Skip Navigation
Skip to contents

Diabetes Metab J : Diabetes & Metabolism Journal



Page Path
HOME > Diabetes Metab J > Volume 43(5); 2019 > Article
Letter: Increased Serum Angiopoietin-Like 6 Ahead of Metabolic Syndrome in a Prospective Cohort Study (Diabetes Metab J 2019;43:521-9)
Jin Hwa Kimorcid
Diabetes & Metabolism Journal 2019;43(5):727-728.
Published online: October 24, 2019
  • 34 Download
  • 1 Crossref
  • 1 Scopus

Department of Endocrinology and Metabolism, Chosun University Hospital, Chosun University College of Medicine, Gwangju, Korea.

Corresponding author: Corresponding author: Jin Hwa Kim. Department of Endocrinology and Metabolism, Chosun University Hospital, Chosun University College of Medicine, 365 Pilmun-daero, Dong-gu, Gwangju 61453, Korea.

Copyright © 2019 Korean Diabetes Association

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

The liver plays a pivotal role in the development of metabolic disorders by the regulation of glucose and lipid metabolism and is now considered as an endocrine organ. Liver-derived proteins known as hepatokines have major functions in regulation of systemic metabolism and energy hemostasis [1]. Cumulative evidences suggest that hepatokines have been associated with metabolic dysfunction, including fetuin A, fibroblast growth factor-21 (FGF-21), retinol-binding protein 4 (RBP4), selenoprotein P, leukocyte derived chemotaxin 2 (LECT2), and angiopoietin-related growth factor (ANGPTL6, also known as angiopoietin-like 6) [23]. Hepatokines may be attractive as emerging therapeutic targets and provide crucial insights that could help us better understand the pathogenesis in metabolic syndromes.
ANGPTL6, which is a multimeric glycoprotein, is recognized as an angiogenic factor and has additional novel effects on energy expenditure and insulin sensitivity [45]. Increasing levels of ANGPTL6 was significantly associated with body weight loss and increasing insulin sensitivity in mice fed a high-fat diet. Conversely, ANGPTL6 deficiency was related to insulin resistance and hyperglycemia. It was suggested that ANGPTL6 antagonized obesity and insulin resistance [6]. However, human studies showed inverse results [789].
In this article entitled “Increased serum angiopoietin-like 6 ahead of metabolic syndrome in a prospective cohort study,” Namkung et al. [10] prospectively evaluated the association between serum ANGPTL6 level and new-onset metabolic syndrome in a rural cohort in Korea. They showed that serum ANGPTL6 level was already significantly elevated before developing new-onset metabolic syndrome, which has an independent predictive value for metabolic syndrome. As the prevalence of metabolic syndrome increases, there is an increasing need to identify persons at risk in early so they may benefit from early precision interventions. Several biomarkers as a predictor of incident metabolic syndrome including albumin, uric acid, and serum calcium were suggested [1112]. The authors suggested the concept that the upregulation of ANGPTL6 is a compensatory mechanism against metabolic stress and is a candidate biomarker of metabolic syndrome. They have clearly showed their results in this manuscript, and this approach is quite valuable and helpful to establish early identification and individual strategies for metabolic syndrome.
In my opinion, it would be interesting to evaluate the level of ANGPTL6 at diagnosis of metabolic syndrome in addition to basal ANGPTL6 levels. Whether there is a change in ANGPTL6 levels between basal and at development of metabolic syndrome will provide an additional information in these research fields. Hopefully a large prospective cohort study will be performed. I also expect to extend the study to discover whether there is an association between the level of ANGPTL6 and prognosis of cardiovascular diseases and mortality. Lastly, it would have more value if they can follow-up for longer, as the authors mentioned. Further studies revealing the underlined mechanism of these paradoxical increase in ANGPTL6 in metabolic syndrome in human will be interesting.

CONFLICTS OF INTEREST: No potential conflict of interest relevant to this article was reported.

