Troglitazone but not metformin restores insulin-stimulated phosphoinositide 3-kinase activity and increases p110beta protein levels in skeletal muscle of type 2 diabetic subjects.
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 HbA(1c) levels. Insulin action on whole-body glucose disposal rate (GDR) was determined before and after treatment using the hyperinsulinemic (300 mU x m(-2) x 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 p110beta 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.
Kim
Young-Bum
YB
Diabetes Unit, Division of Endocrinology and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Massachusetts 02215, USA.
Ciaraldi
Theodore P
TP
Kong
Alice
A
Kim
Dennis
D
Chu
Neelima
N
Mohideen
Pharis
P
Mudaliar
Sunder
S
Henry
Robert R
RR
Kahn
Barbara B
BB
D000328:Adult; D000368:Aged; D002839:Chromans / Q000627:therapeutic use*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000201:enzymology*; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000627:therapeutic use*; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D008687:Metformin / Q000627:therapeutic use; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D013844:Thiazoles / Q000627:therapeutic use*; D045162:Thiazolidinediones; D000077288:Troglitazone
D002839:Chromans; D007004:Hypoglycemic Agents; D007328:Insulin; D007527:Isoenzymes; D013844:Thiazoles; D045162:Thiazolidinediones; D008687:Metformin; D019869:Phosphatidylinositol 3-Kinases; D000077288:Troglitazone