Metformin improves vascular and metabolic insulin action in insulin-resistant muscle

Bradley, Eloise A., Premilovac, Dino, Betik, Andrew C., Hu, Donghua, Attrill, Emily, Richards, Stephen M., Rattigan, Stephen and Keske, Michelle A. 2019, Metformin improves vascular and metabolic insulin action in insulin-resistant muscle, Journal of endocrinology, vol. 243, no. 2, pp. 85-96, doi: 10.1530/JOE-19-0067.

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Title Metformin improves vascular and metabolic insulin action in insulin-resistant muscle
Author(s) Bradley, Eloise A.
Premilovac, Dino
Betik, Andrew C.
Hu, Donghua
Attrill, Emily
Richards, Stephen M.
Rattigan, Stephen
Keske, Michelle A.ORCID iD for Keske, Michelle A.
Journal name Journal of endocrinology
Volume number 243
Issue number 2
Start page 85
End page 96
Total pages 12
Publisher Bioscientifica
Place of publication Bradley Stok, Eng.
Publication date 2019-11
ISSN 0022-0795
Keyword(s) Science & Technology
Life Sciences & Biomedicine
Endocrinology & Metabolism
insulin resistance
glucose metabolism
Summary Insulin stimulates glucose disposal in skeletal muscle in part by increasing microvascular blood flow, and this effect is blunted during insulin resistance. We aimed to determine whether metformin treatment improves insulin-mediated glucose disposal and vascular insulin responsiveness in skeletal muscle of insulin-resistant rats. Sprague–Dawley rats were fed a normal (ND) or high-fat (HFD) diet for 4 weeks. A separate HFD group was given metformin in drinking water (HFD + MF, 150 mg/kg/day) during the final 2 weeks. After the intervention, overnight-fasted (food and metformin removed) anaesthetised rats underwent a 2-h euglycaemic–hyperinsulinaemic clamp (10 mU/min/kg) or saline infusion. Femoral artery blood flow, hindleg muscle microvascular blood flow, muscle glucose disposal and muscle signalling (Ser473-AKT and Thr172-AMPK phosphorylation) were measured. HFD rats had elevated body weight, epididymal fat pad weight, fasting plasma insulin and free fatty acid levels when compared to ND. HFD-fed animals displayed whole-body and skeletal muscle insulin resistance and blunting of insulin-stimulated femoral artery blood flow, muscle microvascular blood flow and skeletal muscle insulin-stimulated Ser473-AKT phosphorylation. Metformin treatment of HFD rats reduced fasting insulin and free fatty acid concentrations and lowered body weight and adiposity. During euglycaemic-hyperinsulinaemic clamp, metformin-treated animals showed improved vascular responsiveness to insulin, improved insulin-stimulated muscle Ser473-AKT phosphorylation but only partially restored (60%) muscle glucose uptake. This occurred without any detectable levels of metformin in plasma or change in muscle Thr172-AMPK phosphorylation. We conclude that 2-week metformin treatment is effective at improving vascular and metabolic insulin responsiveness in muscle of HFD-induced insulin-resistant rats.
Language eng
DOI 10.1530/JOE-19-0067
Indigenous content off
Field of Research 1103 Clinical Sciences
0707 Veterinary Sciences
0702 Animal Production
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2019, Society for Endocrinology
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