Exenatide decreases hepatic fibroblast growth factor 21 resistance in non-alcoholic fatty liver disease in a mouse model of obesity and in a randomised controlled trial.

Aims/hypothesis: Systemic fibroblast growth factor (FGF)21 levels and hepatic FGF21 production are increased in non-alcoholic fatty liver disease patients, suggesting FGF21 resistance. We examined the effects of exenatide on FGF21 in patients with type 2 diabetes and in a diet-induced mouse model of obesity (DIO).

Methods: Type 2 diabetes mellitus patients (n = 24) on diet and/or metformin were randomised (using a table of random numbers) to receive additional treatment consisting of pioglitazone 45 mg/day or combined therapy with pioglitazone (45 mg/day) and exenatide (10 μg twice daily) for 12 months in an open label parallel study at the Baylor Clinic.

Results: Twenty-one patients completed the entire study and were included in the analysis. Pioglitazone treatment (n = 10) reduced hepatic fat as assessed by magnetic resonance spectroscopy, despite a significant increase in body weight (Δ = 3.7 kg); plasma FGF21 levels did not change (1.9  ±  0.6 to 2.2  ±  0.6 ng/ml [mean ± SEM]). However, combined pioglitazone and exenatide therapy (n = 11) was associated with a significant reduction of FGF21 levels (2.3  ±  0.5 to 1.1  ±  0.3 ng/ml) and a greater decrease in hepatic fat. Besides weight gain observed in the pioglitazone-treated patients, lower extremity oedema was observed as a side effect in two of the ten patients. Three patients who received pioglitazone and exenatide combination therapy complained of significant nausea that was self-limiting and did not require them to leave the study. In DIO mice, exendin-4 for 4 weeks significantly reduced hepatic triacylglycerol content, decreased hepatic FGF21 protein and mRNA, and enhanced phosphorylation of hepatic AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase, although no significant difference in weight and body fat was observed. Hepatic FGF21 correlated inversely with hepatic AMPK phosphorylation

Conclusions/interpretation: In type 2 diabetes mellitus, combined pioglitazone and exenatide therapy is associated with a reduction in plasma FGF21 levels, as well as a greater decrease in hepatic fat than that achieved with pioglitazone therapy. In DIO mice, exendin-4 treatment reduces hepatic triacylglycerol and FGF21 protein, and enhances hepatic AMPK phosphorylation, suggesting an improvement of hepatic FGF21 resistance.

Trial Registration Number: ClinicalTrials.gov NCT 01432405.