Interleukin-1β in circulating mononuclear cells predicts steatotic liver disease improvement after weight loss in subjects with obesity and prediabetes or type 2 diabetes

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Adipose tissue; Biomarker; Inflammation; Interleukin-1β; Liver disease; MASLD; Obesity; Prediabetes; Type 2 diabetes; Weight-loss.

Fig. 1

Flow chart. Flow chart of enrolment of participants in the study

Fig. 2

Baseline correlation between IL-1β and glycaemic, inflammatory and metabolic characteristics. Correlation between IL-11β and BMI (panel A), fasting plasma glucose (panel B), HbA1c (panel C), VAT (panel D), MASLD (panel E), platelet count (panel F), chemerin (panel G), IL-1Ra (panel H)

Fig. 3

Effects of liraglutide- or lifestyle-induced weight loss on IL-1β in obese subjects with pre-diabetes or early type 2 diabetes mellitus. Changes in IL-1β in obese subjects after weight loss in obese patients with prediabetes or diabetes diagnosed within one year (panel A), and after liraglutide- or lifestyle counseling-induced weight loss (panel B).

Fig. 4

Correlation between basal tertile of IL-1β and delta MASLD. Correlation between basal IL-1β tertiles and delta MASLD in obese patients with prediabetes or newly-diagnosed diabetes