Troglitazone but not Metformin Restores Insulin-Stimulated Phosphoinositide 3-Kinase Activity and Increases p110β Protein Levels in Skeletal Muscle of Type 2 Diabetic Subjects

  1. Young-Bum Kim1,
  2. Theodore P. Ciaraldi23,
  3. Alice Kong23,
  4. Dennis Kim23,
  5. Neelima Chu23,
  6. Pharis Mohideen23,
  7. Sunder Mudaliar23,
  8. Robert R. Henry23 and
  9. Barbara B. Kahn1
  1. 1Diabetes Unit, Division of Endocrinology and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Massachusetts
  2. 2Veterans Affairs San Diego Healthcare System, San Diego, California
  3. 3Department of Medicine, University of California, San Diego, La Jolla, California

    Abstract

    Insulin stimulation of phosphatidylinositol (PI) 3-kinase activity is defective in skeletal muscle of type 2 diabetic individuals. We studied the impact of antidiabetic therapy on this defect in type 2 diabetic subjects who failed glyburide treatment by the addition of troglitazone (600 mg/day) or metformin (2,550 mg/day) therapy for 3–4 months. Improvement in glycemic control was similar for the two groups, as indicated by changes in fasting glucose and HbA1c levels. Insulin action on whole-body glucose disposal rate (GDR) was determined before and after treatment using the hyperinsulinemic (300 mU · m−2 · min−1) euglycemic (5.0–5.5 mmol/l) clamp technique. Needle biopsies of vastus lateralis muscle were obtained before and after each 3-h insulin infusion. Troglitazone treatment resulted in a 35 ± 9% improvement in GDR (P < 0.01), which was greater than (P < 0.05) the 22 ± 13% increase (P < 0.05) after metformin treatment. Neither treatment had any effect on basal insulin receptor substrate-1 (IRS-1)-associated PI 3-kinase activity in muscle. However, insulin stimulation of PI 3-kinase activity was augmented nearly threefold after troglitazone treatment (from 67 ± 22% stimulation over basal pre-treatment to 211 ± 62% post-treatment, P < 0.05), whereas metformin had no effect. The troglitazone effect on PI 3-kinase activity was associated with a 46 ± 22% increase (P < 0.05) in the amount of the p110β catalytic subunit of PI 3-kinase. Insulin-stimulated Akt activity also increased after troglitazone treatment (from 32 ± 8 to 107 ± 32% stimulation, P < 0.05) but was unchanged after metformin therapy. Protein expression of other key insulin signaling molecules (IRS-1, the p85 subunit of PI 3-kinase, and Akt) was unaltered after either treatment. We conclude that the mechanism for the insulin-sensitizing effect of troglitazone, but not metformin, involves enhanced PI 3-kinase pathway activation in skeletal muscle of obese type 2 diabetic subjects.

    Footnotes

    • Address correspondence and reprint requests to Barbara B. Kahn, Diabetes Unit, Beth Israel Deaconess Medical Center, 99 Brookline Ave., Boston, MA 02215. E-mail: bkahn{at}caregroup.harvard.edu.

      Received for publication 6 August 2001 and accepted in revised form 26 October 2001.

      T.P.C. and S.M. have received honoraria from Parke-Davis, and R.R.H. has received honoraria and research funds from Pfizer. Y.B.K. and T.P.C. contributed equally to this work.

      GDR, glucose disposal rate; IRS-1, insulin receptor substrate-1; PI, phosphatidylinositol; PPAR-γ, peroxisome proliferator-activator receptor-γ TZD, thiazolidinedione.

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