Inhibitory effect of hyperglycemia on insulin-induced Akt/protein kinase B activation in skeletal muscle.

To determine the molecular mechanism underlying hyperglycemia-induced insulin resistance in skeletal muscles, postreceptor insulin-signaling events were assessed in skeletal muscles of neonatally streptozotocin-treated diabetic rats. In isolated soleus muscle of the diabetic rats, insulin-stimulated 2-deoxyglucose uptake, glucose oxidation, and lactate release were all significantly decreased compared with normal rats. Similarly, insulin-induced phosphorylation and activation of Akt/protein kinase B (PKB) and GLUT-4 translocation were severely impaired. However, the upstream signal, including phosphorylation of the insulin receptor (IR) and insulin receptor substrate (IRS)-1 and -2 and activity of phosphatidylinositol (PI) 3-kinase associated with IRS-1/2, was enhanced. The amelioration of hyperglycemia by T-1095, a Na(+)-glucose transporter inhibitor, normalized the reduced insulin sensitivity in the soleus muscle and the impaired insulin-stimulated Akt/PKB phosphorylation and activity. In addition, the enhanced PI 3-kinase activation and phosphorylation of IR and IRS-1 and -2 were reduced to normal levels. These results suggest that sustained hyperglycemia impairs the insulin-signaling steps between PI 3-kinase and Akt/PKB, and that impaired Akt/PKB activity underlies hyperglycemia-induced insulin resistance in skeletal muscle.

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.

Antihyperglycemic effect of T-1095 via inhibition of renal Na+-glucose cotransporters in streptozotocin-induced diabetic rats.

T-1095, a derivative of phlorizin, is an orally active inhibitor of Na+-glucose cotransporter (SGLT). We investigated the acute antihyperglycemic effect of T-1095 in streptozotocin-induced diabetic rats (STZ rats). T-1095 and its metabolite T-1095A inhibited the SGLT activity in brush border membranes prepared from kidneys of both normal and STZ rats, but the latter agent was approximately 10 times more potent than the former. Single oral administration of T-1095 (30-100 mg/kg) dose-dependently induced glycosuria in normal rats. The fed glucose levels in STZ rats were dose-dependently suppressed by single oral administration of T-1095 (3-100 mg/kg), whereas there was only marginal hypoglycemic effect in normal rats. Since there was no effect on blood glucose in nephrectomized STZ rats, inhibition of renal glucose reabsorption rather than intestinal glucose absorption mainly contributes to the antihyperglycemic effect of T-1095. In conclusion, T-1095 is the first orally active agent which has an acute antihyperglycemic action in the absence of endogenous insulin secretion with a low risk of hypoglycemia and has therapeutic potential for treatment of diabetes mellitus.

Correction of hyperglycemia and insulin sensitivity by T-1095, an inhibitor of renal Na+-glucose cotransporters, in streptozotocin-induced diabetic rats.

We investigated the effects of T-1095 (3-(benzo[b]furan-5-yl)-2',6'-dihydroxy-4'-methylpropiophenone 2'-O-(6-O-methoxycarbonyl)-beta-D-glucopyranoside), an orally active inhibitor of Na+-glucose cotransporter, on hyperglycemia and insulin resistance in skeletal muscle of streptozotocin (STZ)-induced diabetic rats. Chronic (4 weeks) administration of T-1095 as food admixture (0.01 -0.1% wt/wt) suppressed the blood glucose level without affecting the food intake and body weight. In addition, the reduced 2-deoxyglucose uptake and lactate release in the soleus muscle of STZ rat was ameliorated by chronic treatment of T-1095. These data suggest that T-1095 improves insulin sensitivity in skeletal muscle through correction of hyperglycemia and has novel therapeutic potential for treatment of diabetes mellitus through removing glucose toxicity.