Simeone Paola Giustina, Costantino Sarah, Liani Rossella, Tripaldi Romina, Di Castelnuovo Augusto, Tartaro Armando, Mengozzi Alessandro, Cosentino Francesco, Cipollone Francesco, Consoli Agostino, Paneni Francesco, Santilli Francesca
Department of Medicine and Aging Sciences, Center for Advanced Studies and Technology (CAST), University "G. d'Annunzio" of Chieti-Pescara, 66100, Chieti, Italy.
Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
Cardiovasc Diabetol. 2025 Jun 13;24(1):247. doi: 10.1186/s12933-025-02706-8.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major cardiovascular risk (CV) factor. Interleukin-1β (IL-1β), a cytokine involved in the pathogenesis of obesity-associated inflammation and type 2 diabetes (T2D), promotes hepatic steatosis. The Canakinumab Anti-inflammatory Thrombosis Outcome (CANTOS) trial showed that the inhibition of the IL-1β pathway was associated with a reduction of CV events in high-risk patients. The present study was designed to determine: (i) whether an equal degree of weight loss by liraglutide or lifestyle changes has a different impact on MASLD extent and IL-1β expression in peripheral blood mononuclear cells from obese subjects with prediabetes or early T2D; (ii) whether baseline IL-1β levels may predict the extent of weight loss and related metabolic changes.
Thirty-two obese subjects with prediabetes (n = 16) or newly diagnosed T2D (n = 16), were randomized to the glucagon-like peptide receptor agonist (GLP1-RA) liraglutide or lifestyle counselling until achieving a comparable weight loss. Visceral adipose tissue (VAT) and gene expression of IL-1β in peripheral blood mononuclear cells were assessed by magnetic resonance and real time PCR, respectively.
At baseline, IL-1β was positively correlated to body mass index (BMI), fasting plasma glucose, HbA1c, VAT, MASLD extent, platelet count, chemerin and interleukin-1 receptor antagonist (IL1-RA). After achievement of the weight loss target in the two groups, a significant but comparable reduction of IL-1β (p for difference = 0.56) was observed in both arms, in parallel with a comparable improvement in glycaemic control, C reactive protein (CRP), BMI and MASLD. Furthermore, basal IL-1β levels independently predicted the extent of MASLD decrease (p = 0.030); subjects in the highest tertile showed a median decrease of - 8.0 (95% CI - 12.3 to - 4.8) compared with - 23.0 (95% CI - 39.5 to - 16.3) in the lowest tertile.
In patients with obesity with initial impairment of glucose metabolism successful weight loss is associated with a reduction of both IL-1β levels and MASLD degree. Of interest, basal levels of IL-1β predict the extent of MASLD improvement, regardless of the intervention. Our results may set the stage for ad-hoc studies investigating the usefulness of baseline IL-1β a level as a drug-response biomarker.
代谢功能障碍相关脂肪性肝病（MASLD）是主要的心血管风险（CV）因素。白细胞介素-1β（IL-1β）是一种参与肥胖相关炎症和2型糖尿病（T2D）发病机制的细胞因子，可促进肝脏脂肪变性。卡那单抗抗炎血栓形成结果（CANTOS）试验表明，抑制IL-1β通路与高危患者心血管事件减少有关。本研究旨在确定：（i）利拉鲁肽或生活方式改变导致的同等程度体重减轻对患有糖尿病前期或早期T2D的肥胖受试者外周血单核细胞中MASLD程度和IL-1β表达是否有不同影响；（ii）基线IL-1β水平是否可预测体重减轻程度及相关代谢变化。
32名患有糖尿病前期（n = 16）或新诊断为T2D（n = 16）的肥胖受试者被随机分为胰高血糖素样肽受体激动剂（GLP1-RA）利拉鲁肽组或接受生活方式咨询，直至实现可比的体重减轻。分别通过磁共振和实时PCR评估内脏脂肪组织（VAT）和外周血单核细胞中IL-1β的基因表达。
在基线时，IL-1β与体重指数（BMI）、空腹血糖、糖化血红蛋白、VAT、MASLD程度、血小板计数、chemerin和白细胞介素-1受体拮抗剂（IL1-RA）呈正相关。两组实现体重减轻目标后，双臂均观察到IL-1β有显著但相当的降低（差异p = 0.56），同时血糖控制、C反应蛋白（CRP）、BMI和MASLD有相当程度的改善。此外，基础IL-1β水平独立预测MASLD降低程度（p = 0.030）；最高三分位数的受试者中位数降低-8.0（95%CI -12.3至-4.8），而最低三分位数为-23.0（95%CI -39.5至-16.3）。
在初始糖代谢受损的肥胖患者中，成功减重与IL-1β水平和MASLD程度降低相关。有趣的是，无论干预措施如何，基础IL-1β水平可预测MASLD改善程度。我们的结果可能为专门研究基线IL-1β水平作为药物反应生物标志物的有用性的研究奠定基础。
