Antidiabetic effect of T-1095, an inhibitor of Na+-glucose cotransporter, in neonatally streptozotocin-treated rats

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Abstract

3-(Benzo[b]furan-5-yl)-2′,6′-dihydroxy-4′-methylpropiophenone-2′-O-(6-O-methoxycarbonyl)-β-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-β-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.

Introduction

Defects in insulin secretion and insulin action are universally present in type 1 diabetes and also in most type 2 diabetes in both human patients and animal models, although it has become increasingly clear that human diabetes is a heterogeneous disorder (Rossetti et al., 1990). When the hyperglycemia becomes of sufficient magnitude to lead to glucosuria and polyuria, a vicious cycle develops in which hyperglycemia leads to the worsening of insulin secretion by β cells and impairment of insulin sensitivity in peripheral tissues, resulting in more hyperglycemia (Rossetti et al., 1990). Thus, there are complex inter-relationships among hyperglycemia, insulinopenia, and insulin resistance, all of which are involved in the pathogenesis of diabetes (Rossetti et al., 1990). To date, several oral drugs and insulin have been developed for the treatment of diabetes (Lebovitz, 1994). However, it is still difficult to maintain good glycemic control in most diabetic patients, although individual drugs may be highly effective for some patients (Lebovitz, 1994).

We have developed a novel agent, 3-(benzo[b]furan-5-yl)-2′,6′-dihydroxy-4′-methylpropiophenone-2′-O-(6-O-methoxycarbonyl)-β-d-glucopyranoside (T-1095) (Tsujihara et al., 1999), which may be useful for the treatment of diabetic patients. T-1095 is a synthetic phlorizin derivative, which inhibits renal Na+-glucose cotransporter activity when administered orally (Oku et al., 1999). After being absorbed from the gut into the blood, T-1095 is metabolized to 3-(benzo[b]furan-5-yl)-2′,6′-dihydroxy-4′-methylpropiophenone-2′-O-β-d-glucopyranoside (T-1095A) and inhibits specifically and competitively Na+-glucose cotransporters (Oku et al., 1999), which are responsible for glucose reabsorption in the proximal tubules Silverman and Turner, 1992, Deetjen et al., 1995. Na+-glucose cotransporter also mediates glucose absorption in the small intestine, but our previous study suggests that the effect of T-1095 on intestinal glucose absorption is negligible, and that the antihyperglycemic effect of T-1095 is primarily mediated by reduced renal glucose reabsorption (Oku et al., 1999). Thus, T-1095 lowers blood glucose by a novel mechanism for an antidiabetic drug.

In the present study, T-1095 was administered orally to diabetic rats that had been treated with streptozotocin as neonates. We now describe the alterations in various parameters associated with diabetic status as well as effects on the insulin secretory capacity and insulin sensitivity of the diabetic rats. Then, we discuss the potential application of T-1095 as a novel antidiabetic drug.

Section snippets

Materials and methods

Experiments were performed in accordance with the National Institute of Health “Principles of Laboratory Animal Care, 1985 revised version,” and had the approval of the ethics committee of Tanabe Seiyaku.

Effect of T-1095 and T-1095A on Na+-glucose cotransporter activity in kidney brush border membrane vesicles of normal and diabetic rats

Since preliminary studies indicated that T-1095A, but not T-1095, is mainly detectable in plasma following T-1095 administration (p.o.) to rats (Oku et al., 1999), we determined the effects of these compounds on Na+-glucose cotransporter activity in vitro. Both T-1095 and T-1095A inhibited Na+-dependent glucose uptake in brush border membrane vesicles prepared from renal tissues of normal (Fig. 3a) and diabetic rats (Fig. 3b). The IC50 values for Na+-glucose cotransporter activity with T-1095,

Discussion

Plasma glucose is filtered in glomeruli and then reabsorbed in epithelial cells of the renal proximal tubules via Na+-glucose cotransporters Silverman and Turner, 1992, Deetjen et al., 1995. Phlorizin, a specific inhibitor of Na+-glucose cotransporter, is reported to promote the excretion of glucose into the urine and lower blood glucose levels in several diabetic animal models upon subcutaneous injection Rossetti et al., 1987, Blondel et al., 1990, Lisato et al., 1992, Crofford, 1995, Khan and

Conclusion

We have shown that T-1095 is a potent antihyperglycemic agent, and that it improves whole-body glucose metabolism, insulin sensitivity, and β cell function. To date, no significant adverse effects have been observed in the diabetic animal model with the T-1095 at doses and periods used in this study. Thus, we suggest that oral administration of the Na+-glucose cotransporter inhibitor, T-1095, is a potentially novel therapeutic approach to the management of diabetes mellitus. Clinical trials are

Acknowledgements

We thank Dr. K. Saito and M. Hongu for the synthesis of T-1095 and T-1095A, and Y. Kuronuma for technical support.

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