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

Abstract

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.

FGF21 as a mediator of adaptive responses to stress and metabolic benefits of anti-diabetic drugs

“…Dissimilar results regarding the effect of exendin-4 on FGF21 expression have also been reported. Hepatic FGF21 expression and serum FGF21 levels were decreased in HFD-fed mice treated with exendin-4 for 4 weeks compared to saline treatment (Samson et al 2011). Consistent with this result, the addition of exenatide reduced FGF21 levels in T2D subjects undergoing pioglitazone treatment (Samson et al 2011).…”

“…Hepatic FGF21 expression and serum FGF21 levels were decreased in HFD-fed mice treated with exendin-4 for 4 weeks compared to saline treatment (Samson et al 2011). Consistent with this result, the addition of exenatide reduced FGF21 levels in T2D subjects undergoing pioglitazone treatment (Samson et al 2011). Furthermore, a decrease in hepatic FGF21 levels was correlated with reduction in hepatic TG content and liver weight in HFD-fed mice after exendin-4 treatment, implying that reduction of FGF21 due to exendin-4 may be secondary to reduced lipid accumulation.…”

Exendin-4 Alleviates High Glucose-Induced Rat Mesangial Cell Dysfunction through the AMPK Pathway

“…Exendin-4 induced phosphorylation of AMPK, which reduced weight gain and insulin resistance in mice with high-fat diets [16]. Additionally, phosphorylated AMPK was down-regulated in the kidneys of db/db mice [17,18]. …”

Successful Glycemic Control Decreases the Elevated Serum FGF21 Level without Affecting Normal Serum GDF15 Levels in a Patient with Mitochondrial Diabetes

“…However, her level of FGF21 after glycemic treatment was significantly decreased to the level under the threshold of a diagnosis of mitochondrial diseases according to a previous study . As for the influence of glycemic treatment on FGF21 levels in type 2 diabetes patients, FGF21 levels decreased after starting glycemic therapies including insulin (Yang et al 2011) or exenatide, a GLP-1 receptor agonist (Samson et al 2011), although no similar studies in mitochondrial diabetes patients were reported. Therefore, the results of FGF21 in WBC, white blood cell count; RBC, red blood cell count; ALB, serum albumin; T-bil, total bilirubin; AST, aspartate aminotranferase; ALT, alanine aminotranferase; CK, creatine kinase; BUN, blood urea nitrogen; TSH, thyroid stimulating hormone; FGF21, fibroblast growth factor 21; GDF15, growth differentiation factor 15; HbA1c, hemoglobin A1c; anti-GAD, anti-glutamic acid decarboxylase antibody; Anti-IA2, anti-insulinoma antigen 2 antibody.…”