Abstract
BackgroundAngiopoietin-like protein 8 (ANGPTL8), an important regulator of lipid metabolism, is increased in diabetes and is associated with insulin resistance. However, the role of ANGPTL8 in the outcomes of diabetic patients remains unclear. This study aimed to investigate circulating levels of ANGPTL8 in participants with and without diabetes and its potential associations with clinical outcomes in a 5 year cohort study.MethodsPropensity-matched cohorts of subjects with and without diabetes from the Risk Evaluation of Cancers in Chinese Diabetic Individuals: A longitudinal (REACTION) study were generated on the basis of age, sex and body mass index at baseline. The primary outcome was all-cause mortality. The secondary outcomes were a composite of new-onset major adverse cardiovascular events, hospitalization for heart failure, and renal dysfunction (eGFR < 60/min/1.73 m2).ResultsWe identified 769 matched pairs of diabetic patients and control subjects. Serum ANGPTL8 levels were elevated in patients with diabetes compared to control subjects (618.82 pm 318.08 vs 581.20 pm 299.54 pg/mL, p = 0.03). Binary logistic regression analysis showed that elevated ANGPTL8 levels were associated with greater risk ratios (RRs) of death (RR in quartile 4 vs. quartile 1, 3.54; 95% CI 1.32–9.50) and renal dysfunction (RR in quartile 4 vs. quartile 1, 12.43; 95% CI 1.48–104.81) only in diabetic patients. Multivariable-adjusted restricted cubic spline analyses revealed a significant, linear relationship between ANGPTL8 and all-cause mortality in diabetic patients (p for nonlinear trend = 0.99, p for linear trend = 0.01) but not in control subjects (p for nonlinear trend = 0.26, p for linear trend = 0.80). According to ROC curve analysis, the inclusion of ANGPTL8 in QFrailty score significantly improved its predictive performance for mortality in patients with diabetes.ConclusionSerum ANGPTL8 levels were associated with an increased risk of all-cause mortality and could be used as a potential biomarker for the prediction of death in patients with diabetes.
Highlights
Angiopoietin-like protein 8 (ANGPTL8), an important regulator of lipid metabolism, is increased in diabetes and is associated with insulin resistance
Angiopoietin-like protein 8 (ANGPTL8), known as betatrophin, TD26, “refeeding induced in fat and liver” (RIFL), lipasin, and PRO1185, is a protein primarily produced in the liver and adipose tissue and it plays an important role in triglyceride (TG) metabolism [10]
The results from the present study that ANGPTL8 was positively correlated with TG and negatively correlated with high-density lipoprotein (HDL) in diabetic patients implied that ANGPTL8 could make a partial contribution to dyslipidaemia by affecting lipid metabolism
Summary
Angiopoietin-like protein 8 (ANGPTL8), an important regulator of lipid metabolism, is increased in diabetes and is associated with insulin resistance. ANGPTL8, together with ANGPTL3 and ANGPTL4, could regulate TG metabolism by inhibiting the activity of lipoprotein lipase (LPL) and subsequently elevating serum TG since LPL is an enzyme for TG hydrolysis and plasma TG clearance [11,12,13] These studies indicated that ANGPTL8 is involved in lipid metabolism and the pathogenesis of atherosclerosis. ANGPTL8 levels were increased in diabetes [14,15,16], dyslipidaemia [17, 18], CVD [19], renal function [20,21,22], obesity [23], hypertension [24], and nonalcoholic fatty liver [25]. Studies have revealed that ANGPTL8 levels increased with age [26, 27], suggesting its potential association with aging and with age-related metabolic diseases
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