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Genetic variability in GLP-1 receptor is associated with inter-individual differences in weight lowering potential of liraglutide in obese women with PCOS: a pilot study

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Abstract

Purpose

The weight lowering potential of glucagon-like peptide 1 (GLP-1) receptor agonists (RAs) is inter-individually different and clinically unpredictable. The potential role of genetic variability of GLP-1R on body weight response to GLP-1 RAs in obese women with polycystic ovary syndrome (PCOS) has not yet been evaluated.

Methods

Fifty-seven obese women with PCOS (aged 30.7 ± 7.0, BMI 38.6 ± 5.3 kg/m2) were assigned to liraglutide 1.2 mg QD s.c. for 12 weeks and classified as strong responders regarding weight loss if they lost 5 % or more of their initial body weight. They were genotyped for common GLP-1R single nucleotide polymorphisms (SNPs) rs6923761 and rs10305420. Changes of measures of obesity were measured before and at the end of the treatment.

Results

Twenty out of 57 subjects were strong responders and lost 7.38 ± 1.74 compared to 2.11 ± 2.17 kg lost in poor responders. Carriers of at least one polymorphic rs10305420 allele had poor treatment response compared to carriers of two wild type alleles (OR = 0.27, 95 % CI = 0.09–0.85, P = 0.025). Carriers of at least one polymorphic rs6923761 allele tended to have stronger treatment response compared to carriers of two wild type alleles (OR = 3.06, 95 % CI = 0.96–9.74, P = 0.058). Fasting glucose and glucose after oral glucose tolerance test (OGTT) comparably decreased in both groups when compared to baseline, whereas no within treatment differences were found in androgen profile. Gastrointestinal adverse events were transit and balanced between strong and poor responders.

Conclusions

GLP-1R rs10305420 polymorphism explained some of the inter-individual differences in response to liraglutide regarding weight loss in obese PCOS women.

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References

  1. Astrup A, Carraro R, Finer N, Harper A, Kunesova M, Lean ME, Niskanen L, Rasmussen MF, Rissanen A, Rossner S, Savolainen MJ, Van Gaal L (2012) Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide. Int J Obes (Lond) 36(6):843–854. doi:10.1038/ijo.2011.158

    Article  CAS  Google Scholar 

  2. Vilsboll T, Christensen M, Junker AE, Knop FK, Gluud LL (2012) Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials. BMJ 344:d7771. doi:10.1136/bmj.d7771

    Article  PubMed Central  PubMed  Google Scholar 

  3. Meier JJ (2012) GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol 8(12):728–742. doi:10.1038/nrendo.2012.140

    Article  CAS  PubMed  Google Scholar 

  4. Dailey MJ, Moran TH (2013) Glucagon-like peptide 1 and appetite. Trends Endocrinol Metab: TEM 24(2):85–91. doi:10.1016/j.tem.2012.11.008

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Skibicka KP (2013) The central GLP-1: implications for food and drug reward. Front Neurosci 7:181. doi:10.3389/fnins.2013.00181

    Article  PubMed Central  PubMed  Google Scholar 

  6. van Bloemendaal L, Ten Kulve JS, la Fleur SE, Ijzerman RG, Diamant M (2014) Effects of glucagon-like peptide 1 on appetite and body weight: focus on the CNS. J Endocrinol 221(1):T1–T16. doi:10.1530/JOE-13-0414

    Article  PubMed  Google Scholar 

  7. Lim SS, Davies MJ, Norman RJ, Moran LJ (2012) Overweight, obesity and central obesity in women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update 18(6):618–637. doi:10.1093/humupd/dms030

    Article  CAS  PubMed  Google Scholar 

  8. Elkind-Hirsch K, Marrioneaux O, Bhushan M, Vernor D, Bhushan R (2008) Comparison of single and combined treatment with exenatide and metformin on menstrual cyclicity in overweight women with polycystic ovary syndrome. J Clin Endocrinol Metab 93(7):2670–2678. doi:10.1210/jc.2008-0115

    Article  CAS  PubMed  Google Scholar 

  9. Kahal H, Abouda G, Rigby AS, Coady AM, Kilpatrick ES, Atkin SL (2014) Glucagon-like peptide-1 analogue, liraglutide, improves liver fibrosis markers in obese women with polycystic ovary syndrome and nonalcoholic fatty liver disease. Clin Endocrinol 81(4):523–528. doi:10.1111/cen.12369

