Vitamin D modifies the associations between circulating betatrophin and cardiometabolic risk factors among youths at risk for metabolic syndrome

Junling Fu, Cong Hou, Lujiao Li, Dan Feng, Ge Li, Mingyao Li, Changhong Li, Shan Gao, Ming Li, Junling Fu, Cong Hou, Lujiao Li, Dan Feng, Ge Li, Mingyao Li, Changhong Li, Shan Gao, Ming Li

Abstract

Background: Betatrophin has been recently reported to play a role in glucose homeostasis by inducing beta-cell proliferation in mice. However, studies in human are inconsistent. As a nutritionally-regulated liver-enriched factor, we hypothesize that betatrophin might be regulated by vitamin D, and ignorance of vitamin D status may explain the discrepancy in previous human studies. The aims of this study were to assess the association between circulating betatrophin and glucose homeostasis as well as other cardiometabolic variables in a cohort of youths at risk for metabolic syndrome and test the possible influence of vitamin D status on the association.

Methods: 559 subjects aged 14-28 years were recruited from Beijing children and adolescents metabolic syndrome study. All underwent a 2 h-oral glucose tolerance test. Serum levels of betatrophin, 25-hydroxy-vitamin D as well as adipokines including adiponectin and fibroblast growth factor 21 (FGF21) were measured by immunoassays. The relationships between betatrophin and insulin resistance, beta-cell function, other cardiometabolic variables and vitamin D status were evaluated.

Results: Participants in the highest quartile of betatrophin levels had the highest levels of total cholesterol (P < 0.001), triglyceride (P < 0.001) and low-density lipoprotein cholesterol (P < 0.001) and the lowest levels of vitamin D (P = 0.003). After stratification by vitamin D status, betatrophin in subjects with vitamin D deficiency were positively correlated with unfavorable metabolic profiles including high blood pressures, dyslipidemia and hyperglycemia, whereas betatrophin in those with higher vitamin D levels only showed negative association with fasting insulin, 2 h-insulin, and insulin resistance. In addition, adiponectin and FGF21 demonstrated the expected associations with metabolic parameters.

Conclusions: Elevated betatrophin levels were associated with cardiometabolic risk factors in this young population, but the association was largely dependent on vitamin D status. These findings may provide valuable insights in the regulation of betatrophin and help explain the observed discrepancies in literature.

Keywords: Adolescents; Betatrophin; Metabolic syndrome; Vitamin D.

Figures

Fig. 1
Fig. 1
Levels of betatrophin in various metabolic abnormalities. Betatrophin concentrations were compared between subjects with and without a central obesity, b elevated blood pressures, c high TG, d low HDL-C and g NAFLD, and subjects with different e glucose tolerance status (normal, IGT/IFG, or T2DM, f number of MS components (0, 1, 2, or ≥ 3) and h vitamin D tertile ( T1, 3.00–11.94 ng/ml; T2, 11.94–17.04 ng/ml; and T3, 17.04–35.61 ng/ml). Data are natural log-transformed and shown as mean ± SEM. All P values were adjusted for gender and age and P* was further adjusted for vitamin D levels. NS no significant difference; TG triglycerides; HDL-C high-density lipoprotein cholesterol; MS metabolic syndrome; IFG impaired fasting glucose; IGT impaired glucose tolerance; T2DM type 2 diabetes mellitus; NAFLD nonalcoholic fatty liver disease
Fig. 2
Fig. 2
Possible associations between betatrophin and cardiometabolic variables and the influence of vitamin D status. SBP Systolic blood pressure; DBP Diastolic blood pressure; LPL lipoprotein lipase; TC total cholesterol; TG triglycerides; LDL-C low density lipoprotein cholesterol; HDL-C high-density lipoprotein cholesterol; 2h-BG 2-hour blood glucose; FINS fasting insulin; 2h-INS 2-hour insulin; HOMA-IR homeostasis model assessment for insulin resistance; ISIM insulin sensitivity Matsuda index; DIO oral disposition index; AST Aspartate transaminase; ALT Alanine aminotransferase; NAFLD nonalcoholic fatty liver disease; FGF21 fibroblast growth factor 21. Color in red indicates the associations with increased concentrations of betatrophin possibly induced by vitamin D deficiency; color in dark blue indicates the associations with low concentrations of betatrophin possibly inhibited by higher levels of vitamin D; dotted black line represents the possible role of vitamin D in regulating betatrophin levels; N dash means no significant association

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