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. Attached Files Name Description MIMEType Size Downloads 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.org/0000-0003-4214-7628 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 1479-6805 Keyword(s) Science & Technology Life Sciences & Biomedicine Endocrinology & Metabolism insulin resistance glucose metabolism metformin nutrition muscle MEDIATED CAPILLARY RECRUITMENT MICROVASCULAR BLOOD-FLOW RAT SKELETAL-MUSCLE AMERICAN-DIABETES-ASSOCIATION GLUCAGON-LIKE PEPTIDE-1 GLUCOSE-UPTAKE IN-VIVO EUROPEAN ASSOCIATION ENDOTHELIAL FUNCTION POSITION STATEMENT 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 Persistent URL http://hdl.handle.net/10536/DRO/DU:30129650 Document type: Journal Article Collections: Faculty of Health Institute for Frontier Materials Related Links Link Description Connect to published version Go to link with your DU access privileges     Unless expressly stated otherwise, the copyright for items in DRO is owned by the author, with all rights reserved. Versions Version Filter Type Fri, 06 Sep 2019, 08:30:03 EST Sat, 07 Sep 2019, 05:00:19 EST Mon, 16 Sep 2019, 07:59:37 EST Tue, 01 Oct 2019, 06:04:55 EST Sat, 05 Oct 2019, 02:32:00 EST Fri, 11 Oct 2019, 12:52:57 EST Fri, 11 Oct 2019, 12:57:31 EST Filtered Full Citation counts:   Cited 0 times in TR Web of Science Cited 0 times in Scopus Search Google Scholar Access Statistics: 57 Abstract Views, 0 File Downloads  -  Detailed Statistics Created: Fri, 06 Sep 2019, 08:30:03 EST

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