Low-calorie sweeteners (LCS) are widely utilized as sugar substitutes due to their intense sweetness, thermal stability, and applicability in weight management and diabetic-friendly products. However, increasing evidence has raised concerns about their potential long-term effects on metabolic health, glucose regulation, cardiovascular function, carcinogenicity, and gut microbiota composition. This review systematically evaluates the pharmacokinetics, metabolic effects, and associated health outcomes of major LCS. Mechanistically, LCS exert effects via sweet taste receptor-mediated pathways, altering glucose absorption, insulin secretion, and intracellular signaling cascades. Additionally, LCS influence gut microbiota composition, with certain agents promoting dysbiosis and glucose intolerance. While some findings support the metabolic benefits of selected LCS, others underscore potential risks, necessitating cautious interpretation. In conclusion, while LCS offer viable alternatives to sugar, their health effects are context-dependent and may vary across different sweeteners and populations. Long-term, high-quality clinical trials are essential to elucidate their safety and efficacy.

Objectives: Although angiopoietin-like 4 (ANGPTL4) is highly associated with glucose hemostasis and lipid metabolism, the relationships between the serum ANGPTL4 level, glucose status and hepatic steatosis remain unclear. Therefore, this study aimed to quantify the independent effects of glucose intolerance and hepatic steatosis on circulating ANGPTL4 concentrations. Methods: A total of 348 age- and sex-matched participants with normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and newly diagnosed diabetes (NDD) with or without hepatic steatosis were recruited for this cross-sectional study. Serum ANGPTL4 levels were measured, and multivariate linear regression analysis was used to evaluate the relationship between ANGPTL4, glycemic status and hepatic steatosis. Results: Compared with NGT, both IGT and NDD were associated with significantly higher serum ANGPTL4 concentrations, irrespective of hepatic steatosis status. Serum ANGPTL4 did not differ by the presence versus absence of hepatic steatosis. In multiple regression analysis, body mass index, homeostasis model assessment of insulin resistance, NGT vs. IGT, and NGT vs. NDD were independently associated with ANGPTL4 levels after adjustment for cardiovascular risk factors and adiponectin, whereas hepatic steatosis was not. Conclusions: Elevated serum ANGPTL4 concentrations were independently associated with prediabetes and diabetes, irrespective of hepatic steatosis.

Background: Elevated serum angiopoietin-like protein 4 (ANGPTL4) levels have been reported in hepatocellular carcinoma (HCC), and they promote tumor aggressiveness and an immunosuppressive tumor microenvironment. However, its association with immunotherapy response in HCC remains unclear. Objectives: To investigate the relationship among serum ANGPTL4, immunotherapy response and clinical outcomes in patients with unresectable HCC. Design: This was a retrospective analysis conducted at a single center. Methods: A total of 70 unresectable HCC patients who received immune checkpoint inhibitor therapy were enrolled. Tumor response was evaluated using modified Response Evaluation Criteria in Solid Tumors. Serum ANGPTL4 concentrations were measured using enzyme-linked immunosorbent assay. Multivariable logistic regression and Cox proportional hazards regression analysis were performed to evaluate associations among serum ANGPTL4 concentration and treatment response, progression-free survival (PFS), and overall survival (OS). Bootstrap resampling was used for internal validation to generate corrected estimates of model accuracy. Results: Responders exhibited significantly lower baseline serum ANGPTL4 concentrations than non-responders (P = 0.004). Higher serum ANGPTL4 concentrations (odds ratio [OR] = 0.82; P = 0.041), macrovascular invasion (OR = 0.25; P = 0.022), and AFP levels ≥ 400 ng/mL (OR = 0.29; P = 0.038) were independently associated with unfavorable immunotherapy response. Higher serum ANGPTL4 concentrations were also independently associated with shorter PFS (hazard ratio [HR] = 1.10; P = 0.021) and OS (HR = 1.13; P = 0.005). Conclusion: Lower baseline serum ANGPTL4 concentrations were independently associated with favorable immunotherapy response and improved survival outcomes in unresectable HCC.