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Pathophysiology

Effects of Metformin and Rosiglitazone Treatment on Insulin Signaling and Glucose Uptake in Patients With Newly Diagnosed Type 2 Diabetes

A Randomized Controlled Study

  1. Håkan K.R. Karlsson1,
  2. Kirsti Hällsten2,
  3. Marie Björnholm1,
  4. Hiroki Tsuchida1,
  5. Alexander V. Chibalin1,
  6. Kirsi A. Virtanen2,
  7. Olli J. Heinonen3,
  8. Fredrik Lönnqvist14,
  9. Pirjo Nuutila25 and
  10. Juleen R. Zierath1
  1. 1Department of Surgical Sciences, Section of Integrative Physiology, Karolinska Institutet, Stockholm, Sweden
  2. 2Turku PET Centre, University of Turku, Turku, Finland
  3. 3Paavo Nurmi Centre, Sports and Exercise Medicine Unit, Department of Physiology, University of Turku, Turku, Finland
  4. 4Biovitrum, Stockholm, Sweden
  5. 5Department of Medicine, University of Turku, Turku, Finland
  1. Address correspondence and reprint requests to Juleen R. Zierath, PhD, Karolinska Institutet, Department of Surgical Sciences, Section of Integrative Physiology, S-171 77 Stockholm, Sweden. E-mail: juleen.zierath{at}fyfa.ki.se
Diabetes 2005 May; 54(5): 1459-1467. https://doi.org/10.2337/diabetes.54.5.1459
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  • FIG. 1.
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    FIG. 1.

    Schematic representation of the study protocol. A euglycemic-hyperinsulinemic clamp procedure was performed before and after 26 weeks of treatment with metformin, rosiglitazone, or placebo. Euglycemic-hyperinsulinemic conditions consisted of a 160-min insulin infusion. Leg muscle glucose uptake was assessed using PET. The arrow represents the time at which muscle biopsies were obtained. One biopsy was obtained under basal conditions, and two biopsies were obtained after insulin infusion (from rested and exercised leg, respectively).

  • FIG. 2.
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    FIG. 2.

    Whole-body and leg muscle glucose uptake rates. Whole-body glucose uptake (A) and leg muscle glucose uptake over the rested (B) and exercised (C) legs were determined during the euglycemic-hyperinsulinemic clamp procedure before (□) and after (▪) treatment. Leg glucose uptake was assessed across a portion of the vastus lateralis skeletal muscle using PET. Data are means ± SE for 9–11 subjects per group. *P < 0.05, **P < 0.01 for post- vs. pretreatment value. Met, metformin, Rosi, rosiglitazone; Plac, placebo.

  • FIG. 3.
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    FIG. 3.

    IRS-1–associated PI 3-kinase activity in skeletal muscle. Muscle biopsies were obtained under basal (□) or insulin-stimulated conditions in rested (▪) or exercised (Embedded Image) legs before and after treatment with metformin (A), rosiglitazone (B), or placebo (C). PI 3-kinase activity was measured in IRS-1 immunoprecipitates. Results were quantitated using a PhosphorImager. Data are means ± SE arbitrary units for six to nine subjects per group. *P < 0.05 vs. basal; †P < 0.05 for post- vs. pretreatment for the insulin-stimulated condition.

  • FIG. 4.
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    FIG. 4.

    Phosphorylation of Akt in skeletal muscle. Muscle biopsies were obtained under basal (□) or insulin-stimulated conditions in rested (▪) or exercised (Embedded Image) legs before and after treatment with metformin (A), rosiglitazone (B), or placebo (C). Phosphorylation of Akt kinase was measured by immunoblot analysis using an anti–phospho-Ser473 Akt antibody. Results were quantitated using densitometry. Data are means ± SE arbitrary units for 7–11 subjects per group. *P < 0.05 vs. basal value.

  • FIG. 5.
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    FIG. 5.

    Phosphorylation of AS160 in skeletal muscle. Muscle biopsies were obtained under basal (□) or insulin-stimulated conditions in rested (▪) or exercised (Embedded Image) legs before and after treatment with metformin (A), rosiglitazone (B), or placebo (C). Phosphorylation of AS160 was measured by immunoblot analysis using an anti–phospho-Akt substrate antibody. Results were quantitated using densitometry. Data are means ± SE arbitrary units for seven to nine subjects per group. *P < 0.05 vs. basal, †P < 0.05 for post- vs. pretreatment for the insulin-stimulated condition.

  • FIG. 6.
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    FIG. 6.

    Correlation analysis. A: Correlation between insulin-stimulated whole-body glucose uptake (GU) and insulin-stimulated leg muscle glucose uptake in the rested leg in the entire study cohort before pharmacological intervention (r = 0.88, P < 0.001, n = 30). B: Correlation between insulin-stimulated IRS-1–associated PI 3-kinase activity and insulin-stimulated leg muscle glucose uptake in the rested leg before pharmacological intervention (r = 0.57, P < 0.01, n = 21). C: Correlation between insulin-stimulated Akt phosphorylation and insulin-stimulated leg muscle glucose uptake in the rested leg before pharmacological intervention (r = 0.51, P < 0.05, n = 24).

