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

in Journal of Endocrinology
Authors:
Eloise A Bradley Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia

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Dino Premilovac Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia
School of Medicine, University of Tasmania, Hobart, Tasmania, Australia

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Andrew C Betik Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University, Geelong, Victoria, Australia

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Donghua Hu Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia

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Emily Attrill School of Medicine, University of Tasmania, Hobart, Tasmania, Australia

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Stephen M Richards Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia
School of Medicine, University of Tasmania, Hobart, Tasmania, Australia

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Stephen Rattigan Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia

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Michelle A Keske Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia
Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University, Geelong, Victoria, Australia

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Correspondence should be addressed to M A Keske: Michelle.Keske@deakin.edu.au

*(E A Bradley and D Premilovac contributed equally to this work)

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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.

Supplementary Materials

    • Supplementary Figure 1: Example immunoblot of skeletal muscle total Akt (panel A) and Ser473Akt (panel B). ND = normal diet fed; HFD = high fat diet fed; HFD+MF = HFD+metformin; SAL = saline; INS = insulin.
    • Supplementary Figure 2: Example immunoblot of skeletal muscle total AMPK (panel A) and Thr172AMPK(panel B). EX CTRL = exercised muscle as a positive control; ND = normal diet fed; HFD = high fat diet fed; HFD+MF = HFD+metformin; SAL = saline; INS = insulin.
    • Supplementary Figure 3: Mean arterial pressure time course during a 2 hour euglycemic hyperinsulinemic clamp (10mU/min/kg) or saline infusion in normal diet (ND, panel A), high fat diet (HFD, panel B) and high fat diet + Metformin (HFD + MF, panel C) treated rats. Mean arterial pressure at the conclusion of the 2 hour experiment in ND, HFD and HFD+MF rats (panel D). Data are means ± SEM for n= 14-17 rats in each group. Two-way-ANOVA.
    • Supplementary Figure 4: Heart rate time course during a 2 hour euglycemic hyperinsulinemic clamp (10mU/min/kg) or saline infusion in normal diet (ND, panel A), high fat diet (HFD, panel B) and high fat diet + Metformin (HFD + MF, panel C) treated rats. Heart rate at the conclusion of the 2 hour experiment in ND, HFD and HFD+MF rats (panel D). Data are means ± SEM for n= 14-17 rats in each group. Two-way-ANOVA.

 

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