Thiazolidinediones (AD-4833 and CS-045) Improve Hepatic Insulin Resistance in Streptozotocin-Induced Diabetic Rats.

Abstract

To investigate whether thiazolidinediones (AD-4833 and CS-045), new oral antidiabetic agents, are effective in insulin-dependent diabetes mellitus, the effect of thiazolidinediones on streptozotocin-induced diabetic rats was studied by the glucose clamp technique. Diabetic rats were divided into five groups: (1) intensively insulin treated group given a daily injection of 4-6 units Ultralente insulin, (2) AD-4833 group treated with a daily injection of 2 units Ultralente insulin, the minimal dose to make urinary ketones negative, and ingestion of 10mg/kg 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) CS-045 group treated with the same insulin injection and ingestion of 200mg/kg CS-045 suspended in 0.5% chlormethyl cellulose, (5) chlormethyl cellulose group treated as the control for the CS-045 group. Seven days after these treatments, all five groups of diabetic rats and normal control rats were subjected to the glucose clamp study in which 3mU•kg^-1•min^-1 porcine insulin was continuously infused. Glucose infusion rates (GIR) for the gum arabic and chlormethyl cellulose groups were significantly lower than in control rats, and the rates of hepatic glucose output (HGO) of these two groups were not suppressed, indicating the presence of hepatic insulin resistance. Intensive insulin treatment 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 concluded that thiazolidinediones improved hepatic insulin resistance in the presence of a minimal dose of insulin.