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Signal Transduction

Increased p85/55/50 Expression and Decreased Phosphotidylinositol 3-Kinase Activity in Insulin-Resistant Human Skeletal Muscle

  1. Gautam K. Bandyopadhyay,
  2. Joseph G. Yu,
  3. Jachelle Ofrecio and
  4. Jerold M. Olefsky
  1. Department of Medicine, Division of Endocrinology and Metabolism, University of California, La Jolla, California
  1. Address correspondence and reprint requests to Jerrold M. Olefsky, MD, University of California at San Diego, Department of Medicine (0673), 225 Stein Clinical Research Bldg., 9500 Gilman Dr., La Jolla, CA 92093. E-mail: jolefsky{at}ucsd.edu
Diabetes 2005 Aug; 54(8): 2351-2359. https://doi.org/10.2337/diabetes.54.8.2351
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  • FIG. 1.
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    FIG. 1.

    PI 3-kinase regulatory subunits in human muscle. A: A representative Western blot analysis of the basal muscle homogenates with a pan anti-p85 antibody and antiactin antibody. B: The ratio subunit to actin in lean, obese (Ob), and type 2 diabetic subjects for individual subunits as well as for combined subunits. *P < 0.01, **P < 0.001 vs. lean.

  • FIG. 2.
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    FIG. 2.

    Phosphorylation of IRS-1. A: A representative Western blot for pSer307 IRS-1 and pY IRS-1. Areas representing insulin-stimulated levels of pSer307 IRS-1/total IRS-1 (B) and pY-IRS-1/total IRS-1 (C) in lean, obese (Ob), and type 2 diabetic subjects are shown. *P < 0.001 vs. lean basal; **P < 0.001 vs. lean insulin stimulated.

  • FIG. 3.
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    FIG. 3.

    Interaction of p85 and p110 with IRS-1. A: Western blot analysis of IRS-1 bound p85 and p110 in the IRS-1 immunoprecipitates is shown. The signal intensities showing insulin-stimulated binding of p110 to IRS-1 (B) and p85 to IRS-1 (C) are shown. *P < 0.05, **P < 0.001 vs. lean. Ob, obese.

  • FIG. 4.
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    FIG. 4.

    PI 3-kinase activity. A: A representative autoradiogram showing PI 3-phosphate (PI-3P) formed by the kinase activity in the anti-IRS-1 immunoprecipitates. B: Quantitative comparison of insulin-stimulated PI 3-kinase activity in human muscle from lean, obese (Ob), and type 2 diabetic subjects. *P < 0.05, **P < 0.01 vs. lean. CPM, counts per minute.

  • FIG. 5.
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    FIG. 5.

    Insulin-stimulated activation of PKC-ζ/λ. Insulin-stimulated PKC activity was measured in the immune agarose beads obtained after immunoprecipitation of PKC-ζ/λ from the lysates with anti–COOH-terminal PKC-ζ antiserum. *P < 0.01 vs. lean basal; **P < 0.005 vs. lean insulin stimulated. CPM, counts per minute; Ob, obese.

  • FIG. 6.
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    FIG. 6.

    Insulin-stimulated phosphorylation of Akt in human muscle. Comparison of insulin-stimulated phosphorylation of Thr (308)-Akt (A and B) and Ser (473)-Akt (C and D) in human muscle from lean, obese (Ob), and type 2 diabetic subjects.

  • FIG. 7.
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    FIG. 7.

    Insulin-stimulated PKC-θ activity and phosphorylation of JNK-1 and IKK-β. PKC-θ activities in the lysates from muscle obtained before and after insulin infusion (A) and the cytosol and membrane fractions (B). *P < 0.01 vs. lean basal. Representative Western blots for phospho-JNK (p-JNK) and total JNK (C) and phospho-IKK-β (pIKKβ) and total IKK-β signals (E). Results from densitometric scans for pJNK (D) and pIKK-β signals (F). *P < 0.05, **P < 0.01 vs. lean basal. Ob, obese.

  • FIG. 8.
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    FIG. 8.

    Insulin-stimulated phosphorylation of ERK-1 and p38 kinase. Representative Western blots for phospho-ERK (A) and phospho-p38 (C). B and D: The results after densitometric quantitation. *P < 0.05 vs. lean basal (B) or P = 0.05 vs. lean basal (D). **P < 0.05 vs. lean basal; §P < 0.01 vs. lean insulin stimulated.

Tables

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  • TABLE 1

    Subject characteristics

    NondiabeticObeseType 2 diabetic
    n887
    Age (years)47.25 ± 4.843.5 ± 4.048.0 ± 5.2
    Weight (kg)75.2 ± 5.496.7 ± 4.0110.0 ± 5.4
    BMI (kg/m2)24.4 ± 1.233.3 ± 1.06*37.1 ± 2.64*
    Fasting plasma glucose (mmol/l)5.09 ± 0.125.1 ± 0.111.3 ± 1.5*
    Glucose infusion rate (mg · kg−1 · min−1)9.9 ± 0.937.0 ± 0.37†2.26 ± 0.76*
    Basal insulin (pmol/l)66.7 ± 10125.36 ± 26‡315 ± 78‡
    Insulin after 300-min clamping (pmol/l)1,070 ± 471,290 ± 961,090 ± 74
    Basal plasma free fatty acids (μmol/l)346 ± 36400 ± 30§750 ± 120‡
    Free fatty acids after insulin clamping (μmol/l)19 ± 3.816 ± 3.5270 ± 100
    Triacylglycerol (mg/dl)88.75 ± 6.8128.6 ± 21‖390 ± 127†
    • Data are means ± SE. All P values were determined by comparing with nondiabetic subjects.

    • *

      * P < 0.005;

    • †

      † P < 0.05;

    • ‡

      ‡ P < 0.02;

    • §

      § NS;

    • ‖

      ‖ P = 0.05.

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Increased p85/55/50 Expression and Decreased Phosphotidylinositol 3-Kinase Activity in Insulin-Resistant Human Skeletal Muscle
Gautam K. Bandyopadhyay, Joseph G. Yu, Jachelle Ofrecio, Jerold M. Olefsky
Diabetes Aug 2005, 54 (8) 2351-2359; DOI: 10.2337/diabetes.54.8.2351

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Increased p85/55/50 Expression and Decreased Phosphotidylinositol 3-Kinase Activity in Insulin-Resistant Human Skeletal Muscle
Gautam K. Bandyopadhyay, Joseph G. Yu, Jachelle Ofrecio, Jerold M. Olefsky
Diabetes Aug 2005, 54 (8) 2351-2359; DOI: 10.2337/diabetes.54.8.2351
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