Serum Angiopoietin-like Protein 6, Risk of Type 2 Diabetes, and Response to Hyperglycemia: A Prospective Cohort Study

Kang Chih Fan, Hung Tsung Wu, Jung Nan Wei, Lee Ming Chuang, Chih Yao Hsu, I. Weng Yen, Chia Hung Lin, Mao Shin Lin, Shyang Rong Shih, Shu Huei Wang, Tien Jyun Chang, Hung Yuan Li

Research output: Contribution to journalArticle

Abstract

CONTEXT: Angiopoietin-like protein 6 (ANGPTL6) is a hepatokine that improves insulin sensitivity in animals. However, serum ANGPTL6 concentration was found to be higher in human participants with diabetes or metabolic syndrome in cross-sectional studies, implying that ANGPTL6 may be induced to counteract hyperglycemia. OBJECTIVE: To investigate whether serum ANGPTL6 can predict incident diabetes and explore whether glucose or insulin can regulate ANGPTL6 expression and secretion. DESIGN: This cohort study included adults without diabetes at baseline who were followed every 2 years for incident diabetes. Serum ANGPTL6 concentrations were measured at baseline and during oral glucose tolerance tests (OGTTs). A hepatic cell line, HepG2, and diet-induced obesity mouse model were used to evaluate the response of ANGPTL6 expression and secretion to hyperglycemia and the metabolic syndrome. RESULTS: We recruited 1103 participants without diabetes at baseline. During the 4.22-year follow-up, 113 (10.2%) participants developed incident diabetes. Serum ANGPTL6 was negatively associated with the incidence of diabetes (adjusted hazard ratio, 0.77; P = 0.042). However, serum ANGPTL6 level was higher in participants with prediabetes (P = 0.018) and was elevated during OGTT. In HepG2 cells, treatment with glucose, but not insulin, induced ANGPTL6 expression. Hepatic ANGPTL6 expression and serum ANGPTL6 concentrations were significantly higher in mice fed with a high-fat diet than in those fed with a standard chow (both P < 0.05). CONCLUSION: A high serum ANGPTL6 level is associated with a low incidence of diabetes in humans. ANGPTL6 is expressed and secreted in response to hyperglycemia to maintain glucose homeostasis.

Original languageEnglish
JournalThe Journal of clinical endocrinology and metabolism
Volume105
Issue number5
DOIs
Publication statusPublished - May 1 2020

Keywords

  • angiopoietin-like protein 6
  • biomarker
  • diabetes
  • hyperglycemia

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

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  • Cite this

    Fan, K. C., Wu, H. T., Wei, J. N., Chuang, L. M., Hsu, C. Y., Yen, I. W., Lin, C. H., Lin, M. S., Shih, S. R., Wang, S. H., Chang, T. J., & Li, H. Y. (2020). Serum Angiopoietin-like Protein 6, Risk of Type 2 Diabetes, and Response to Hyperglycemia: A Prospective Cohort Study. The Journal of clinical endocrinology and metabolism, 105(5). https://doi.org/10.1210/clinem/dgaa103