Long-term treatment with the Na⁺-glucose cotransporter inhibitor T-1095 causes sustained improvement in hyperglycemia and prevents diabetic neuropathy in Goto-Kakizaki Rats

Abstract

We examined the effects of T-1095, an orally active inhibitor of Na⁺-glucose cotransporter (SGLT), on the development and severity of diabetes in Goto-Kakizaki (GK) rat, a spontaneous, non-obese model of type 2 diabetes. T-1095 was administered as dietary admixture (0.1% w/w) beginning at 7 weeks of age for 32 weeks. Untreated male GK rats were hyperglycemic compared with Wistar rats. Throughout the study, T-1095 treatment significantly decreased both blood glucose and hemoglobin A_1C levels in the GK rats. The concomitant increase of urinary glucose excretion indicated that the hypoglycemic action of T-1095 is derived from the enhancement of urinary glucose disposal. Although food intake was not changed in the T-1095-treated rats, the body weight gain was retarded. T-1095 treatment partially ameliorated oral glucose tolerance but not the impaired glucose-induced insulin secretion. Homeostasis model assessment (HOMA) indicated the existence of insulin resistance in GK rats and a significant restoration by T-1095-treatment. There was a reduction of the thermal response in tail-flick testing following long-term hyperglycemia (diabetic neuropathy). Treatment of T-1095 significantly prevented the development of diabetic neuropathy in male GK rats. Sustained improvement of hyperglycemia and prevention of diabetic neuropathy by the T-1095-treatment provide further support the use of SGLT inhibitors for the treatment of diabetes.

Introduction

Recent epidemiological studies have indicated that intensive glycemic control inhibits the onset and progression of chronic complications in diabetic patients (DCCT (The Diabetes Control and Complications Trial Research Group), 1993, Shichiri et al., 2000, UKPDS (UK Prospective Diabetes Study Group), 1998a, UKPDS (UK Prospective Diabetes Study Group), 1998b). In type 2 diabetes, caloric restriction and increase of physical activity to correct the inadequate energy balance are particularly important for not only weight control but also the prevention of postprandial hyperglycemia, hyperinsulinemia, and hyperlipidemia (ADA (AMERICAN DIABETES ASSOCIATION), 2000, Kelley et al., 1993). Inhibitors of Na⁺-glucose cotransporter (SGLT) suppress tubular glucose reabsorption, excrete excess plasma glucose into urine, and thus eliminate hyperglycemia (Tsujihara et al., 1996, Tsujihara et al., 1999). We have recently reported that the beneficial effects of T-1095, a novel SGLT inhibitor, on hyperglycemia in various diabetic animal models and diabetic nephropathy in db/db mice (Adachi et al., 2000, Arakawa et al., 2001, Nawano et al., 1999, Nawano et al., 2000, Oku et al., 1999, Oku et al., 2000a, Oku et al., 2000b, Oku et al., 2000c, Oku et al., 2001).

Goto-Kakizaki (GK) rats have been developed by selective breeding from nondiabetic Wistar rat with glucose intolerance as a selective index over many generations (Goto et al., 1988a). Moderate and stable hyperglycemia but not a ketotic state nor obesity develops from weaning in these animals (Goto et al., 1988b). While plasma insulin levels are normal or even elevated, the early phase of glucose-induced insulin secretion is impaired (Kimura et al., 1982) similar to patients with type 2 diabetes (Ward et al., 1984). Euglycemic-hyperinsulinemic clamp studies have also indicated the development of insulin resistance in peripheral tissues of these animals (Bisbis et al., 1993, Farese et al., 1994, O'Rourke et al., 1997). In addition, it has been reported that there are progressive neuropathic changes with increasing age in GK rats (Suzuki et al., 1990, Wada et al., 1999, Yagihashi et al., 1982).

In the present study, we evaluated long-term pharmacological effects of T-1095 with special regard to blood glucose control and prevention of diabetic neuropathy in GK rats.