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Published in: Cardiovascular Diabetology 1/2016

Open Access 01-12-2016 | Original investigation

Circulating angiopoietin-like protein 8 (ANGPTL8) and ANGPTL3 concentrations in relation to anthropometric and metabolic profiles in Korean children: a prospective cohort study

Authors: Hye Soo Chung, Min Jung Lee, Soon Young Hwang, Hyun Jung Lee, Hye Jin Yoo, Ji-A Seo, Sin Gon Kim, Nan Hee Kim, Sei Hyun Baik, Dong Seop Choi, Seon Mi Kim, Kyung Mook Choi

Published in: Cardiovascular Diabetology | Issue 1/2016

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Abstract

Background

Previous studies have shown that angiopoietin-like protein 8 (ANGPTL8), also called as betatrophin, acts together with ANGPTL3 to regulate lipid metabolism, glucose metabolism, and energy homeostasis. Moreover, ANGPTL8 promotes proliferation of pancreatic β-cells and induces insulin secretion. However, there are no previous longitudinal studies in humans.

Methods

We analyzed the age- and sex-matched data of 240 normal weight and overweight Korean children from the Korean Metabolic disorders and Obesity Study in Elementary School children (K-MOSES), a prospective observational cohort study.

Results

At baseline, ANGPTL8 concentrations were positively associated with triglycerides (TG) (r = 0.168, P = 0.010), whereas ANGPTL3 levels were associated with fasting insulin (r = 0.248, P < 0.001) and the homeostasis model assessment of insulin resistance (HOMA-IR) (r = 0.197, P = 0.002). Although both ANGPTL8 and ANGPTL3 levels did not differ between children with normal weight and children with overweight, ANGPTL8 levels were increased in males compared to females (341.2 [267.4–436.5] vs. 270.2 [213.9–378.8] pg/ml, P = 0.001). In particular, there was no significant inter-relationship between circulating ANGPTL8 and ANGPTL3 concentrations in Korean boys and girls (r = −0.073, P = 0.265). Multivariate analysis showed that baseline ANGPTL8 concentrations were independently associated with future changes of serum TG levels in Korean children after adjusting for confounding factors after a 3 year follow-up period (r = −0.165, P = 0.016).