    Article  CAS  Google Scholar 

  10. Jensterle M, Kocjan T, Kravos NA, Pfeifer M, Janez A (2014) Short-term intervention with liraglutide improved eating behavior in obese women with polycystic ovary syndrome. Endocr Res: 1–6 doi:10.3109/07435800.2014.966385

  11. Jensterle Sever M, Kocjan T, Pfeifer M, Kravos NA, Janez A (2014) Short-term combined treatment with liraglutide and metformin leads to significant weight loss in obese women with polycystic ovary syndrome and previous poor response to metformin. Eur J Endocrinol/Eur Fed Endocr Soc 170(3):451–459. doi:10.1530/EJE-13-0797

    Article  Google Scholar 

  12. Niswender K, Pi-Sunyer X, Buse J, Jensen KH, Toft AD, Russell-Jones D, Zinman B (2013) Weight change with liraglutide and comparator therapies: an analysis of seven phase 3 trials from the liraglutide diabetes development programme. Diabetes, Obes Metab 15(1):42–54. doi:10.1111/j.1463-1326.2012.01673.x

    Article  CAS  Google Scholar 

  13. Sathananthan A, Man CD, Micheletto F, Zinsmeister AR, Camilleri M, Giesler PD, Laugen JM, Toffolo G, Rizza RA, Cobelli C, Vella A (2010) Common genetic variation in GLP1R and insulin secretion in response to exogenous GLP-1 in nondiabetic subjects: a pilot study. Diabetes Care 33(9):2074–2076. doi:10.2337/dc10-0200

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. de Luis DA, Pacheco D, Aller R, Izaola O (2014) 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 65(4):259–263. doi:10.1159/000365975

    Article  PubMed  Google Scholar 

  15. Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM, Sirotkin K (2001) dbSNP: the NCBI database of genetic variation. Nucleic Acids Res 29(1):308–311

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Zawadzki JK, Dunaif A (1992) Diagnostic criteria for polycystic ovary syndrome. In: Dunaif A, Haseltine F, Merriam GR (eds) Polycystic ovary syndromeed. Blackwell Scientific Publications, Boston, pp 377–384

    Google Scholar 

  17. Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne-Parikka P, Keinanen-Kiukaanniemi S, Laakso M, Louheranta A, Rastas M, Salminen V, Uusitupa M, Finnish Diabetes Prevention Study G (2001) Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 344(18):1343–1350

    Article  CAS  PubMed  Google Scholar 

  18. McCarthy JJ, Hilfiker R (2000) The use of single-nucleotide polymorphism maps in pharmacogenomics. Nat Biotechnol 18(5):505–508. doi:10.1038/75360

    Article  CAS  PubMed  Google Scholar 

  19. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28(7):412–419

    Article  CAS  PubMed  Google Scholar 

  20. Tregouet DA, Garelle V (2007) A new JAVA interface implementation of THESIAS: testing haplotype effects in association studies. Bioinformatics 23(8):1038–1039. doi:10.1093/bioinformatics/btm058

    Article  CAS  PubMed  Google Scholar 

  21. Erculj N, Kovac V, Hmeljak J, Franko A, Dodic-Fikfak M, Dolzan V (2012) The influence of gemcitabine pathway polymorphisms on treatment outcome in patients with malignant mesothelioma. Pharmacogenet Genomics 22(1):58–68. doi:10.1097/FPC.0b013e32834e3572

    Article  CAS  PubMed  Google Scholar 

  22. Rasmussen CB, Lindenberg S (2014) The effect of liraglutide on weight loss in women with polycystic ovary syndrome: an observational study. Front Endocrinol 5:140. doi:10.3389/fendo.2014.00140

    Article  Google Scholar 

  23. Lean ME, Carraro R, Finer N, Hartvig H, Lindegaard ML, Rossner S, Van Gaal L, Astrup A (2014) Tolerability of nausea and vomiting and associations with weight loss in a randomized trial of liraglutide in obese, non-diabetic adults. Int J Obes (Lond) 38(5):689–697. doi:10.1038/ijo.2013.149

    Article  CAS  Google Scholar 

  24. Imai K, Tsujimoto T, Goto A, Goto M, Kishimoto M, Yamamoto-Honda R, Noto H, Kajio H, Noda M (2014) Prediction of response to GLP-1 receptor agonist therapy in Japanese patients with type 2 diabetes. Diabetol Metab Syndr 6(1):110. doi:10.1186/1758-5996-6-110

