LEAP2 is Associated with Cardiometabolic Markers, but is Unchanged by Antidiabetic Treatment in People with Prediabetes.

Abstract

Aims To examine whether fasting plasma liver-expressed antimicrobial peptide 2 (FP-LEAP2) is associated with markers of cardiometabolic disease susceptibility in a cohort with prediabetes and overweight/obesity and whether antidiabetic interventions affect FP-LEAP2 levels. Materials and methods The analysis included 115 individuals with prediabetes (hemoglobin A1c (HbA1c) 39-47 mmol/mol, 5.7-6.4%) and overweight/obesity (BMI ≥ 25 kg/m2) from a randomized controlled trial. Changes in FP-LEAP2 levels were assessed in relation to treatment with dapagliflozin (10 mg once daily), metformin (1700 mg daily) or interval-based exercise (5 days/week, 30 min/session) compared to control (habitual lifestyle) after 6 and 13 weeks of treatment. Results FP-LEAP2 levels were associated with (standardized beta-coefficient (95%-CI)): BMI 0.22 (0.03:0.41), p=0.027; body weight 0.27 (0.06:0.48), p=0.013; fat mass 0.2 (0.00:0.4), p=0.048; lean mass 0.47 (0.13:0.8), p=0.008; HbA1c 0.35 (0.17:0.53), p<0.001; fasting plasma glucose (FPG) 0.32 (0.12:0.51), p=0.001; fasting serum insulin 0.28 (0.09:0.47), p=0.005; insulin sensitivity -0.22 (-0.41:-0.03), p=0.022; total cholesterol 0.19 (0.01:0.38), p=0.043; triglycerides: 0.31 (0.13:0.5), p<0.001; transaminases and Fatty Liver Index (standardized beta-coefficients 0.23-0.32), all p<0.020; and eGFR -0.34 (-0.56:-0.12), p=0.003. FP-LEAP2 levels were not associated with fat distribution or body fat percentage, fasting glucagon, post-load glucose, beta cell function or low-density lipoprotein. The interventions were not associated with changes in FP-LEAP2. Conclusion FP-LEAP2 is associated with body mass, impaired insulin sensitivity, liver specific enzymes and kidney function. The findings highlight the importance of LEAP2 in obesity, type 2 diabetes, and non-alcoholic fatty liver disease. FP-LEAP2 was not affected by metformin, dapaglifloxin, or exercise in this population.