Analysis of genetic polymorphisms of OCT1, MATE1, MATE2 and GLP1R in rats with experimentally induced obesity
DOI:
https://doi.org/10.2478/amb-2024-0041Keywords:
obesity, metformin, liraglutide, polymorphisms, receptorsAbstract
The experimental model of obesity based on a cafeteria diet is a common model to investigate different aspects of obesity. The present study aimed to evaluate the link between genetic variants of OCT1, MATE1, MATE2 and GLP1R and the treatment effects
in male obese rats. After 19-weeks of feeding with a standard chow food and Cafeteria-diet (CAF), the rats were divided into three groups: control group (only CAF), metformin group (CAF and metformin treatment) and liraglutide group (CAF and GLP1 agonist treatment). The genetic variations of the receptors for metformin in liver and kidney (OCT1, MATE1, MATE2) and for liraglutide (GLP1R) were examined. The results demonstrated a significant decrease in body mass index, blood glucose and a significant increase in plasma HDL-cholesterol levels in both groups treated with either metformin or liraglutide compared to the control group. No effect on plasma triglycerides and VLDL-cholesterol levels was shown between the three groups. According to the genetic analysis, all rats were “wild type” for the genetic variants tested in OCT, MATE1, MATE2 and GLP1R, not affecting the effects of treatment. This raises the possibility of other potential genes implicated in the underlying mechanism of obesity and metformin/liraglutide therapy.
References
Lalanza JF, Snoeren EMS. The cafeteria diet: A standardized protocol and its effects on behavior. Neurosci Biobehav Rev. 2021;122:92-119.
Muscogiuri G, El Ghoch M, Colao A, et al. European Guidelines for Obesity Management in Adults with a Very Low-Calorie Ketogenic Diet: A Systematic Review and Meta-Analysis. Obes Facts. 2021;14(2):222-45.
El-Arabey AA. Update on off label use of metformin for obesity. Prim Care Diabetes. 2018;12(3):284-5.
Singh S, Usman K, Banerjee M. Pharmacogenetic studies update in type 2 diabetes mellitus. World J Diabetes. 2016;7(15):302-15.
Committee ADAPP. 8. Obesity and Weight Management for the Prevention and Treatment of Type 2 Diabetes: Standards of Medical Care in Diabetes – 2022. Diabetes Care. 2021; 45(Suppl_1):S113-S24.
Hansen KB, Vilsboll T, Knop FK. Incretin mimetics: a novel therapeutic option for patients with type 2 diabetes - a review. Diabetes Metab Syndr Obes. 2010; 3:155-63.
Campbell Jonathan E, Drucker Daniel J. Pharmacology, Physiology, and Mechanisms of Incretin Hormone Action. Cell Metabolism. 2013; 17(6):819-37.
Jakhar K, Vaishnavi S, Kaur P, et al. Pharmacogenomics of GLP-1 receptor agonists: Focus on pharmacological profile. Eur J Pharmacol. 2022; 936:175356.
Chedid V, Vijayvargiya P, Carlson P, et al. Allelic variant in the glucagon-like peptide 1 receptor gene associated with greater effect of liraglutide and exenatide on gastric emptying: A pilot pharmacogenetics study. Neurogastroenterol Motil. 2018; 30(7):e13313.
Marathe CS, Rayner CK, Jones KL, Horowitz M. Effects of GLP-1 and incretin-based therapies on gastrointestinal motor function. Exp Diabetes Res. 2011; 2011:279530.
Hendricks EJ. Off-label drugs for weight management. Diabetes Metab Syndr Obes. 2017; 10:223-34. 12. Seifarth C, Schehler B, Schneider HJ. Effectiveness of metformin on weight loss in non-diabetic individuals with obesity. Exp Clin Endocrinol Diabetes. 2013; 121(1):27-31.
Shu Y, Sheardown SA, Brown C, et al. Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest. 2007; 117(5):1422-31.
Hyrsova L, Smutny T, Trejtnar F, Pavek P. Expression of organic cation transporter 1 (OCT1): unique patterns of indirect regulation by nuclear receptors and hepatospecific gene regulation. Drug Metab Rev. 2016; 48(2):139-58.
Florez JC. The pharmacogenetics of metformin. Diabetologia. 2017; 60(9):1648-55.
Becker ML, Visser LE, van Schaik RH, et al. Interaction between polymorphisms in the OCT1 and MATE1 transporter and metformin response. Pharmacogenet Genomics. 2010; 20(1):38-44.
Todd JN, Florez JC. An update on the pharmacogenomics of metformin: progress, problems and potential. Pharmacogenomics. 2014; 15(4):529-39.
Zolk O. Disposition of metformin: Variability due to polymorphisms of organic cation transporters. Annals of Medicine. 2012; 44(2):119-29.
