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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.
Diabetologia. 2011 Dec; 54(12):3093-100.D

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.

TRIAL REGISTRATION NUMBER

ClinicalTrials.gov NCT 01432405.

Authors+Show Affiliations

Diabetes and Endocrinology Research Center, Endocrinology Division, Baylor College of Medicine, 1709 Dryden Street, Houston, TX 77030, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Randomized Controlled Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21956711

Citation

Samson, S L., et al. "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." Diabetologia, vol. 54, no. 12, 2011, pp. 3093-100.
Samson SL, Sathyanarayana P, Jogi M, et al. 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. Diabetologia. 2011;54(12):3093-100.
Samson, S. L., Sathyanarayana, P., Jogi, M., Gonzalez, E. V., Gutierrez, A., Krishnamurthy, R., Muthupillai, R., Chan, L., & Bajaj, M. (2011). 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. Diabetologia, 54(12), 3093-100. https://doi.org/10.1007/s00125-011-2317-z
Samson SL, et al. 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. Diabetologia. 2011;54(12):3093-100. PubMed PMID: 21956711.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Samson,S L, AU - Sathyanarayana,P, AU - Jogi,M, AU - Gonzalez,E V, AU - Gutierrez,A, AU - Krishnamurthy,R, AU - Muthupillai,R, AU - Chan,L, AU - Bajaj,M, Y1 - 2011/09/29/ PY - 2011/06/12/received PY - 2011/08/26/accepted PY - 2011/9/30/entrez PY - 2011/10/1/pubmed PY - 2012/3/20/medline SP - 3093 EP - 100 JF - Diabetologia JO - Diabetologia VL - 54 IS - 12 N2 - 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. SN - 1432-0428 UR - https://www.unboundmedicine.com/medline/citation/21956711/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_ L2 - https://doi.org/10.1007/s00125-011-2317-z DB - PRIME DP - Unbound Medicine ER -