Effects of GLP-1 Receptor Polymorphisms on Adolescent Obesity
-
Mahafarin Maralani
,
Tufan Cankaya
,
Esra Ataman
,
Yavuz Tokgoz
,
Erkan Kaytankas
,
Nur Arslan
,
Behzad Baradaran
,
Khalil Hajiasgharzadeh
,
Ayfer Ulgenalp
Abstract
Obesity is becoming a concerning disease in developing countries. Like other multifactorial diseases, genetics plays a substantial role in the development of this disease. We tried to investigate genetic variations (mutation/polymorphism) of GLP-1R gene in children diagnosed with obesity and to identify their possible connections with obesity and other conditions. Genomic DNA was extracted from 162 overweight/obese patients and 100 controls. Later, full exon sequencing and association studies were carried out. Three polymorphisms and one mutation were detected in the fourth and fifth exons of the GLP-1R gene. Some variations were detected in three cases from which 1/3 had non-alcoholic fatty liver disease (NAFLD) but none showed insulin resistance (IR). There were also statistically meaningful results for ‘Odds Ratio’ among different genotypes and allele frequencies in groups with NAFLD and/or IR. In addition, there was an increase in risk for NAFLD and a decrease in risk for IR. In the homozygous group, also the prospect of IR was double declined. Patients with the A allele of this polymorphism showed a drop in risk for IR as well. GLP-1R polymorphisms could influence obesity and diabetes and thus the functional analysis of the GLP-1R polymorphisms is benevolent.
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16. Tokuyama Y, Matsui K, Egashira T, Nozaki O, Ishizuka T, Kanatsuka A. Five missense mutations in glucagon-like peptide 1 receptor gene in Japanese population. Diabetes Res Clin Pract 2004;66:63-9.
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25. De Luis DA, Pacheco D, Aller R, Izaola O. Role of the rs6923761 Gene Variant in Glucagon-Like Peptide 1 Receptor Gene on Cardiovascular Risk Factors and Weight Loss after Biliopancreatic Diversion Surgery. Ann Nutr Metab 2014;65:259-63.
26. Sathananthan A, Dalla Man C, Micheletto F, Zinsmeister AR, Camilleri M, Giesler PD, et al. Common genetic variation in GLP1R and insulin secretion in response to exogenous GLP-1 in nondiabetic subjects: a pilot study. Diabetes Care 2010;33:2074-6.
27. Mohammadzadeh R, Baradaran B, Valizadeh H, Yousefi B, Zakeri-Milani P. Reduced ABCB1 Expression and Activity in the Presence of Acrylic Copolymers. Adv Pharm Bull 2014;4:219-24.
28. Muhammad AB, Xing B, Liu C, Naji A, Ma X, Simmons RA, et al. Menin and PRMT5 suppress GLP1 receptor transcript and PKA-mediated phosphorylation of FOXO1 and CREB. Am J Physiol Endocrinol Metab 2017;313:E148-66.
29. Burmeister MA, Ayala JE, Smouse H, Landivar-Rocha A, Brown JD, Drucker DJ, et al. The Hypothalamic Glucagon-Like Peptide 1 Receptor Is Sufficient but Not Necessary for the Regulation of Energy Balance and Glucose Homeostasis in Mice. Diabetes 2017;66:372-84.
30. Ghosal S, Packard AEB, Mahbod P, McKlveen JM, Seeley RJ, Myers B, et al. Disruption of Glucagon-Like Peptide 1 Signaling in Sim1 Neurons Reduces Physiological and Behavioral Reactivity to Acute and Chronic Stress. J Neurosci 2017;37:184-93.
2. Spinelli A, Buoncristiano M, Kovacs VA, Yngve A, Spiroski I, Obreja G, et al. Prevalence of Severe Obesity among Primary School Children in 21 European Countries. Obes Facts 2019;12:244-58.
3. Choquet H, Meyre D. Genetics of Obesity: What have we Learned? Curr Genomics 2011;12:169-79.
4. Algoblan A, Alalfi M, Khan M. Mechanism linking diabetes mellitus and obesity. Diabetes Metab Syndr Obes 2014;7:587-91.
5. Sarwar R, Pierce N, Koppe S. Obesity and nonalcoholic fatty liver disease: current perspectives. Diabetes Metab Syndr Obes 2018;11:533-42.
6. DeFronzo RA, Ferrannini E, Groop L, Henry RR, Herman WH, Holst JJ, et al. Type 2 diabetes mellitus. Nat Nat Rev Dis Primers 2015;1:15019.
7. Benedict M, Zhang X. Non-alcoholic fatty liver disease: An expanded review. World J Hepatol 2017;9:715-32.
8. Manco M. Insulin Resistance and NAFLD: A Dangerous Liaison beyond the Genetics. Children (Basel) 2017;4:74.
9. Meloni AR, DeYoung MB, Lowe C, Parkes DG. GLP-1 receptor activated insulin secretion from pancreatic β-cells: mechanism and glucose dependence. Diabetes Obes Metab 2013;15:15-27.
10. Baggio LL, Drucker DJ. Biology of Incretins: GLP-1 and GIP. Gastroenterology 2007;132:2131-57.
11. Anderson SL, Trujillo JM, McDermott M, Saseen JJ. Determining predictors of response to exenatide in type 2 diabetes. J Am Pharm Assoc (2003) 2012;52:466-71.