Conclusions

This longitudinal study demonstrated for the first time that baseline ANGPTL8 levels were associated with baseline and future changes in TG levels in Korean children.
Literature
2.
go back to reference Zhu JZ, Yu CH, Li YM. Betatrophin provides a new insight into diabetes treatment and lipid metabolism (review). Biomed Rep. 2014;2:447–51.PubMedPubMedCentral Zhu JZ, Yu CH, Li YM. Betatrophin provides a new insight into diabetes treatment and lipid metabolism (review). Biomed Rep. 2014;2:447–51.PubMedPubMedCentral
3.
go back to reference Zhang R. Lipasin, a novel nutritionally-regulated liver-enriched factor that regulates serum triglyceride levels. Biochem Biophys Res Commun. 2012;424:786–92.CrossRefPubMed Zhang R. Lipasin, a novel nutritionally-regulated liver-enriched factor that regulates serum triglyceride levels. Biochem Biophys Res Commun. 2012;424:786–92.CrossRefPubMed
4.
go back to reference Ren G, Kim JY, Smas CM. Identification of RIFL, a novel adipocyte-enriched insulin target gene with a role in lipid metabolism. Am J Physiol Endocrinol Metab. 2012;303:E334–51.CrossRefPubMedPubMedCentral Ren G, Kim JY, Smas CM. Identification of RIFL, a novel adipocyte-enriched insulin target gene with a role in lipid metabolism. Am J Physiol Endocrinol Metab. 2012;303:E334–51.CrossRefPubMedPubMedCentral
5.
go back to reference Espes D, Lau J, Carlsson PO. Increased circulating levels of betatrophin in individuals with long-standing type 1 diabetes. Diabetologia. 2014;57:50–3.CrossRefPubMedPubMedCentral Espes D, Lau J, Carlsson PO. Increased circulating levels of betatrophin in individuals with long-standing type 1 diabetes. Diabetologia. 2014;57:50–3.CrossRefPubMedPubMedCentral
6.
go back to reference Hu H, Sun W, Yu S, Hong X, Qian W, Tang B, Wang D, Yang L, Wang J, Mao C, et al. Increased circulating levels of betatrophin in newly diagnosed type 2 diabetic patients. Diabetes Care. 2014;37:2718–22.CrossRefPubMed Hu H, Sun W, Yu S, Hong X, Qian W, Tang B, Wang D, Yang L, Wang J, Mao C, et al. Increased circulating levels of betatrophin in newly diagnosed type 2 diabetic patients. Diabetes Care. 2014;37:2718–22.CrossRefPubMed
7.
go back to reference Gusarova V, Alexa CA, Na E, Stevis PE, Xin Y, Bonner-Weir S, Cohen JC, Hobbs HH, Murphy AJ, Yancopoulos GD, Gromada J. ANGPTL8/betatrophin does not control pancreatic beta cell expansion. Cell. 2014;159:691–6.CrossRefPubMedPubMedCentral Gusarova V, Alexa CA, Na E, Stevis PE, Xin Y, Bonner-Weir S, Cohen JC, Hobbs HH, Murphy AJ, Yancopoulos GD, Gromada J. ANGPTL8/betatrophin does not control pancreatic beta cell expansion. Cell. 2014;159:691–6.CrossRefPubMedPubMedCentral
8.
go back to reference Santulli G. Angiopoietin-like proteins: a comprehensive look. Front Endocrinol (Lausanne). 2014;5:4. Santulli G. Angiopoietin-like proteins: a comprehensive look. Front Endocrinol (Lausanne). 2014;5:4.
9.
go back to reference Quagliarini F, Wang Y, Kozlitina J, Grishin NV, Hyde R, Boerwinkle E, Valenzuela DM, Murphy AJ, Cohen JC, Hobbs HH. Atypical angiopoietin-like protein that regulates ANGPTL3. Proc Natl Acad Sci USA. 2012;109:19751–6.CrossRefPubMedPubMedCentral Quagliarini F, Wang Y, Kozlitina J, Grishin NV, Hyde R, Boerwinkle E, Valenzuela DM, Murphy AJ, Cohen JC, Hobbs HH. Atypical angiopoietin-like protein that regulates ANGPTL3. Proc Natl Acad Sci USA. 2012;109:19751–6.CrossRefPubMedPubMedCentral
