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

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.

Intron retention as an alternative splice variant of the cattle ANGPTL6 gene.

Angiopoietin-like protein 6, which is encoded by ANGPTL6 gene (also known as angiopoietin growth factor, AGF), has been extensively characterized with regard to its proposed functions as angiogenesis and energy metabolism. The present results showed the occurrence of alternative splicing by intron retention (IR) event in the bovine ANGPTL6 gene (bANGPTL6). By means of RT-PCR, TA clone and sequencing, we have shown that the bANGPTL6 gene has a splice variant generated by the retention of its partial intron 3. The computational analysis of the bANGPTL6 genomic sequence showed that its intron 3 has a high percentage of GC (62.31%) and a length of 199 nt, characteristics that have been associated with an IR event. The IR event does not interfere with the coding region as the bANGPTL6 prepropeptide is entirely coded in the third exon. Additionally, both the intronless (namely, bANGPTL6α) and intron-retaining (namely, bANGPTL6ß) ANGPTL6 transcripts are constitutively co-expressed in the bovine liver. Further, the relative expression level of different variants in liver was tested by both semi-RT-PCR and RT-qPCR methods. The results suggested bANGPTL6ß are significantly higher than bANGPTL6α. Overall, our findings will be helpful for studies on the molecular mechanism of IR events and the functions of ANGPTL6 gene. Specially, bANGPTL6ß gene probably contributes to a new target for treatment of obesity and obesity-related diseases.

Angiopoietin-like protein 2 and angiopoietin-like protein 6 levels in patients with nonalcoholic fatty liver disease.

INTRODUCTION: The aim of the current study was to examine the difference between patients detected with nonalcoholic fatty liver disease (NAFLD) and healthy subjects in terms of serum angiopoietin-like protein (ANGPTL) 2 and ANGPTL6 levels and to evaluate the correlation between ANGPTL2 and ANGPTL6 levels and liver enzyme levels, fasting glucose, lipid levels, and steatosis degree on ultrasonography (USG). MATERIAL AND METHODS: A total of 159 participants were included in the study. The participants were divided into 3 groups depending on the steatosis degree on USG and serum alanine aminotransferase (ALT) levels: the NAFLD group with increased ALT, the NAFLD group with normal ALT, and the healthy control group. The groups were compared in terms of biochemical and ultrasonographic findings, insulin resistance, metabolic syndrome (MetS), and anthropometric parameters. RESULTS: There was no significant difference between NAFLD patients and healthy subjects with respect to serum ANGPTL2 and ANGPTL6 levels (p > 0.05). ANGPTL2 levels did not correlate with serum, biochemical, or ultrasonographic findings, or anthropometric parameters (p > 0.05). A positive correlation was found between serum ANGPTL6 levels and fasting blood glucose, ALT, alkaline phosphatase, γ-glutamyl transpeptidase, fasting insulin, and HOMA-IR levels. CONCLUSIONS: While our findings suggest no relationship between serum ANGPTL2 and ANGPTL6 levels and NAFLD, ANGPTL6 levels may be related to metabolic and biochemical parameters. The effects of ANGPTL2 and ANGPTL6 in the pathogenesis of NAFLD should be investigated further.

Longitudinal Changes in Serum Levels of Angiopoietin-Like Protein 6 and Selenoprotein P After Gastric Bypass Surgery.

BACKGROUND: Bariatric surgery has beneficial effects on weight loss and metabolic profiles. Recent evidence suggests that liver-derived hepatokines play a role in the pathophysiology of metabolic diseases. However, few studies have reported longitudinal changes in hepatokines after gastric bypass surgery. We investigated changes in the serum levels of angiopoietin-like protein 6 (Angptl6) and selenoprotein P after gastric bypass surgery. METHODS: We followed 10 patients who were treated with gastric bypass for weight loss. We measured metabolic parameters and the serum levels of Angptl6 and selenoprotein P before, 1 month after, and 9 months after surgery. We investigated the changes in those hepatokines after surgery and the associations between changes in Angptl6 and selenoprotein P, respectively, and metabolic parameters. RESULTS: Body mass index decreased linearly. Levels of hemoglobin A1c (HbA1c), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyltransferase (GGT), total cholesterol, triglyceride, LDL cholesterol, and Angptl6 were significantly lower 1 and 9 months after surgery. Fasting plasma glucose was normal throughout the study. Fasting insulin decreased 1 month after surgery but increased 9 months post-surgery. Levels of selenoprotein P increased linearly. Significant correlations were detected between the levels of Angptl6 and LDL cholesterol and fasting insulin. Changes in Angptl6 levels were significantly correlated with changes in total cholesterol and LDL cholesterol. Selenoprotein P levels were inversely correlated with GGT, and changes in selenoprotein P were inversely correlated with changes in homeostasis model assessment for insulin resistance (HOMA-IR). CONCLUSIONS: Our results suggest that gastric bypass may alter the serum levels of hepatokines independent of weight loss, and these changes are related to certain hepatic metabolic changes.

Systolic blood pressure and fatty acid-binding protein 4 predict pregnancy-induced hypertension in overweight nulliparous women.

INTRODUCTION: The insulin-sensitivity regulator adipocyte fatty acid-binding protein 4 (FABP4) integrates metabolic and inflammatory responses. We hypothesize that there is relationship between FABP4 and factors related to metabolic syndrome in pregnancy-induced hypertension (PIH). METHODS: In this prospective observational study, among the 72 relatively overweight (BMI ≥24 kg/m2) nulliparous women, 14 developed non-proteinuric PIH and 12 developed proteinuric PIH (preeclampsia), whereas 46 had normotensive pregnancies. Insulin sensitivity was assessed via the whole-body insulin sensitivity index (ISI) and the homeostatic model of assessment - insulin resistance (HOMA-IR) at 24 weeks of gestation. Maternal serum levels of FABP4, high-sensitive C-reactive protein (hs-CRP), total testosterone, and non-protein-bound calculated free testosterone (cfT) were determined at 24 and 32 weeks. RESULTS: Measures of ISI, HOMA-IR, hs-CRP, testosterone and lipids did not differ at 24 and/or at 32 weeks in women who were subsequently hypertensive. SBP was higher at all time points and FABP4 levels tended to be higher at 24 and 32 weeks in patients compared to controls. In logistic regression analysis, baseline FABP4 (OR [95% CI] 1.069 [1.020-1.121], P = 0.006) and SBP after 10 min standing (OR [95% CI] 1.087 [1.029-1.149], P = 0.003) were associated with the development of PIH. FABP4 levels at 24 weeks did not correlate with insulin sensitivity. Neither was correlation seen between FABP4 levels at 24 and 32 weeks, vs. those of hs-CRP and testosterone. DISCUSSION AND CONCLUSIONS: Serum FABP4 concentration and SBP after 10 min standing in an orthostatic test at 24 weeks are associated with subsequent development of PIH.