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Intravascular Follistatin gene delivery improves glycemic control in a mouse model of type 2 diabetes

Citation

Davey, JR and Estevez, E and Thomson, RE and Whitham, M and Watt, KI and Hagg, A and Qian, H and Henstridge, DC and Ludlow, H and Hedger, MP and McGee, SL and Coughlan, MT and Febbraio, MA and Gregorevic, P, Intravascular Follistatin gene delivery improves glycemic control in a mouse model of type 2 diabetes, FASEB Journal, 34, (4) pp. 5697-5714. ISSN 0892-6638 (2020) [Refereed Article]

Copyright Statement

2020 Federation of American Societies for Experimental Biology

DOI: doi:10.1096/fj.201802059RRR

Abstract

Type 2 diabetes (T2D) manifests from inadequate glucose control due to insulin resistance, hypoinsulinemia, and deteriorating pancreatic β-cell function. The pro-inflammatory factor Activin has been implicated as a positive correlate of severity in T2D patients, and as a negative regulator of glucose uptake by skeletal muscle, and of pancreatic β-cell phenotype in mice. Accordingly, we sought to determine whether intervention with the Activin antagonist Follistatin can ameliorate the diabetic pathology. Here, we report that an intravenous Follistatin gene delivery intervention with tropism for striated muscle reduced the serum concentrations of Activin B and improved glycemic control in the db/db mouse model of T2D. Treatment reversed the hyperglycemic progression with a corresponding reduction in the percentage of glycated-hemoglobin to levels similar to lean, healthy mice. Follistatin gene delivery promoted insulinemia and abundance of insulin-positive pancreatic β-cells, even when treatment was administered to mice with advanced diabetes, supporting a mechanism for improved glycemic control associated with maintenance of functional β-cells. Our data demonstrate that single-dose intravascular Follistatin gene delivery can ameliorate the diabetic progression and improve prognostic markers of disease. These findings are consistent with other observations of Activin-mediated mechanisms exerting deleterious effects in models of obesity and diabetes, and suggest that interventions that attenuate Activin signaling could help further understanding of T2D and the development of novel T2D therapeutics.

Item Details

Item Type:Refereed Article
Keywords:Activin, diabetes, Follistatin, gene therapy, skeletal muscle
Research Division:Biomedical and Clinical Sciences
Research Group:Clinical sciences
Research Field:Endocrinology
Objective Division:Expanding Knowledge
Objective Group:Expanding knowledge
Objective Field:Expanding knowledge in the biomedical and clinical sciences
UTAS Author:Henstridge, DC (Mr Darren Henstridge)
ID Code:139614
Year Published:2020
Web of Science® Times Cited:3
Deposited By:Health Sciences
Deposited On:2020-06-23
Last Modified:2020-07-16
Downloads:0

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