THE EFFECTS OF EXENATIDE TREATMENT ON METABOLIC PARAMETERS, GHRELIN, GDF-15 AND FGF-21 IN OBESE TYPE 2 DIABETIC PATIENTS

Abstract

Objective: Exenatide and similar drugs which have Glucagon Like Peptide-1(GLP-1) like effects have been used frequently in the treatment of diabetes and obesity in recent years. In this study we aimed to investigate the effects of exenatide on ghrelin, FGF-21 and GDF-15 which are known to be associated with appetite and metabolic disorders.

Material and Methods: Thirty patients with Type 2 Diabetes Mellitus with a Body Mass Index of 35 kg/m2 and above who are still ongoing treatment for diabetes but not on target (HbA1c>7%) and exenatide treatment was started were included in the study. Venous blood samples were collected for the measurements of complete blood count, biochemical parameters, HbA1c, ghrelin, FGF-21, GDF-15. After 3 months of treatment initial evaluations and biochemical tests were repeated.

Results: Mean age of the patients was 50.43±10.35 years. Twenty-one (70%) were female and 9 (30%) were male. Mean Hb A1c of the patients was 9.68±2.02%. After 3 months of exenatide treatment a significant decrease in body weight and body mass index was observed (p<0.001). There was also significant decrease in Ghrelin and GDF-15 levels (p<0.001).

Conclusion: Our study is the first study in which these three markers were evaluated together in obese type 2 diabetics. It is thought to be that Ghrelin, FGF-21 and GDF-15 are play role in obesity and type 2 diabetes mellitus pathogenesis together in different ways.

Keywords

• obesity
• exenatide
• ghrelin
• Fibroblast Growth Factor 21
• Growth Differentiation Factor 15

Obez Tip 2 Diyabetik Hastalarda Eksenatid Tedavisinin Metabolik Parametreler, Ghrelin, GDF-15 ve FGF-21 Üzerine Etkileri

Abstract

Amaç: Glukagon Benzeri Peptid-1(GLP-1) benzeri etkileri olan eksenatid ve benzeri ilaçlar son yıllarda diyabet ve obezite tedavisinde sıklıkla kullanılmaktadır. Bu çalışmada eksenatidin iştah ve metabolik bozukluklarla ilişkili olduğu bilinen hormonal özellikli peptidler olan ghrelin, FGF-21 ve GDF-15 üzerine etkilerini araştırmayı amaçladık.

Gereç ve Yöntemler: Tip 2 Diabetes Mellitus'lu, Vücut Kitle İndeksi 35 kg/m2 ve üzerinde olan, diyabet tedavisi devam eden ancak hedefte olmayan (Hb A1c>%7) ve eksenatid tedavisi başlanan 30 hasta çalışmaya dahil edildi. Tam kan sayımı, biyokimyasal parametreler, HbA1c, ghrelin, FGF-21, GDF-15 ölçümleri için venöz kan örnekleri alındı. 3 aylık tedaviden sonra ilk değerlendirmeler ve biyokimyasal testler tekrarlandı.

Bulgular: Hastaların yaş ortalaması 50.43±10.35 yıl olup; 21’i (%70) kadın, 9’u (%30) erkekti. Hastaların ortalama Hb A1c’si %9.68±2.02 idi. Eksenatid tedavisinden sonra vücut ağırlığında ve vücut kitle indeksinde önemli bir azalma gözlendi (p<0.001). Ghrelin ve GDF-15 düzeylerinde de anlamlı düşüş vardı (p<0.001).

Sonuç: Çalışmamız, obez tip 2 diyabetlilerde bu üç belirtecin birlikte değerlendirildiği ilk çalışmadır. Ghrelin, FGF-21 ve GDF-15'in obezite ve tip 2 diabetes mellitus patogenezinde birlikte farklı şekillerde rol oynadığı düşünülmektedir.

Keywords

• obezite
• eksenatid
• ghrelin
• Fibroblast Büyüme Faktörü 21
• Büyüme Farklılaşma Faktörü 15

References

1. 1. Kreymann B, Williams G, Ghatei MA, Bloom SR. Glucagon-like peptide-1 7-36: a physiological incretin in man. Lancet. 1987;2(8571):1300-4.
2. 2. Turton MD, O’Shea D, Gunn I, Beak SA, Edwards CM, Meeran K et al. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature. 1996:4;379(6560):69-72.
3. 3. Fakhoury WK, Lereun C, Wright D. A meta-analysis of placebo-controlled clinical trials assessing the efficacy and safety of incretin-based medications in patients with type 2 diabetes. Pharmacology. 2010;86(1):44-57.
4. 4. Guclu M, Kiyici S, Gul Z, Cavun S. Exenatide treatment causes suppression of serum fasting ghrelin levels in patients with type 2 diabetes mellitus. Endocr Connect. 2018;7(1):193-98.
5. 5. Hu Y, Liu J, Zhang H, Xu Y, Hong T, Wang G. Exenatide treatment decreases fasting fibroblast growth factor 21 levels in patients with newly diagnosed type 2 diabetes mellitus. Diabetes Metab. 2016;42(5):358-63.
6. 6. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402(6762):656-60.
7. 7. Van der Lely AJ, Tschop M, Heiman ML, Ghigo E. Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocr Rev. 2004;25(3):426-57.
8. 8. Broglio F, Arvat E, Benso A, Gottero C, Muccioli G, Papotti M et al. Ghrelin, a natural GH secretagogue produced by the stomach, induces hyperglycemia and reduces insulin secretion in humans. J Clin Endocrinol Metab. 2001;86(10):5083-6.

