THIAZOLIDINEDIONES (AD-4833 AND CS-045) IMPROVE HEPATIC INSULIN-RESISTANCE IN STREPTOZOTOCIN-INDUCED DIABETIC RATS

To investigate whether thiazolidinediones (AD-4833 and CS-045), new or al antidiabetic agents, are effective in insulin-dependent diabetes me llitus, the effect of thiazolidinediones on streptozotocin-induced dia betic rats was studied by the glucose clamp technique. Diabetic rats w ere divided into five groups: (1) intensively insulin treated group gi ven a daily injection of 4-6 units Ultralente insulin, (2) AD-4833 gro up treated with a daily injection of 2 units Ultralente insulin, the m inimal dose to make urinary ketones negative, and ingestion of 10 mg/k g of AD-4833 suspended in 5% gum arabic, (3) gum arabic group treated in the same way as the AD-4833 group except for the active drug, (4) C S-045 group treated with the same insulin injection and ingestion of 2 00 mg/kg CS-045 suspended in 0.5% chlormethyl cellulose, (5) chlormeth yl cellulose group treated as the control for the CS-045 group. Seven days after these treatments, all five groups of diabetic rats and norm al control rats were subjected to the glucose clamp study in which 3 m U.kg-1.min-1 porcine insulin was continuously infused. Glucose infusio n rates (GIR) for the gum arabic and chlormethyl cellulose groups were significantly lower than in control rats, and the rates of hepatic gl ucose output (HGO) of these two groups were not suppressed, indicating the presence of hepatic insulin resistance. Intensive insulin treatme nt as well as administration of AD-4833 and CS-045 with a minimal dose of insulin restored both GIR and HGO towards normal levels. It is con cluded that thiazolidinediones improved hepatic insulin resistance in the presence of a minimal dose of insulin.