title: 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: OBJECTIVE
  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
  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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT 01432405.
authors.affiliation: Diabetes and Endocrinology Research Center, Endocrinology Division, Baylor College of Medicine, 1709 Dryden Street, Houston, TX 77030, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Samson
authors.forename: P
authors.initials: P
authors.lastname: Sathyanarayana
authors.forename: M
authors.initials: M
authors.lastname: Jogi
authors.forename: E V
authors.initials: EV
authors.lastname: Gonzalez
authors.forename: A
authors.initials: A
authors.lastname: Gutierrez
authors.forename: R
authors.initials: R
authors.lastname: Krishnamurthy
authors.forename: R
authors.initials: R
authors.lastname: Muthupillai
authors.forename: L
authors.initials: L
authors.lastname: Chan
authors.forename: M
authors.initials: M
authors.lastname: Bajaj
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000178:diet therapy / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004487:Edema / Q000139:chemically induced; D000077270:Exenatide; D005234:Fatty Liver / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D035002:Lower Extremity / Q000503:physiopathology; D008297:Male; D008687:Metformin / Q000627:therapeutic use; D051379:Mice; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D065626:Non-alcoholic Fatty Liver Disease; D009765:Obesity / Q000378:metabolism; D010455:Peptides / Q000009:adverse effects / Q000627:therapeutic use*; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000627:therapeutic use; D014688:Venoms / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D007004:Hypoglycemic Agents; D010455:Peptides; D045162:Thiazolidinediones; D014688:Venoms; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D008687:Metformin; D000077270:Exenatide; D000077205:Pioglitazone