  • 1. Stefan N, Haring HU. The role of hepatokines in metabolism. Nat Rev Endocrinol 2013;9:144-152. ArticlePubMedPDF
  • 2. Esfahani M, Baranchi M, Goodarzi MT. The implication of hepatokines in metabolic syndrome. Diabetes Metab Syndr 2019;13:2477-2480. ArticlePubMed
  • 3. Meex RCR, Watt MJ. Hepatokines: linking nonalcoholic fatty liver disease and insulin resistance. Nat Rev Endocrinol 2017;13:509-520. ArticlePubMedPDF
  • 4. Oike Y, Ito Y, Maekawa H, Morisada T, Kubota Y, Akao M, Urano T, Yasunaga K, Suda T. Angiopoietin-related growth factor (AGF) promotes angiogenesis. Blood 2004;103:3760-3765. ArticlePubMedPDF
  • 5. Hato T, Tabata M, Oike Y. The role of angiopoietin-like proteins in angiogenesis and metabolism. Trends Cardiovasc Med 2008;18:6-14. ArticlePubMed
  • 6. Oike Y, Akao M, Yasunaga K, Yamauchi T, Morisada T, Ito Y, Urano T, Kimura Y, Kubota Y, Maekawa H, Miyamoto T, Miyata K, Matsumoto S, Sakai J, Nakagata N, Takeya M, Koseki H, Ogawa Y, Kadowaki T, Suda T. Angiopoietin-related growth factor antagonizes obesity and insulin resistance. Nat Med 2005;11:400-408. ArticlePubMedPDF
  • 7. Ebert T, Kralisch S, Loessner U, Jessnitzer B, Stumvoll M, Fasshauer M, Tonjes A. Relationship between serum levels of angiopoietin-related growth factor and metabolic risk factors. Horm Metab Res 2014;46:685-690. ArticlePubMed
  • 8. Namkung J, Koh SB, Kong ID, Choi JW, Yeh BI. Serum levels of angiopoietin-related growth factor are increased in metabolic syndrome. Metabolism 2011;60:564-568. ArticlePubMed
  • 9. Nie H, Liang Y, Wang HX, Ren HL, Wang YW, Li FD, Zheng YH. Angiopoietin-related growth factor is independently associated with lower extremity peripheral arterial disease. J Diabetes Complications 2017;31:433-438. ArticlePubMed
  • 10. Namkung J, Sohn JH, Chang JS, Park SW, Kim JY, Koh SB, Kong ID, Park KS. Increased serum angiopoietin-like 6 ahead of metabolic syndrome in a prospective cohort study. Diabetes Metab J 2019;43:521-529. ArticlePubMedPMCPDF
  • 11. Lee YB, Jun JE, Lee SE, Ahn J, Kim G, Jee JH, Bae JC, Jin SM, Kim JH. Utility of serum albumin for predicting incident metabolic syndrome according to hyperuricemia. Diabetes Metab J 2018;42:529-537. ArticlePubMedPMCPDF
  • 12. Baek JH, Jin SM, Bae JC, Jee JH, Yu TY, Kim SK, Hur KY, Lee MK, Kim JH. Serum calcium and the risk of incident metabolic syndrome: a 4.3-year retrospective longitudinal study. Diabetes Metab J 2017;41:60-68. ArticlePubMedPDF

Figure & Data



    Citations to this article as recorded by  
    • Angiopoietin-like proteins in atherosclerosis
      Yi-Zhang Liu, Chi Zhang, Jie-Feng Jiang, Zhe-Bin Cheng, Zheng-Yang Zhou, Mu-Yao Tang, Jia-Xiang Sun, Liang Huang
      Clinica Chimica Acta.2021; 521: 19.     CrossRef

    • PubReader PubReader
    • Cite
      export Copy
      Download Citation
      Download a citation file in RIS format that can be imported by all major citation management software, including EndNote, ProCite, RefWorks, and Reference Manager.

      • RIS — For EndNote, ProCite, RefWorks, and most other reference management software
      • BibTeX — For JabRef, BibDesk, and other BibTeX-specific software
      • Citation for the content below
      Letter: Increased Serum Angiopoietin-Like 6 Ahead of Metabolic Syndrome in a Prospective Cohort Study (Diabetes Metab J 2019;43:521-9)
      Diabetes Metab J. 2019;43(5):727-728.   Published online October 24, 2019
    • XML DownloadXML Download
    Related articles

    Diabetes Metab J : Diabetes & Metabolism Journal