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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 Wang, Yu

PloS one, 2013-06, Vol.8 (6), p.e65763 [Periódico revisado por pares]

United States: Public Library of Science

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Título:
LY2405319, an Engineered FGF21 Variant, Improves the Metabolic Status of Diabetic Monkeys
Autor: 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
Wang, Yu
Assuntos: Adipokines - blood ; Adiponectin ; Adipose tissue ; Animals ; Anticholesteremic agents ; Biology ; Blood glucose ; Blood Glucose - analysis ; Body weight ; Care and treatment ; Cholesterol ; Development and progression ; Dextrose ; Diabetes ; Diabetes mellitus ; Diabetes Mellitus, Experimental - metabolism ; Disease Progression ; Dose-Response Relationship, Drug ; Drug dosages ; Endocrinology ; Energy Intake - drug effects ; Fibroblast growth factor ; Fibroblast growth factors ; Fibroblast Growth Factors - pharmacokinetics ; Fibroblast Growth Factors - pharmacology ; Fibroblasts ; Glucose ; Glucose metabolism ; Growth factors ; Homeostasis ; Insulin ; Insulin - blood ; Laboratories ; Leptin ; Lipids ; Macaca mulatta ; Medical treatment ; Medicine ; Metabolic disorders ; Metabolism ; Monkeys ; Monkeys & apes ; Mutation ; Pharmacology ; Pichia pastoris ; Primates ; Rodents ; Therapy ; Type 2 diabetes ; Washout ; Weight Loss - drug effects
É parte de: PloS one, 2013-06, Vol.8 (6), p.e65763
Notas: Conceived and designed the experiments: AK BCH VLR SRM JAM HWS. Performed the experiments: CAH BCH ARI JAM HWS VJW. Analyzed the data: ACA CAH BCH ARI JAM SRM VLR HWS VJW AK. Contributed reagents/materials/analysis tools: CAH BCH ARI JAM SRM VLR HWS VJW. Wrote the paper: ACA AK.
Competing Interests: The authors have the following interests: All authors of the manuscript except Barbara C. Hansen are employees of Eli Lilly and Company, the funder of this study. There are no ongoing clinical development studies with LY2405319. LY2405319 holds the following patents relating to material pertinent to this research: Christopher Carl Frye, Lihua Huang, Radmila Micanovic; WO 2006/028595 (US 7,582,607), filed July 26, 2005 (Eli Lilly and Company). There are no further patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials. Barbara C. Hansen has no competing interests.
Descrição: 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.
Editor: United States: Public Library of Science
Idioma: Inglês

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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 Wang, Yu

United States: Public Library of Science

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