The relationship between insulin action and control of the adipocyte-derived factor adiponectin was studied in age-and weight-matched obese individuals with type 2 diabetes failing sulfonylurea therapy. After initial metabolic characterization, subjects were randomized to troglitazone or metformin treatment groups; all subjects received glyburide (10 mg BID) as well. Treatment was continued for 3 months. The extent of glycemic control after treatment was similar in both groups. However, the increase in maximal insulin-stimulated glucose disposal rate was greater following troglitazone therapy (؉44%) compared with metformin treatment (؉20%). Troglitazone treatment increased serum adiponectin levels nearly threefold. There was no change in serum adiponectin with metformin treatment. A positive correlation was found between increases in wholebody glucose disposal rates and serum adiponectin levels after troglitazone; no such relationship was seen with metformin. The adiponectin protein content of subcutaneous abdominal adipocytes was increased following troglitazone treatment and unchanged after metformin. Adiponectin release from adipocytes was also augmented with troglitazone treatment. Adiponectin was present in adipocytes and plasma in several multimeric forms; a trimer was the major form secreted from adipocytes. These results indicate that increases in adiponectin content and secretion are associated with improved insulin action but are not directly related to glycemic control. Modulation of adipocyte function, including upregulation of adiponectin synthesis and secretion, may be an important mechanism by which thiazolidinediones influence insulin action. Diabetes

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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.

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