10.
go back to reference Zhang R, Abou-Samra AB. A dual role of lipasin (betatrophin) in lipid metabolism and glucose homeostasis: consensus and controversy. Cardiovasc Diabetol. 2014;13:133.CrossRefPubMedPubMedCentral Zhang R, Abou-Samra AB. A dual role of lipasin (betatrophin) in lipid metabolism and glucose homeostasis: consensus and controversy. Cardiovasc Diabetol. 2014;13:133.CrossRefPubMedPubMedCentral
11.
go back to reference Choi KM, Yannakoulia M, Park MS, Cho GJ, Kim JH, Lee SH, Hwang TG, Yang SJ, Kim TN, Yoo HJ, et al. Serum adipocyte fatty acid-binding protein, retinol-binding protein 4, and adiponectin concentrations in relation to the development of the metabolic syndrome in Korean boys: a 3 year prospective cohort study. Am J Clin Nutr. 2011;93:19–26.CrossRefPubMedPubMedCentral Choi KM, Yannakoulia M, Park MS, Cho GJ, Kim JH, Lee SH, Hwang TG, Yang SJ, Kim TN, Yoo HJ, et al. Serum adipocyte fatty acid-binding protein, retinol-binding protein 4, and adiponectin concentrations in relation to the development of the metabolic syndrome in Korean boys: a 3 year prospective cohort study. Am J Clin Nutr. 2011;93:19–26.CrossRefPubMedPubMedCentral
12.
go back to reference Lee SH, Kim SM, Park HS, Choi KM, Cho GJ, Ko BJ, Kim JH. Serum 25-hydroxyvitamin D levels, obesity and the metabolic syndrome among Korean children. Nutr Metab Cardiovasc Dis. 2013;23:785–91.CrossRefPubMed Lee SH, Kim SM, Park HS, Choi KM, Cho GJ, Ko BJ, Kim JH. Serum 25-hydroxyvitamin D levels, obesity and the metabolic syndrome among Korean children. Nutr Metab Cardiovasc Dis. 2013;23:785–91.CrossRefPubMed
13.
go back to reference Committe on Health and Statistics. Korean physical growth standards for children and adolescents. Seoul: Korean Pediatric Society; 2007. Committe on Health and Statistics. Korean physical growth standards for children and adolescents. Seoul: Korean Pediatric Society; 2007.
14.
go back to reference Taylor SJ, Whincup PH, Hindmarsh PC, Lampe F, Odoki K, Cook DG. Performance of a new pubertal self-assessment questionnaire: a preliminary study. Paediatr Perinat Epidemiol. 2001;15:88–94.CrossRefPubMed Taylor SJ, Whincup PH, Hindmarsh PC, Lampe F, Odoki K, Cook DG. Performance of a new pubertal self-assessment questionnaire: a preliminary study. Paediatr Perinat Epidemiol. 2001;15:88–94.CrossRefPubMed
15.
go back to reference Mattijssen F, Kersten S. Regulation of triglyceride metabolism by Angiopoietin-like proteins. Biochim Biophys Acta. 2012;1821:782–9.CrossRefPubMed Mattijssen F, Kersten S. Regulation of triglyceride metabolism by Angiopoietin-like proteins. Biochim Biophys Acta. 2012;1821:782–9.CrossRefPubMed
16.
go back to reference Jung CH, Lee WJ, Lee MJ, Kang YM, Jang JE, Leem J, La Lee Y, Seol SM, Yoon HK, Park JY. Association of serum angiopoietin-like protein 2 with carotid intima-media thickness in subjects with type 2 diabetes. Cardiovasc Diabetol. 2015;14:35.CrossRefPubMedPubMedCentral Jung CH, Lee WJ, Lee MJ, Kang YM, Jang JE, Leem J, La Lee Y, Seol SM, Yoon HK, Park JY. Association of serum angiopoietin-like protein 2 with carotid intima-media thickness in subjects with type 2 diabetes. Cardiovasc Diabetol. 2015;14:35.CrossRefPubMedPubMedCentral
17.
