OBJECTIVE -Traditional cardiovascular risk factors (CVRF) only partly explain the excessive risk of cardiovascular disease in patients with type 2 diabetes. There is now an increasing appreciation for many novel CVRF that occur largely as a result of insulin resistance and hyperinsulinemia. Therefore, we investigated whether diabetes medications that vary in their mechanism of action and ability to reduce insulin resistance may differ in their effects on both traditional and novel CVRF. RESEARCH DESIGN AND METHODS-We compared the addition of metformin or troglitazone therapy on CVRF in 22 subjects with type 2 diabetes who remained in poor glycemic control (with HbA 1c Ͼ8.5%) while taking glyburide 10 mg twice daily. Subjects were initially randomized to either metformin 850 mg once daily or troglitazone 200 mg once daily. Both medications were then titrated upward as needed to achieve fasting plasma glucose Ͻ120 mg/dl. Measures of glucose control, insulin resistance, and CVRF (blood pressure, lipids, plasminogen activator inhibitor-1, C-reactive protein, fibrinogen, and small dense LDL) were assessed both before and after therapy.RESULTS -After 4 months of treatment, both metformin and troglitazone led to similar decreases in fasting plasma glucose and HbA 1c . The reduction in insulin resistance determined by hyperinsulinemic-euglycemic clamp was nearly twofold greater with troglitazone than metformin. Metformin did not induce significant changes in blood pressure, LDL cholesterol, LDL size, HDL cholesterol, triglycerides, or plasminogen activator inhibitor-1. However, C-reactive protein did decrease by 33% (6 Ϯ 1 to 4 Ϯ 1 ng/l; P Ͻ 0.01). Troglitazone therapy was associated with increases in LDL size (26.21 Ϯ 0.22 to 26.56 Ϯ 0.25 nm; P ϭ 0.04) and HDL cholesterol (33 Ϯ 3 to 36 Ϯ 3 mg/dl; P ϭ 0.05) and decreases in triglycerides (197 Ϯ 19 to 155 Ϯ 23 mg/dl; P ϭ 0.07) and C-reactive protein by 60% (8 Ϯ 3 to 3 Ϯ 1 ng/l, P Ͻ 0.01).CONCLUSIONS -For patients with type 2 diabetes in whom maximal sulfonylurea therapy failed, the addition of the insulin sensitizer troglitazone seemed to have greater benefits on several traditional and novel CVRF than metformin therapy. These differences were not related to glycemic improvement but reflected, in part, the greater reduction in insulin resistance obtained with addition of troglitazone. These data suggest that medications that more effectively address this underlying metabolic defect may be more beneficial in reducing cardiovascular risk in type 2 diabetes.

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 ⅐ m ؊2 ⅐ 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 p110␤ 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. Diabetes 51: [443][444][445][446][447][448] 2002

Type 2 diabetic subjects failing glyburide therapy were randomized to receive additional therapy with either metformin (2,550 mg/day) or troglitazone (600 mg/day) for 3-4 months. Biopsies of subcutaneous abdominal adipose tissue were obtained before and after therapy. Glycemic control was similar with both treatments. Metformin treatment increased insulin-stimulated whole-body glucose disposal rates by 20% (P < 0.05); the response to troglitazone was greater (44% increase, P < 0.01 vs. baseline, P < 0.05 vs. metformin). Troglitazone-treated subjects displayed a tendency toward weight gain (5 ؎ 2 kg, P < 0.05), increased adipocyte size, and increased serum leptin levels. Metformintreated subjects were weight-stable, with unchanged leptin levels and reduced adipocyte size (to 84 ؎ 4% of control, P < 0.005). Glucose transport in isolated adipocytes from metformin-treated subjects was unaltered from pretreatment. Glucose transport in both the absence (321 ؎ 134% of pre-Rx, P < 0.05) and presence of insulin (418 ؎ 161%, P < 0.05) was elevated after troglitazone treatment. Metformin treatment had no effect on adipocyte content of GLUT1 or GLUT4 proteins. After troglitazone treatment, GLUT4 protein expression was increased twofold (202 ؎ 42%, P < 0.05). Insulin-stimulated serine phosphorylation of Akt was augmented after troglitazone (170 ؎ 34% of pre-Rx response, P < 0.05) treatment and unchanged by metformin. We conclude that the ability of troglitazone to upregulate adipocyte glucose transport, GLUT4 expression, and insulin signaling can contribute to its greater effect on whole-body glucose disposal. Diabetes 51: 30 -36, 2002