):1016-1023.   PubMed, PubMedCentral, CrossRef
  11. Achari AE, Jain SK. Adiponectin, a therapeutic target for obesity, diabetes, and endothelial dysfunction. Int J Mol Sci. 2017;18(6):1321.
    PubMed, PubMed, CrossRef
  12. DeFronzo RA. Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009. Diabetologia. 2010;53(7):1270-1287. PubMed, PubMed, CrossRef
  13. Ferré P. The biology of peroxisome proliferator-activated receptors: relationship with lipid metabolism and insulin sensitivity. Diabetes. 2004;53 Suppl 1:S43-S50.   PubMed, CrossRef
  14. Monsalve FA, Pyarasani RD, Delgado-Lopez F, Moore-Carrasco R. Peroxisome proliferator-activated receptor targets for the treatment of metabolic diseases. Mediators Inflamm. 2013;2013:549627. PubMed, PubMedCentral, CrossRef
  15. Cave MC, Hurt RT, Frazier TH, Matheson PJ, Garrison RN, McClain CJ, McClave SA.  Obesity, inflammation, and the potential application of pharmaconutrition. Nutr Clin Pract. 2008;23(1):16-34. PubMed, CrossRef
  16. Abdel-Razek HAD. Beneficial effect of L-carnitine on the neuromuscular performance in diabetic rats. Menoufia Med J. 2010; 23: 159-173.
  17. Patel J, Goyal R, Bhatt P. Beneficial effects of levo-carnitine on lipid metabolism and cardiac function in neonatal streptozotocin rat model of diabetes. Int J Diabetes Metab. 2008; 16: 29-34.
  18. Rodrigues B, Xiang H, McNeill JH.  Effect of L-carnitine treatment on lipid metabolism and cardiac performance in chronically diabetic rats. Diabetes. 1988;37(10):1358-1364. PubMed, CrossRef
  19. Szkudelski T. Streptozotocin-nicotinamide-induced diabetes in the rat. Characteristics of the experimental model. Exp Biol Med (Maywood). 2012;237(5):481-490. PubMed, CrossRef
  20. Sharma S, Sun X, Rafikov R, Kumar S, Hou Y, Oishi PE, Datar SA, Raff G, Fineman JR, Black SM. PPAR-γ regulates carnitine homeostasis and mitochondrial function in a lamb model of increased pulmonary blood flow. PLoS One. 2012;7(9):e41555. PubMed, PubMedCentral, CrossRef
  21. Gavrilova O, Haluzik M, Matsusue K, Cutson JJ, Johnson L, Dietz KR, Nicol CJ, Vinson C, Gonzalez FJ, Reitman ML. Liver peroxisome proliferator-activated receptor gamma contributes to hepatic steatosis, triglyceride clearance, and regulation of body fat mass. J Biol Chem. 2003;278(36):34268-34276.  PubMed, CrossRef
  22. Pala R, Genc E, Tuzcu M, Orhan C, Sahin N, Er B, Cinar V, Sahin K. L-Carnitine supplementation increases expression of PPAR-γ and glucose transporters in skeletal muscle of chronically and acutely exercised rats. Cell Mol Biol. 2018;64(1):1-6. PubMed, CrossRef
  23. Deepa SS, Zhou L, Ryu J, Wang C, Mao X, Li C, Zhang N, Musi N, DeFronzo RA, Liu F, Dong LQ. APPL1 mediates adiponectin-induced LKB1 cytosolic localization through the PP2A-PKCzeta signaling pathway. Mol Endocrinol. 2011;25(10):1773-1785. PubMed, PubMed, CrossRef
  24. Deepa SS, Dong LQ.  APPL1: role in adiponectin signaling and beyond. Am J Physiol Endocrinol Metab. 2009;296(1):E22-E36. PubMed, PubMed, CrossRef
  25. Mao X, Kikani CK, Riojas RA, Langlais P, Wang L, Ramos FJ, Fang Q, Christ-Roberts CY, Hong JY, Kim RY, Liu F, Dong LQ. APPL1 binds to adiponectin receptors and mediates adiponectin signalling and function. Nat Cell Biol. 2006;8(5):516-523. PubMed, CrossRef
  26. Mingrone G, Greco AV, Capristo E, Benedetti G, Giancaterini A, De Gaetano A, Gasbarrini G. L-carnitine improves glucose disposal in type 2 diabetic patients. J Am Coll Nutr. 1999;18(1):77-82. PubMed, CrossRef
  27. Bonora E, Formentini G, Calcaterra F, Lombardi S, Marini F, Zenari L, Saggiani F, Maurizio Poli M, Perbellini S, Raffaelli A, Cacciatori V,  Santi L, Targher G, Bonadonna R, Muggeo M. HOMA-estimated insulin resistance is an independent predictor of cardiovascular disease in type 2 diabetic subjects: prospective data from the Verona Diabetes Complications Study. Diabetes Care. 2002;25(7):1135-1141.  PubMed, CrossRef
  28. Salgado ALFA, Carvalho L, Oliveira AC, Santos VN, Vieira JG, Parise ER. Insulin resistance index (HOMA-IR) in the differentiation of patients with non-alcoholic fatty liver disease and healthy individuals. Arq Gastroenterol. 2010;47(2):165-169. PubMed, CrossRef

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License.