go back to reference Nidhina Haridas PA, Soronen J, Sadevirta S, Mysore R, Quagliarini F, Pasternack A, Metso J, Perttila J, Leivonen M, Smas CM, et al. Regulation of angiopoietin-like proteins (ANGPTLs) 3 and 8 by insulin. J Clin Endocrinol Metab. 2015;100:E1299–307.CrossRefPubMed Nidhina Haridas PA, Soronen J, Sadevirta S, Mysore R, Quagliarini F, Pasternack A, Metso J, Perttila J, Leivonen M, Smas CM, et al. Regulation of angiopoietin-like proteins (ANGPTLs) 3 and 8 by insulin. J Clin Endocrinol Metab. 2015;100:E1299–307.CrossRefPubMed
18.
go back to reference Chen X, Lu P, He W, Zhang J, Liu L, Yang Y, Liu Z, Xie J, Shao S, Du T, et al. Circulating betatrophin levels are increased in patients with type 2 diabetes and associated with insulin resistance. J Clin Endocrinol Metab. 2015;100:E96–100.CrossRefPubMed Chen X, Lu P, He W, Zhang J, Liu L, Yang Y, Liu Z, Xie J, Shao S, Du T, et al. Circulating betatrophin levels are increased in patients with type 2 diabetes and associated with insulin resistance. J Clin Endocrinol Metab. 2015;100:E96–100.CrossRefPubMed
19.
go back to reference Ebert T, Kralisch S, Hoffmann A, Bachmann A, Lossner U, Kratzsch J, Bluher M, Stumvoll M, Tonjes A, Fasshauer M. Circulating angiopoietin-like protein 8 is independently associated with fasting plasma glucose and type 2 diabetes mellitus. J Clin Endocrinol Metab. 2014;99:E2510–7.CrossRefPubMed Ebert T, Kralisch S, Hoffmann A, Bachmann A, Lossner U, Kratzsch J, Bluher M, Stumvoll M, Tonjes A, Fasshauer M. Circulating angiopoietin-like protein 8 is independently associated with fasting plasma glucose and type 2 diabetes mellitus. J Clin Endocrinol Metab. 2014;99:E2510–7.CrossRefPubMed
20.
go back to reference Abu-Farha M, Abubaker J, Noronha F, Al-Khairi I, Cherian P, Alarouj M, Bennakhi A, Elkum N. Lack of associations between betatrophin/ANGPTL8 level and C-peptide in type 2 diabetic subjects. Cardiovasc Diabetol. 2015;14:112.CrossRefPubMedPubMedCentral Abu-Farha M, Abubaker J, Noronha F, Al-Khairi I, Cherian P, Alarouj M, Bennakhi A, Elkum N. Lack of associations between betatrophin/ANGPTL8 level and C-peptide in type 2 diabetic subjects. Cardiovasc Diabetol. 2015;14:112.CrossRefPubMedPubMedCentral
21.
go back to reference Gao T, Jin K, Chen P, Jin H, Yang L, Xie X, Yang M, Hu C, Yu X. Circulating betatrophin correlates with triglycerides and postprandial glucose among different glucose tolerance statuses—a case-control study. PLoS One. 2015;10:e0133640.CrossRefPubMedPubMedCentral Gao T, Jin K, Chen P, Jin H, Yang L, Xie X, Yang M, Hu C, Yu X. Circulating betatrophin correlates with triglycerides and postprandial glucose among different glucose tolerance statuses—a case-control study. PLoS One. 2015;10:e0133640.CrossRefPubMedPubMedCentral
22.
go back to reference Gokulakrishnan K, Manokaran K, Pandey GK, Amutha A, Ranjani H, Anjana RM, Mohan V. Relationship of betatrophin with youth onset type 2 diabetes among Asian Indians. Diabetes Res Clin Pract. 2015;109:71–6.CrossRefPubMed Gokulakrishnan K, Manokaran K, Pandey GK, Amutha A, Ranjani H, Anjana RM, Mohan V. Relationship of betatrophin with youth onset type 2 diabetes among Asian Indians. Diabetes Res Clin Pract. 2015;109:71–6.CrossRefPubMed
23.
go back to reference Gomez-Ambrosi J, Pascual E, Catalan V, Rodriguez A, Ramirez B, Silva C, Gil MJ, Salvador J, Fruhbeck G. Circulating betatrophin concentrations are decreased in human obesity and type 2 diabetes. J Clin Endocrinol Metab. 2014;99:E2004–9.CrossRefPubMed Gomez-Ambrosi J, Pascual E, Catalan V, Rodriguez A, Ramirez B, Silva C, Gil MJ, Salvador J, Fruhbeck G. Circulating betatrophin concentrations are decreased in human obesity and type 2 diabetes. J Clin Endocrinol Metab. 2014;99:E2004–9.CrossRefPubMed
