期刊
DIABETOLOGIA
卷 54, 期 12, 页码 3093-3100出版社
SPRINGER
DOI: 10.1007/s00125-011-2317-z
关键词
AMPK; Exenatide; FGF21; GLP-1; Hepatic steatosis; NAFLD; Pioglitazone
资金
- American Diabetes Association
- Ron MacDonald Foundation at St Luke's Episcopal Hospital
- Amylin Pharmaceuticals
- Eli-Lilly
- NIH [T-32 HL-66991]
- NIH Diabetes and Endocrinology Research Center (DERC) at Baylor College of Medicine
- T.T. and W.F. Chao Foundation
- Diabetes and Endocrinology Research Center DERC [P30DK079638]
- Rutherford Chair for Diabetes Research from St Luke's Episcopal Hospital
Aims/hypothesis Systemic fibroblast growth factor (FGF) 21 levels and hepatic FGF21 production are increased in nonalcoholic 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 mu g 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 (Delta=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.
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