Chonnam Med J.  2015 Dec;51(3):115-119. 10.4068/cmj.2015.51.3.115.

Circulating Betatrophin Levels Are Associated with the Lipid Profile in Type 2 Diabetes

• Ghasemi H
• Tavilani H
• Khodadadi
• Saidijam M
• Karimi J

• KMID: 2172127
• DOI: http://doi.org/10.4068/cmj.2015.51.3.115

Abstract

Betatrophin is a newly characterized circulating hormone that is produced in tissues such as adipose tissue and liver and stimulates pancreatic beta-cell proliferation. The purpose of the current study was to examine circulating betatrophin levels in Iranian patients with type 2 diabetes mellitus (T2DM) and in normal controls. Seventy-five subjects were enrolled in this case-control study in the following two groups: T2DM patients (n=40) and a group of age-, sex-, and BMI-matched normal control subjects (n=35). Circulating betatrophin concentrations as well as the blood lipid profile, body mass index (BMI), fasting blood sugar (FBS), glycated hemoglobin (HbA1c), and insulin resistance were determined. Circulating betatrophin levels were significantly higher in patients with T2DM than in the normal subjects (4.79+/-1.53 ng/mL vs. 2.79+/-1.11 ng/mL respectively; p=0.001). Serum triacylglycerol and total cholesterol were also significantly higher in patients with T2DM than in the control group. In the patients with T2DM, serum betatrophin was positively correlated with age, FBS, TG, total cholesterol, and HbA1c. The results of this initial study in Iran have shown that circulating betatrophin levels are significantly increased in Iranian patients with T2DM compared with a control group. Additionally, it is postulated that betatrophin as a novel hormone may be involved in the generation of an atherogenic lipid profile.

Keyword

Diabetes mellitus; Type 2; Insulin resistance; Human

MeSH Terms

Adipose Tissue
Blood Glucose
Body Mass Index
Case-Control Studies
Cholesterol
Diabetes Mellitus
Diabetes Mellitus, Type 2
Fasting
Hemoglobin A, Glycosylated
Humans
Insulin Resistance
Iran
Liver
Triglycerides
Blood Glucose
Cholesterol
Triglycerides

Figure

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  FIG. 1 Mean betatrophin levels in controls and in patients with type 2 diabetes mellitus (T2DM). Data are mean±SD. *p=0.001 versus control group.

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  FIG. 2 Correlation between betatrophin concentrations and (A) triacylglycerol (TG), (B) cholesterol, (C) fasting blood sugar (FBS), (D) glycated hemoglobin (HbA1c), and (E) age in patients with type 2 diabetes mellitus (T2DM). p values indicate statistical significance.

Reference

1. Tuomi T, Santoro N, Caprio S, Cai M, Weng J, Groop L. The many faces of diabetes: a disease with increasing heterogeneity. Lancet. 2014; 383:1084–1094.

2. Seymour PA, Serup P. Bulking up on beta cells. N Engl J Med. 2013; 369:777–779.

3. Yi P, Park JS, Melton DA. Betatrophin: a hormone that controls pancreatic β cell proliferation. Cell. 2013; 153:747–758.

4. Kulkarni RN, Mizrachi EB, Ocana AG, Stewart AF. Human β-cell proliferation and intracellular signaling: driving in the dark without a road map. Diabetes. 2012; 61:2205–2213.

5. El Ouaamari A, Kawamori D, Dirice E, Liew CW, Shadrach JL, Hu J, et al. Liver-derived systemic factors drive β cell hyperplasia in insulin-resistant states. Cell Rep. 2013; 3:401–410.

6. Lickert H. Betatrophin fuels β cell proliferation: first step toward regenerative therapy? Cell Metab. 2013; 18:5–6.

7. Kugelberg E. Diabetes: Betatrophin--inducing β-cell expansion to treat diabetes mellitus? Nat Rev Endocrinol. 2013; 9:379.

8. Gusarova V, Alexa CA, Na E, Stevis PE, Xin Y, Bonner-Weir S, et al. ANGPTL8/betatrophin does not control pancreatic beta cell expansion. Cell. 2014; 159:691–696.