12. Liu Y, Wei R, Hong TP. Potential roles of glucagon-like peptide-1-based therapies in treating non-alcoholic fatty liver disease. World J Gastroenterol 2014;20:9090-7.
13. Kalogirou M, Sinakos E. Treating nonalcoholic steatohepatitis with antidiabetic drugs: Will GLP-1 agonists end the struggle? World J Hepatol 2018;10:790-4.
14. Drucker DJ. Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1. Cell Metab 2018;27:740-56.
15. Koole C, Wootten D, Simms J, Valant C, Miller LJ, Christopoulos A, et al. Polymorphism and Ligand Dependent Changes in Human Glucagon-Like Peptide-1 Receptor (GLP-1R) Function: Allosteric Rescue of Loss of Function Mutation. Mol Pharmacol 2011;80:486-97.
16. Tokuyama Y, Matsui K, Egashira T, Nozaki O, Ishizuka T, Kanatsuka A. Five missense mutations in glucagon-like peptide 1 receptor gene in Japanese population. Diabetes Res Clin Pract 2004;66:63-9.
17. Cole TJ, Lobstein T. Extended international (IOTF) body mass index cut-offs for thinness, overweight and obesity. Pediatr Obes 2012;7:284-94.
18. Quinn S, Gosink B. Characteristic sonographic signs of hepatic fatty infiltration. AJR Am J Roentgenol 1985;145:753-5.
19. Tamhane AR, Westfall AO, Burkholder GA, Cutter GR. Prevalence odds ratio versus prevalence ratio: choice comes with consequences. Stat Med 2016;35:5730-5.
20. Iqbal U, Perumpail B, Akhtar D, Kim D, Ahmed A. The Epidemiology, Risk Profiling and Diagnostic Challenges of Nonalcoholic Fatty Liver Disease. Medicines (Basel) 2019;6:41.
21. Imai K, Tsujimoto T, Goto A, Goto M, Kishimoto M, Yamamoto-Honda R, et al. Prediction of response to GLP-1 receptor agonist therapy in Japanese patients with type 2 diabetes. Diabetol Metab Syndr 2014;6:110.
22. Mahgoub MO, Ali II, Adeghate JO, Tekes K, Kalász H, Adeghate EA. An Update on the Molecular and Cellular Basis of Pharmacotherapy in Type 2 Diabetes Mellitus. Int J Mol Sci 2023;24:9328.
23. Portha B, Tourrel-Cuzin C, Movassat J. Activation of the GLP-1 Receptor Signalling Pathway: A Relevant Strategy to Repair a Deficient Beta-Cell Mass. J Diabetes Res 2011;2011:376509.
24. Duart Duart MJ, Arroyo CO, Moreno Frígols JL. Validation of a Kinetic Model for the Reactions in RIA. Clin Chem Lab Med 2002;40:1161-7.
25. De Luis DA, Pacheco D, Aller R, Izaola O. Role of the rs6923761 Gene Variant in Glucagon-Like Peptide 1 Receptor Gene on Cardiovascular Risk Factors and Weight Loss after Biliopancreatic Diversion Surgery. Ann Nutr Metab 2014;65:259-63.
26. Sathananthan A, Dalla Man C, Micheletto F, Zinsmeister AR, Camilleri M, Giesler PD, et al. Common genetic variation in GLP1R and insulin secretion in response to exogenous GLP-1 in nondiabetic subjects: a pilot study. Diabetes Care 2010;33:2074-6.
27. Mohammadzadeh R, Baradaran B, Valizadeh H, Yousefi B, Zakeri-Milani P. Reduced ABCB1 Expression and Activity in the Presence of Acrylic Copolymers. Adv Pharm Bull 2014;4:219-24.
28. Muhammad AB, Xing B, Liu C, Naji A, Ma X, Simmons RA, et al. Menin and PRMT5 suppress GLP1 receptor transcript and PKA-mediated phosphorylation of FOXO1 and CREB. Am J Physiol Endocrinol Metab 2017;313:E148-66.
29. Burmeister MA, Ayala JE, Smouse H, Landivar-Rocha A, Brown JD, Drucker DJ, et al. The Hypothalamic Glucagon-Like Peptide 1 Receptor Is Sufficient but Not Necessary for the Regulation of Energy Balance and Glucose Homeostasis in Mice. Diabetes 2017;66:372-84.
30. Ghosal S, Packard AEB, Mahbod P, McKlveen JM, Seeley RJ, Myers B, et al. Disruption of Glucagon-Like Peptide 1 Signaling in Sim1 Neurons Reduces Physiological and Behavioral Reactivity to Acute and Chronic Stress. J Neurosci 2017;37:184-93.
| Files | ||
| Issue | Vol 61 No 4 (2023) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/acta.v61i4.13175 | |
| Keywords | ||
| Glucagon-like peptide-1 Glucagon-like peptide-1 (GLP-1) receptor Single-nucleotide polymorphism Obesity development | ||
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Maralani M, Cankaya T, Ataman E, Tokgoz Y, Kaytankas E, Arslan N, Baradaran B, Hajiasgharzadeh K, Ulgenalp A. Effects of GLP-1 Receptor Polymorphisms on Adolescent Obesity. Acta Med Iran. 2023;61(4):238-246.
