To determine the contribution of
hyperglycemia to the
insulin resistance in various
insulin-sensitive tissues of Zucker diabetic fatty (ZDF) rats,
T-1095, an oral
sodium-dependent
glucose transporter (SGLT) inhibitor, was administered by being mixed into food. Long-term treatment with
T-1095 lowered both fed and fasting
blood glucose levels to near normal ranges. A hyperinsulinemic euglycemic clamp study that was performed after 4 wk of
T-1095 treatment demonstrated partial recovery of the reduced
glucose infusion rate (GIR) in the T-1095-treated group. In the livers of T-1095-treated ZDF rats, hepatic
glucose production rate (HGP) and
glucose utilization rate (
GUR) showed marked recovery, with almost complete normalization of reduced
glucokinase/
glucose-6-phosphatase (G-6-Pase) activities ratio. In adipose tissues, decreased
GUR was also shown to be significantly improved with a normalization of
insulin-induced GLUT-4 translocation. In contrast, in skeletal muscles, the reduced
GUR was not significantly improved in response to amelioration of
hyperglycemia by
T-1095 treatment. These results suggest that the contribution of
hyperglycemia to
insulin resistance in ZDF rats is very high in the liver and considerably elevated in adipose tissues, although it is very low in skeletal muscle.