Toyama K, Yonezawa A, Masuda S, et al. Loss of multidrug and toxin extrusion 1 (MATE1) is associated with metformin-induced lactic acidosis. Br J Pharmacol. 2012; 166(3):1183-91.
Okuda M, Saito H, Urakami Y, et al. cDNA cloning and functional expression of a novel rat kidney organic cation transporter, OCT2. Biochem Biophys Res Commun. 1996; 224(2):500-7.
Chan SL, Samaranayake N, Ross CJ, et al. Genetic diversity of variants involved in drug response and metabolism in Sri Lankan
populations: implications for clinical implementation of pharmacogenomics. Pharmacogenet Genomics. 2016; 26(1):28-39.
Belzung C, Lemoine M. Criteria of validity for animal models of psychiatric disorders: focus on anxiety disorders and depression. Biol Mood Anxiety Disord. 2011; 1(1):9.
Caimari A, Oliver P, Keijer J, Palou A. Peripheral blood mononuclear cells as a model to study the response of energy
homeostasis-related genes to acute changes in feeding conditions. OMICS. 2010; 14(2):129-41.
Heyne A, Kiesselbach C, Sahun I, et al. An animal model of compulsive food-taking behaviour. Addict Biol. 2009; 14(4):373-83.
Vickers SP, Jackson HC, Cheetham SC. The utility of animal models to evaluate novel anti-obesity agents. Br J Pharmacol. 2011; 164(4):1248-62.
Novelli EL, Diniz YS, Galhardi CM, et al. Anthropometrical parameters and markers of obesity in rats. Lab Anim. 2007; 41(1):111-9.
Lewis AR, Singh S, Youssef FF. Cafeteria-diet induced obesity results in impaired cognitive functioning in a rodent model. Heliyon. 2019; 5(3):e01412.
Sampey BP, Vanhoose AM, Winfield HM, et al. Cafeteria diet is a robust model of human metabolic syndrome with liver
and adipose inflammation: comparison to high-fat diet. Obesity (Silver Spring). 2011;19(6):1109-17.
Malin SK, Kashyap SR. Effects of metformin on weight loss: potential mechanisms. Curr Opin Endocrinol Diabetes Obes. 2014; 21(5):323-9.
Leigh SJ, Kendig MD, Morris MJ. Palatable Western-style Cafeteria Diet as a Reliable Method for Modeling Diet-induced Obesity in Rodents. J Vis Exp. 2019 (153).
Jensterle M, Salamun V, Kocjan T, et al. Short term monotherapy with GLP-1 receptor agonist liraglutide or PDE 4 inhibitor roflumilast is superior to metformin in weight loss in obese PCOS women: a pilot randomized study. J Ovarian Res. 2015; 8:32.
Kim YW, Kim JY, Park YH, et al. Metformin restores leptin sensitivity in high-fat-fed obese rats with leptin resistance. Diabetes. 2006; 55(3):716-24.
Fontbonne A, Charles MA, Juhan-Vague I, et al. The effect of metformin on the metabolic abnormalities associated with upper-body fat distribution. BIGPRO Study Group. Diabetes Care. 1996; 19(9):920-6.
Jelsing J, Vrang N, Hansen G, et al. Liraglutide: short-lived effect on gastric emptying - long lasting effects on body weight.
Diabetes Obes Metab. 2012; 14(6):531-8.
Yamazaki S, Satoh H, Watanabe T. Liraglutide enhances insulin sensitivity by activating AMP-activated protein kinase in male Wistar rats. Endocrinology. 2014; 155(9):3288-301.
D’Alessio DA, Kahn SE, Leusner CR, Ensinck JW. Glucagonlike peptide 1 enhances glucose tolerance both by stimulation of insulin release and by increasing insulin-independent glucose disposal. J Clin Invest. 1994; 93(5):2263-6.
D’Alessio DA, Prigeon RL, Ensinck JW. Enteral enhancement of glucose disposition by both insulin-dependent and insulin-independent processes. A physiological role of glucagon-like peptide I. Diabetes. 1995; 44(12):1433-7.
Abbasi F, McLaughlin T, Lamendola C, et al. Fasting remnant lipoprotein cholesterol and triglyceride concentrations are elevated in nondiabetic, insulin-resistant, female volunteers. J Clin Endocrinol Metab. 1999; 84(11):3903-6.
Alalwani AD, Hummdi LA, Qahl SH. Effect of nano extracts of olea europaea leaves, ficus carica and liraglutide in lipidemic liver of type 2 diabetic rat model. Saudi J Biol Sci. 2022; 29(7):103333.
Taher J, Baker CL, Cuizon C, et al. GLP-1 receptor agonism ameliorates hepatic VLDL overproduction and de novo lipogenesis in insulin resistance. Mol Metab. 2014; 3(9):823-33.
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