Antidiabetic effect of T-1095, an inhibitor of Na(+)-glucose cotransporter, in neonatally streptozotocin-treated rats.
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.
Oku
A
A
Discovery Research Laboratory, Tanabe Seiyaku, 2-2-50 Kawagishi Toda, Saitama 335-8505, Japan.
Ueta
K
K
Nawano
M
M
Arakawa
K
K
Kano-Ishihara
T
T
Matsumoto
M
M
Saito
A
A
Tsujihara
K
K
Anai
M
M
Asano
T
T
D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D001786:Blood Glucose / Q000378:metabolism; D002254:Carbonates / Q000737:chemistry / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D005960:Glucosides / Q000737:chemistry / Q000494:pharmacology*; D006029:Glycosuria / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D008297:Male; D008871:Microvilli / Q000187:drug effects / Q000378:metabolism; D009004:Monosaccharide Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism
D001786:Blood Glucose; D002254:Carbonates; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D005960:Glucosides; D007004:Hypoglycemic Agents; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495694:Slc2a4 protein, rat; C121396:T 1095; D012964:Sodium; D005947:Glucose