24.
go back to reference Fenzl A, Itariu BK, Kosi L, Fritzer-Szekeres M, Kautzky-Willer A, Stulnig TM, Kiefer FW. Circulating betatrophin correlates with atherogenic lipid profiles but not with glucose and insulin levels in insulin-resistant individuals. Diabetologia. 2014;57:1204–8.CrossRefPubMed Fenzl A, Itariu BK, Kosi L, Fritzer-Szekeres M, Kautzky-Willer A, Stulnig TM, Kiefer FW. Circulating betatrophin correlates with atherogenic lipid profiles but not with glucose and insulin levels in insulin-resistant individuals. Diabetologia. 2014;57:1204–8.CrossRefPubMed
25.
go back to reference Wang Y, Quagliarini F, Gusarova V, Gromada J, Valenzuela DM, Cohen JC, Hobbs HH. Mice lacking ANGPTL8 (betatrophin) manifest disrupted triglyceride metabolism without impaired glucose homeostasis. Proc Natl Acad Sci USA. 2013;110:16109–14.CrossRefPubMedPubMedCentral Wang Y, Quagliarini F, Gusarova V, Gromada J, Valenzuela DM, Cohen JC, Hobbs HH. Mice lacking ANGPTL8 (betatrophin) manifest disrupted triglyceride metabolism without impaired glucose homeostasis. Proc Natl Acad Sci USA. 2013;110:16109–14.CrossRefPubMedPubMedCentral
26.
go back to reference Koishi R, Ando Y, Ono M, Shimamura M, Yasumo H, Fujiwara T, Horikoshi H, Furukawa H. Angptl3 regulates lipid metabolism in mice. Nat Genet. 2002;30:151–7.CrossRefPubMed Koishi R, Ando Y, Ono M, Shimamura M, Yasumo H, Fujiwara T, Horikoshi H, Furukawa H. Angptl3 regulates lipid metabolism in mice. Nat Genet. 2002;30:151–7.CrossRefPubMed
27.
go back to reference Shimizugawa T, Ono M, Shimamura M, Yoshida K, Ando Y, Koishi R, Ueda K, Inaba T, Minekura H, Kohama T, Furukawa H. ANGPTL3 decreases very low density lipoprotein triglyceride clearance by inhibition of lipoprotein lipase. J Biol Chem. 2002;277:33742–8.CrossRefPubMed Shimizugawa T, Ono M, Shimamura M, Yoshida K, Ando Y, Koishi R, Ueda K, Inaba T, Minekura H, Kohama T, Furukawa H. ANGPTL3 decreases very low density lipoprotein triglyceride clearance by inhibition of lipoprotein lipase. J Biol Chem. 2002;277:33742–8.CrossRefPubMed
28.
go back to reference Shimamura M, Matsuda M, Kobayashi S, Ando Y, Ono M, Koishi R, Furukawa H, Makishima M, Shimomura I. Angiopoietin-like protein 3, a hepatic secretory factor, activates lipolysis in adipocytes. Biochem Biophys Res Commun. 2003;301:604–9.CrossRefPubMed Shimamura M, Matsuda M, Kobayashi S, Ando Y, Ono M, Koishi R, Furukawa H, Makishima M, Shimomura I. Angiopoietin-like protein 3, a hepatic secretory factor, activates lipolysis in adipocytes. Biochem Biophys Res Commun. 2003;301:604–9.CrossRefPubMed
29.
go back to reference Shimamura M, Matsuda M, Yasumo H, Okazaki M, Fujimoto K, Kono K, Shimizugawa T, Ando Y, Koishi R, Kohama T, et al. Angiopoietin-like protein3 regulates plasma HDL cholesterol through suppression of endothelial lipase. Arterioscler Thromb Vasc Biol. 2007;27:366–72.CrossRefPubMed Shimamura M, Matsuda M, Yasumo H, Okazaki M, Fujimoto K, Kono K, Shimizugawa T, Ando Y, Koishi R, Kohama T, et al. Angiopoietin-like protein3 regulates plasma HDL cholesterol through suppression of endothelial lipase. Arterioscler Thromb Vasc Biol. 2007;27:366–72.CrossRefPubMed
30.
