3-(
Benzo[b]furan-5-yl)-2', 6'-dihydroxy-4'-methylpropiophenone-2'-O-(6-O-methoxycarbonyl)-bet a-D -glucopyranoside (T-1095) is a derivative of
phlorizin, a potent inhibitor of Na(+)-
glucose cotransporters. We determined the
antidiabetic effect of
T-1095 in neonatally
streptozotocin-treated diabetic rats. Orally administered
T-1095 is metabolized to an active form, 3-(
benzo[b]furan-5-yl)-2', 6'-dihydroxy-4'-methylpropiophenone-2'-O-beta-D-glucopyranoside (T-1095A), which inhibits renal Na(+)-
glucose cotransporters as potently as
phlorizin in vitro. A single
oral administration of
T-1095 (30 and 100 mg/kg, p.o.) markedly lowered
blood glucose levels with a concomitant increase in urinary
glucose excretion; whereas the effect on
blood glucose levels in non-diabetic rats was minimal. Continuous administration of
T-1095 to diabetic rats for 6 weeks (0.1% in diet) improved not only
hyperglycemia, but also the elevation of plasma
free fatty acid and plasma
ketone body levels. In addition, oral
glucose tolerance testing clearly illustrated the improvement of
glucose tolerance and insulin secretion with
T-1095. In fact, amelioration of impaired
insulin sensitivity in diabetic rats was demonstrated by the increase of whole-body and skeletal-muscle
insulin-mediated
glucose utilization with normalization of muscle
glucose transporter (GLUT)4 content, and decrease of the hepatic
glucose production rate. Consequently,
polyuria and glucosuria were also improved in the T-1095-treated group. Therefore,
T-1095 has a therapeutic potential as a means of ameliorating abnormal
glucose metabolism via diminished
glucose toxicity.