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LY2405319, an Engineered FGF21 Variant, Improves the Metabolic Status of Diabetic Monkeys

Fibroblast growth factor 21 (FGF21) is a novel metabolic regulator that represents a promising target for the treatment of several metabolic diseases. Administration of recombinant wild type FGF21 to diabetic animals leads to a dramatic improvement in glycaemia and ameliorates other systemic measure...

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Autores principales: Adams, Andrew C., Halstead, Carolyn A., Hansen, Barbara C., Irizarry, Armando R., Martin, Jennifer A., Myers, Sharon R., Reynolds, Vincent L., Smith, Holly W., Wroblewski, Victor J., Kharitonenkov, Alexei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3688819/
https://www.ncbi.nlm.nih.gov/pubmed/23823755
http://dx.doi.org/10.1371/journal.pone.0065763
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author Adams, Andrew C.
Halstead, Carolyn A.
Hansen, Barbara C.
Irizarry, Armando R.
Martin, Jennifer A.
Myers, Sharon R.
Reynolds, Vincent L.
Smith, Holly W.
Wroblewski, Victor J.
Kharitonenkov, Alexei
author_facet Adams, Andrew C.
Halstead, Carolyn A.
Hansen, Barbara C.
Irizarry, Armando R.
Martin, Jennifer A.
Myers, Sharon R.
Reynolds, Vincent L.
Smith, Holly W.
Wroblewski, Victor J.
Kharitonenkov, Alexei
author_sort Adams, Andrew C.
collection PubMed
description Fibroblast growth factor 21 (FGF21) is a novel metabolic regulator that represents a promising target for the treatment of several metabolic diseases. Administration of recombinant wild type FGF21 to diabetic animals leads to a dramatic improvement in glycaemia and ameliorates other systemic measures of metabolic health. Here we report the pharmacologic outcomes observed in non-human primates upon administration of a recently described FGF21 analogue, LY2405319 (LY). Diabetic rhesus monkeys were treated subcutaneously with LY once daily for a period of seven weeks. The doses of LY used were 3, 9 and 50 mg/kg each delivered in an escalating fashion with washout measurements taken at 2, 4, 6 and 8 weeks following the final LY dose. LY therapy led to a dramatic and rapid lowering of several important metabolic parameters including glucose, body weight, insulin, cholesterol and triglyceride levels at all doses tested. In addition, we observed favorable changes in circulating profiles of adipokines, with increased adiponectin and reduced leptin indicative of direct FGF21 action on adipose tissue. Importantly, and for the first time we show that FGF21 based therapy has metabolic efficacy in an animal with late stage diabetes. While the glycemic efficacy of LY in this animal was partially attenuated its lipid lowering effect was fully preserved suggesting that FGF21 may be a viable treatment option even in patients with advanced disease progression. These findings support continued exploration of the FGF21 pathway for the treatment of metabolic disease.
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spelling pubmed-36888192013-07-02 LY2405319, an Engineered FGF21 Variant, Improves the Metabolic Status of Diabetic Monkeys Adams, Andrew C. Halstead, Carolyn A. Hansen, Barbara C. Irizarry, Armando R. Martin, Jennifer A. Myers, Sharon R. Reynolds, Vincent L. Smith, Holly W. Wroblewski, Victor J. Kharitonenkov, Alexei PLoS One Research Article Fibroblast growth factor 21 (FGF21) is a novel metabolic regulator that represents a promising target for the treatment of several metabolic diseases. Administration of recombinant wild type FGF21 to diabetic animals leads to a dramatic improvement in glycaemia and ameliorates other systemic measures of metabolic health. Here we report the pharmacologic outcomes observed in non-human primates upon administration of a recently described FGF21 analogue, LY2405319 (LY). Diabetic rhesus monkeys were treated subcutaneously with LY once daily for a period of seven weeks. The doses of LY used were 3, 9 and 50 mg/kg each delivered in an escalating fashion with washout measurements taken at 2, 4, 6 and 8 weeks following the final LY dose. LY therapy led to a dramatic and rapid lowering of several important metabolic parameters including glucose, body weight, insulin, cholesterol and triglyceride levels at all doses tested. In addition, we observed favorable changes in circulating profiles of adipokines, with increased adiponectin and reduced leptin indicative of direct FGF21 action on adipose tissue. Importantly, and for the first time we show that FGF21 based therapy has metabolic efficacy in an animal with late stage diabetes. While the glycemic efficacy of LY in this animal was partially attenuated its lipid lowering effect was fully preserved suggesting that FGF21 may be a viable treatment option even in patients with advanced disease progression. These findings support continued exploration of the FGF21 pathway for the treatment of metabolic disease. Public Library of Science 2013-06-18 /pmc/articles/PMC3688819/ /pubmed/23823755 http://dx.doi.org/10.1371/journal.pone.0065763 Text en © 2013 Adams et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Adams, Andrew C.
Halstead, Carolyn A.
Hansen, Barbara C.
Irizarry, Armando R.
Martin, Jennifer A.
Myers, Sharon R.
Reynolds, Vincent L.
Smith, Holly W.
Wroblewski, Victor J.
Kharitonenkov, Alexei
LY2405319, an Engineered FGF21 Variant, Improves the Metabolic Status of Diabetic Monkeys
title LY2405319, an Engineered FGF21 Variant, Improves the Metabolic Status of Diabetic Monkeys
title_full LY2405319, an Engineered FGF21 Variant, Improves the Metabolic Status of Diabetic Monkeys
title_fullStr LY2405319, an Engineered FGF21 Variant, Improves the Metabolic Status of Diabetic Monkeys
title_full_unstemmed LY2405319, an Engineered FGF21 Variant, Improves the Metabolic Status of Diabetic Monkeys
title_short LY2405319, an Engineered FGF21 Variant, Improves the Metabolic Status of Diabetic Monkeys
title_sort ly2405319, an engineered fgf21 variant, improves the metabolic status of diabetic monkeys
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3688819/
https://www.ncbi.nlm.nih.gov/pubmed/23823755
http://dx.doi.org/10.1371/journal.pone.0065763
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