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  • TABLE 1

    Clinical and metabolic characteristics of the patients

    Metformin
    Rosiglitazone
    Placebo
    PretreatmentPosttreatmentPretreatmentPosttreatmentPretreatmentPosttreatment
    n (M/F)9 (6/3)10 (8/2)11 (9/2)
    Age (years)57.7 ± 2.9—58.2 ± 2.1—58.6 ± 2.5—
    BMI (kg/m²)28.8 ± 1.328.0 ± 1.1*28.2 ± 1.028.2 ± 1.229.4 ± 1.329.5 ± 1.3
    HbA1c (%)7.1 ± 0.36.4 ± 0.3‡6.8 ± 0.36.4 ± 0.26.3 ± 0.16.2 ± 0.1
    Glucose (mmol/l)8.3 ± 0.67.1 ± 0.4*7.0 ± 0.36.8 ± 0.37.2 ± 0.37.5 ± 0.3
    Insulin (mU/l)10.8 ± 2.48.4 ± 1.36.8 ± 0.56.4 ± 0.410.2 ± 1.89.8 ± 1.2
    C-peptide (nmol/l)0.89 ± 0.120.61 ± 0.07*0.72 ± 0.060.57 ± 0.05*0.83 ± 0.090.71 ± 0.05*
    Fasting FFA (μmol/l)458 ± 71496 ± 63596 ± 59552 ± 86598 ± 70511 ± 58
    Clamp FFA (μmol/l)145 ± 26102 ± 16*110 ± 1457 ± 5†100 ± 2093 ± 19
    Total cholesterol (mmol/l)4.2 ± 0.24.4 ± 0.24.9 ± 0.35.5 ± 0.4*4.5 ± 0.34.4 ± 0.3
    HDL cholesterol (mmol/l)1.0 ± 0.11.1 ± 0.1†1.1 ± 0.11.1 ± 0.11.3 ± 0.11.3 ± 0.1
    LDL cholesterol (mmol/l)2.6 ± 0.22.5 ± 0.22.9 ± 0.33.7 ± 0.3†2.7 ± 0.32.7 ± 0.3
    Triglycerides (mmol/l)1.4 ± 0.11.5 ± 0.21.8 ± 0.31.5 ± 0.21.1 ± 0.11.0 ± 0.1
    Plasma lactate (mmol/l)1.0 ± 0.11.0 ± 0.10.9 ± 0.10.8 ± 0.10.8 ± 0.10.8 ± 0.1
    • Data are means ± SE.

    • *

      * P < 0.05,

    • †

      † P < 0.01,

    • ‡

      ‡ P < 0.001 vs. pretreatment.

  • TABLE 2

    mRNA expression in skeletal muscle posttreatment

    MetforminRosiglitazonePlaceboP value
    n91010
    Lipid transport and metabolism
        CD361060 ± 1861027 ± 1331000 ± 161NS
        FAT410.5 ± 2.310.5 ± 2.312.3 ± 4.4NS
        ACC-α2.7 ± 0.63.3 ± 0.63.4 ± 0.9NS
        ACC-β61 ± 1365 ± 1368 ± 12NS
        LPL104 ± 25253 ± 88144 ± 28NS
        SCD0.7 ± 0.31.4 ± 0.40.9 ± 0.2NS
        UCP3420 ± 87285 ± 46480 ± 114NS
        DGK δ36 ± 1030 ± 438 ± 14NS
    Glucose transport and metabolism
        GLUT4145 ± 40151 ± 35193 ± 47NS
        Hexokinase 225 ± 1128 ± 922 ± 8NS
        CAP265 ± 40281 ± 39224 ± 33NS
        Adiponectin receptor 1322 ± 49277 ± 42244 ± 40NS
    Transcription factors
        PPAR-γ3.4 ± 0.84.2 ± 0.65.1 ± 2.0NS
        PGC1-α148 ± 16169 ± 29126 ± 15NS
        PGC1-β11.8 ± 2.214.4 ± 2.917.6 ± 5.6NS
        PRC7.3 ± 1.67.3 ± 1.67.6 ± 1.9NS
        NRF-152 ± 1447 ± 870 ± 33NS
        FOXO1A30 ± 524 ± 328 ± 3NS
        SREBP133.6 ± 7.727.7 ± 4.232.3 ± 8.8NS
    • Data are mean ± SE arbitrary units normalized to GAPDH.

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Effects of Metformin and Rosiglitazone Treatment on Insulin Signaling and Glucose Uptake in Patients With Newly Diagnosed Type 2 Diabetes
Håkan K.R. Karlsson, Kirsti Hällsten, Marie Björnholm, Hiroki Tsuchida, Alexander V. Chibalin, Kirsi A. Virtanen, Olli J. Heinonen, Fredrik Lönnqvist, Pirjo Nuutila, Juleen R. Zierath
Diabetes May 2005, 54 (5) 1459-1467; DOI: 10.2337/diabetes.54.5.1459

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Effects of Metformin and Rosiglitazone Treatment on Insulin Signaling and Glucose Uptake in Patients With Newly Diagnosed Type 2 Diabetes
Håkan K.R. Karlsson, Kirsti Hällsten, Marie Björnholm, Hiroki Tsuchida, Alexander V. Chibalin, Kirsi A. Virtanen, Olli J. Heinonen, Fredrik Lönnqvist, Pirjo Nuutila, Juleen R. Zierath
Diabetes May 2005, 54 (5) 1459-1467; DOI: 10.2337/diabetes.54.5.1459
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