    Article  PubMed Central  PubMed  Google Scholar 

  25. Koole C, Savage EE, Christopoulos A, Miller LJ, Sexton PM, Wootten D (2013) Minireview: signal bias, allosterism, and polymorphic variation at the GLP-1R: implications for drug discovery. Mol Endocrinol 27(8):1234–1244. doi:10.1210/me.2013-1116

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Donnelly D (2012) The structure and function of the glucagon-like peptide-1 receptor and its ligands. Br J Pharmacol 166(1):27–41. doi:10.1111/j.1476-5381.2011.01687.x

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. UniProt: a hub for protein information (2015) Nucleic Acids Res 43(Database issue):D204–D212. doi:10.1093/nar/gku989

    Google Scholar 

  28. Cunningham F, Amode MR, Barrell D, Beal K, Billis K, Brent S, Carvalho-Silva D, Clapham P, Coates G, Fitzgerald S, Gil L, Giron CG, Gordon L, Hourlier T, Hunt SE, Janacek SH, Johnson N, Juettemann T, Kahari AK, Keenan S, Martin FJ, Maurel T, McLaren W, Murphy DN, Nag R, Overduin B, Parker A, Patricio M, Perry E, Pignatelli M, Riat HS, Sheppard D, Taylor K, Thormann A, Vullo A, Wilder SP, Zadissa A, Aken BL, Birney E, Harrow J, Kinsella R, Muffato M, Ruffier M, Searle SM, Spudich G, Trevanion SJ, Yates A, Zerbino DR, Flicek P (2015) Ensembl 2015. Nucleic Acids Res 43(Database issue):D662–D669. doi:10.1093/nar/gku1010

    Article  PubMed Central  PubMed  Google Scholar 

  29. Dezelak M, Bavec A (2011) Third intracellular loop of glucagon like-peptide-1 receptor is coupled with endogenous mono-ADP-ribosyltransferase - novel type of receptor regulation? Eur J Pharmacol 666(1–3):35–42. doi:10.1016/j.ejphar.2011.05.033

    Article  CAS  PubMed  Google Scholar 

  30. Mathi SK, Chan Y, Li X, Wheeler MB (1997) Scanning of the glucagon-like peptide-1 receptor localizes G protein-activating determinants primarily to the N terminus of the third intracellular loop. Mol Endocrinol 11(4):424–432. doi:10.1210/mend.11.4.9913

    Article  CAS  PubMed  Google Scholar 

  31. Bavec A, Hallbrink M, Langel U, Zorko M (2003) Different role of intracellular loops of glucagon-like peptide-1 receptor in G-protein coupling. Regul Pept 111(1–3):137–144

    Article  CAS  PubMed  Google Scholar 

  32. de Luis DA, Aller R, Izaola O, Bachiller R (2014) Role of rs6923761 gene variant in glucagon-like peptide 1 receptor in basal GLP-1 levels, cardiovascular risk factor and serum adipokine levels in naive type 2 diabetic patients. J Endocrinol Investig. doi:10.1007/s40618-014-0161-y

    Google Scholar 

  33. Vidan-Jeras B, Jurca B, Dolzan V, Jeras M, Breskvar K, Bohinjec M (1998) Slovenian Caucasian normal. In: Gjertson D, Terasaki P (eds) HLA 1998ed. American society for histocompatibility and immunogenetics, Lenexa, pp180–181

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Conflict of interest

The authors declare that they have no competing interests.

Funding

This study was supported by the grant number 20120047 of the University Medical Centre Ljubljana, Slovenia and by the Slovenian Research Agency (ARRS Grant No.P1-0170).

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Authors and Affiliations

  1. Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, Zaloska 7, 1525, Ljubljana, Slovenia

    Mojca Jensterle & Andrej Janež

  2. Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia

    Boštjan Pirš, Katja Goričar & Vita Dolžan

Authors
  1. Mojca Jensterle
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  2. Boštjan Pirš
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  4. Vita Dolžan
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  5. Andrej Janež
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Correspondence to Andrej Janež.

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Jensterle, M., Pirš, B., Goričar, K. et al. Genetic variability in GLP-1 receptor is associated with inter-individual differences in weight lowering potential of liraglutide in obese women with PCOS: a pilot study. Eur J Clin Pharmacol 71, 817–824 (2015). https://doi.org/10.1007/s00228-015-1868-1

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  • DOI: https://doi.org/10.1007/s00228-015-1868-1

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