9. Zhang R. Lipasin, a novel nutritionally-regulated liver-enriched factor that regulates serum triglyceride levels. Biochem Biophys Res Commun. 2012; 424:786–792.

10. Zhang R, Abou-Samra AB. Emerging roles of Lipasin as a critical lipid regulator. Biochem Biophys Res Commun. 2013; 432:401–405.

11. Wang Y, Quagliarini F, Gusarova V, Gromada J, Valenzuela DM, Cohen JC, et al. Mice lacking ANGPTL8 (Betatrophin) manifest disrupted triglyceride metabolism without impaired glucose homeostasis. Proc Natl Acad Sci U S A. 2013; 110:16109–16114.

12. Fenzl A, Itariu BK, Kosi L, Fritzer-Szekeres M, Kautzky-Willer A, Stulnig TM, et al. Circulating betatrophin correlates with atherogenic lipid profiles but not with glucose and insulin levels in insulin-resistant individuals. Diabetologia. 2014; 57:1204–1208.

13. Fu Z, Berhane F, Fite A, Seyoum B, Abou-Samra AB, Zhang R. Elevated circulating lipasin/betatrophin in human type 2 diabetes and obesity. Sci Rep. 2014; 4:5013.

14. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2010; 33:Suppl 1. S62–S69.

15. Katsuki A, Sumida Y, Gabazza EC, Murashima S, Furuta M, Araki-Sasaki R, et al. Homeostasis model assessment is a reliable indicator of insulin resistance during follow-up of patients with type 2 diabetes. Diabetes Care. 2001; 24:362–365.

16. Espes D, Martinell M, Carlsson PO. Increased circulating betatrophin concentrations in patients with type 2 diabetes. Int J Endocrinol. 2014; 2014:323407.

17. Hu H, Sun W, Yu S, Hong X, Qian W, Tang B, et al. Increased circulating levels of betatrophin in newly diagnosed type 2 diabetic patients. Diabetes Care. 2014; 37:2718–2722.

18. Espes D, Lau J, Carlsson PO. Increased circulating levels of betatrophin in individuals with long-standing type 1 diabetes. Diabetologia. 2014; 57:50–53.

19. Gokulakrishnan K, Manokaran K, Pandey GK, Amutha A, Ranjani H, Anjana RM, et al. Relationship of betatrophin with youth onset type 2 diabetes among Asian Indians. Diabetes Res Clin Pract. 2015; 109:71–76.

20. Gómez-Ambrosi J, Pascual E, Catalán V, Rodríguez A, Ramírez B, Silva C, et al. Circulating betatrophin concentrations are decreased in human obesity and type 2 diabetes. J Clin Endocrinol Metab. 2014; 99:E2004–E2009.

21. Uyeda K, Repa JJ. Carbohydrate response element binding protein, ChREBP, a transcription factor coupling hepatic glucose utilization and lipid synthesis. Cell Metab. 2006; 4:107–110.

22. Filhoulaud G, Guilmeau S, Dentin R, Girard J, Postic C. Novel insights into ChREBP regulation and function. Trends Endocrinol Metab. 2013; 24:257–268.

23. Jeong YS, Kim D, Lee YS, Kim HJ, Han JY, Im SS, et al. Integrated expression profiling and genome-wide analysis of ChREBP targets reveals the dual role for ChREBP in glucose-regulated gene expression. PLoS One. 2011; 6:e22544.

24. Saisho Y, Butler AE, Manesso E, Elashoff D, Rizza RA, Butler PC. β-cell mass and turnover in humans: effects of obesity and aging. Diabetes Care. 2013; 36:111–117.

25. Fu Z, Yao F, Abou-Samra AB, Zhang R. Lipasin, thermoregulated in brown fat, is a novel but atypical member of the angiopoietin-like protein family. Biochem Biophys Res Commun. 2013; 430:1126–1131.

26. Yamada H, Saito T, Aoki A, Asano T, Yoshida M, Ikoma A, et al. Circulating betatrophin is elevated in patients with type 1 and type 2 diabetes. Endocr J. 2015; 62:417–421.