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

Glycogen synthase kinase (GSK)-

We examined the regulation of free fatty acid (FFA, palmitate) uptake into skeletal muscle cells of nondiabetic and type 2 diabetic subjects. Palmitate uptake included a protein-mediated component that was inhibited by phloretin. The protein-mediated component of uptake in muscle cells from type 2 diabetic subjects (78 ± 13 nmol · mg protein-1 · min-1) was reduced compared with that in nondiabetic muscle (150 ± 17, P < 0.01). Acute insulin exposure caused a modest (16 ± 5%, P < 0.025) but significant increase in protein-mediated uptake in nondiabetic muscle. There was no significant insulin effect in diabetic muscle (+19 ± 19%, P = not significant). Chronic (4 day) treatment with a series of thiazolidinediones, troglitazone (Tgz), rosiglitazone (Rgz), and pioglitazone (Pio) increased FFA uptake. Only the phloretin-inhibitable component was increased by treatment, which normalized this activity in diabetic muscle cells. Under the same conditions, FFA oxidation was also increased by thiazolidinedione treatment. Increases in FFA uptake and oxidation were associated with upregulation of fatty acid translocase (FAT/CD36) expression. FAT/CD36 protein was increased by Tgz (90 ± 22% over control), Rgz (146 ± 42%), and Pio (111 ± 37%, P < 0.05 for all 3) treatment. Tgz treatment had no effect on fatty acid transporter protein-1 and membrane-associated plasmalemmal fatty acid-binding protein mRNA expression. We conclude that FFA uptake into cultured muscle cells is, in part, protein mediated and acutely insulin responsive. The basal activity of FFA uptake is impaired in type 2 diabetes. In addition, chronic thiazolidinedione treatment increased FFA uptake and oxidation into cultured human skeletal muscle cells in concert with upregulation of FAT/CD36 expression. Increased FFA uptake and oxidation may contribute to lower circulating FFA levels and reduced insulin resistance in skeletal muscle of individuals with type 2 diabetes following thiazolidinedione treatment.