Improved Glucagon Sensitivity Following Weight Loss: A Systematic Review and Meta‐Analysis

ABSTRACT Objective This systematic review and meta‐analysis investigated the effect of weight loss in people with obesity on two biomarkers of glucagon resistance: fasting plasma glucagon and alanine. Methods A comprehensive search was conducted in Medline and Embase. Random‐effects meta‐analyses and correlation analyses were performed. Risk of bias was assessed using the Cochrane RoB 2 and MINORS tools. Results Forty‐seven studies comprising 69 interventions and 2061 participants were included. Pooled mean weight loss was −18.23 kg (95% CI [−20.20, −16.27]). Both fasting glucagon and alanine decreased following weight loss: −4.05 pmol/L (95% CI [−4.50, −3.60]; p < 0.001) and −17.9% (95% CI [−22.7, −13.1]; p < 0.0001), respectively. Glucagon reduction occurred with all weight‐loss intervention types: surgical −3.85 pmol/L (95% CI [−5.48, −2.22]; p < 0.0001), dietary −2.87 pmol/L (95% CI [−4.20, −1.54]; p < 0.0001), and pharmacological −5.32 pmol/L (95% CI [−9.85, −0.78]; p < 0.0001). Greater weight loss correlated with larger reductions in fasting glucagon (Pearson r = 0.3255, p = 0.0064). Heterogeneity was high, and overall risk of bias was moderate. Conclusions Weight loss is associated with significant reductions in fasting glucagon and alanine concentrations, suggesting improved hepatic glucagon sensitivity and partial restoration of the liver–α‐cell axis.