go back to reference Robciuc MR, Maranghi M, Lahikainen A, Rader D, Bensadoun A, Oorni K, Metso J, Minicocci I, Ciociola E, Ceci F, et al. Angptl3 deficiency is associated with increased insulin sensitivity, lipoprotein lipase activity, and decreased serum free fatty acids. Arterioscler Thromb Vasc Biol. 2013;33:1706–13.CrossRefPubMed Robciuc MR, Maranghi M, Lahikainen A, Rader D, Bensadoun A, Oorni K, Metso J, Minicocci I, Ciociola E, Ceci F, et al. Angptl3 deficiency is associated with increased insulin sensitivity, lipoprotein lipase activity, and decreased serum free fatty acids. Arterioscler Thromb Vasc Biol. 2013;33:1706–13.CrossRefPubMed
31.
go back to reference Yilmaz Y, Ulukaya E, Atug O, Dolar E. Serum concentrations of human angiopoietin-like protein 3 in patients with nonalcoholic fatty liver disease: association with insulin resistance. Eur J Gastroenterol Hepatol. 2009;21:1247–51.CrossRefPubMed Yilmaz Y, Ulukaya E, Atug O, Dolar E. Serum concentrations of human angiopoietin-like protein 3 in patients with nonalcoholic fatty liver disease: association with insulin resistance. Eur J Gastroenterol Hepatol. 2009;21:1247–51.CrossRefPubMed
32.
go back to reference Mehta N, Qamar A, Qu L, Qasim AN, Mehta NN, Reilly MP, Rader DJ. Differential association of plasma angiopoietin-like proteins 3 and 4 with lipid and metabolic traits. Arterioscler Thromb Vasc Biol. 2014;34:1057–63.CrossRefPubMedPubMedCentral Mehta N, Qamar A, Qu L, Qasim AN, Mehta NN, Reilly MP, Rader DJ. Differential association of plasma angiopoietin-like proteins 3 and 4 with lipid and metabolic traits. Arterioscler Thromb Vasc Biol. 2014;34:1057–63.CrossRefPubMedPubMedCentral
33.
go back to reference Angelakopoulou A, Shah T, Sofat R, Shah S, Berry DJ, Cooper J, Palmen J, Tzoulaki I, Wong A, Jefferis BJ, et al. Comparative analysis of genome-wide association studies signals for lipids, diabetes, and coronary heart disease: cardiovascular biomarker genetics collaboration. Eur Heart J. 2012;33:393–407.CrossRefPubMedPubMedCentral Angelakopoulou A, Shah T, Sofat R, Shah S, Berry DJ, Cooper J, Palmen J, Tzoulaki I, Wong A, Jefferis BJ, et al. Comparative analysis of genome-wide association studies signals for lipids, diabetes, and coronary heart disease: cardiovascular biomarker genetics collaboration. Eur Heart J. 2012;33:393–407.CrossRefPubMedPubMedCentral
34.
go back to reference Wang Y, McNutt MC, Banfi S, Levin MG, Holland WL, Gusarova V, Gromada J, Cohen JC, Hobbs HH. Hepatic ANGPTL3 regulates adipose tissue energy homeostasis. Proc Natl Acad Sci USA. 2015;112:11630–5.CrossRefPubMedPubMedCentral Wang Y, McNutt MC, Banfi S, Levin MG, Holland WL, Gusarova V, Gromada J, Cohen JC, Hobbs HH. Hepatic ANGPTL3 regulates adipose tissue energy homeostasis. Proc Natl Acad Sci USA. 2015;112:11630–5.CrossRefPubMedPubMedCentral
Metadata
Title
Circulating angiopoietin-like protein 8 (ANGPTL8) and ANGPTL3 concentrations in relation to anthropometric and metabolic profiles in Korean children: a prospective cohort study
Authors
Hye Soo Chung
Min Jung Lee
Soon Young Hwang
Hyun Jung Lee
Hye Jin Yoo
Ji-A Seo
Sin Gon Kim
Nan Hee Kim
Sei Hyun Baik
Dong Seop Choi
Seon Mi Kim
Kyung Mook Choi
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Cardiovascular Diabetology / Issue 1/2016
Electronic ISSN: 1475-2840
DOI
https://doi.org/10.1186/s12933-015-0324-y

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