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 10 mg/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 200 mg/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 3 mU.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.