9. 9. Beenken A, Mohammadi M. The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov. 2009;8(3):235-53.
10. 10. Angelin B, Larsson TE, Rudling M. Circulating fibroblast growth factors as metabolic regulators--a critical appraisal. Cell Metab. 2012;16(6):693-705.
11. 11. Unsicker K, Spittau B, Krieglstein K. The multiple facets of the TGF-b family cytokine growth/differentiation factor-15/macrophage inhibitory cytokine-1. Cytokine Growth Factor Rev. 2013;24(4):373-84.
12. 12. Adela R, Banerjee SK. GDF-15 as a target and biomarker for diabetes and cardiovascular diseases: a translational prospective. J Diabetes Res. 2015;2015.490842.
13. 13. Kempf T, Guba-Quint A, Torgerson J, Magnone MC, Haefliger C, Bobadilla M et al. Growth differentiation factor 15 predicts future insulin resistance and impaired glucose control in obese nondiabetic individuals: results from the XENDOS trial. Eur J Endocrinol. 2012;167(5):671-8.
14. 14. Hong JH, Choi YK, Min BK, Park KS, Seong K, Lee IK et al. Relationship between hepcidin and GDF15 in anemic patients with type 2 diabetes without overt renal impairment. Diabetes Res Clin Pract. 2015;109(1):64-70.
15. 15. American Diabetes Association Standards of Medical Care in diabetes. Diabetes Care. 2020;43:48-65.
16. 16. Bhavsar S, Mudaliar S, Cherrington A. Evolution of exenatide as a diabetes therapeutic. Curr Diabetes Rev. 2013;9(2):161-93.
17. 17. Gagnon J, Zhu L, Anini Y, Wang Q. Neutralizing circulating ghrelin by expressing a growth hormone secretagogue receptor-based protein protects against high-fat diet-induced obesity in mice. Gene Ther. 2015;22(9):750-7.
18. 18. Alamri BN, Shin K, Chappe V, Anini Y. The role of ghrelin in the regulation of glucose homeostasis. Horm Mol Biol Clin Investig. 2016 ;26(1):3-11.
19. 19. Varela L, Vázquez MJ, Cordido F, Nogueiras R, Vidal-Puig A, Diéguez C, López M. Ghrelin and lipid metabolism: key partners in energy balance. J Mol Endocrinol. 2011;46(2):R43-63.
20. 20. Chavez AO, Molina-Carrion M, Abdul-Ghani MA, Folli F, Defronzo RA, Tripathy D. Circulating fibroblast growth factor-21 is elevated in impaired glucose tolerance and type 2 diabetes and correlates with muscle and hepatic insulin resistance. Diabetes Care. 2009;32(8):1542-6.
21. 21. Wente W, Efanov AM, Bfenner M, Kharitonenkov A, Köster A, Sandusky GE et al. Fibroblast growth factor-21 improves pancreatic beta-cell function and survival by activation of extracellular signal-regulated kinase 1/2 and Akt signaling pathways. Diabetes. 2006;55(9):2470-8.
22. 22. Yang M, Dong J, Liu H, Li L, Yang G. Effects of short-term continuous subcutaneous insulin infusion on fasting plasma fibroblast growth factor-21 levels in patients with newly diagnosed type 2 diabetes mellitus. PLoS ONE. 2011;6:e26359.
23. 23. Cheng X, Zhu B, Jiang F, Fan H. Serum FGF-21 levels in type 2 diabetic patients. Endocr Res. 2011;36(4):142-8.
24. 24. Dushay J, Chui PC, Gopalakrishnan GS, Varela-Rey M, Crawley M, Fisher FM et al. Increased fibroblast growth factor 21 in obesity and nonalcoholic fatty liver disease. Gastroenterology. 2010;139(2):456-63.
25. 25. Hanssen MJ, Broeders E, Samms RJ, Vosselman MJ, van der Lans AA, Cheng CC et al. Serum FGF21 levels are associated with brown adipose tissue activity in humans. Sci Rep. 2015;5:10275.
26. 26. Díaz-Delfín J, Hondares E, Iglesias R, Giralt M, Caelles C, Villarroya F et al. TNF represses Klotho expression and impairs FGF21 action in adipose cells: involvement of JNK1 in the FGF21 pathway. Endocrinology. 2012;153(9):4238-45.
27. 27. Khan SQ, Ng K, Dhillon O, Kelly D, Quinn P, Squire IB et al. Growth differentiation factor-15 as a prognostic marker in patients with acute myocardial infarction. Eur Heart J. 2009;30(9):1057-65.
28. 28. Vila G, Riedl M, Anderwald C, Resl M, Handisurya A, Clodi M et al. The relationship between insulin resistance and the cardiovascular biomarker growth differentiation factor-15 in obese patients. Clin Chem. 2011;57(2):309-16.
29. 29. Bao X, Borné Y, Muhammad IF, Nilsson J, Lind L, Melander O et al. Growth differentiation factor 15 is positively associated with incidence of diabetes mellitus: the Malmö Diet and Cancer-Cardiovascular Cohort. Diabetologia. 2019;62(1):78-86.
30. 30. Pavo N, Wurm R, Neuhold S, Adlbrecht C, Vila G, Strunk G et al. GDF-15 Is Associated with Cancer Incidence in Patients with Type 2 Diabetes. Clin Chem. 2016;62(12):1612-20.