title: 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.
authors.affiliation: Pharmacology Research Laboratories, Tanabe Seiyaku Co., Ltd., 2-2-50 Kawagishi, Toda, Saitama 335-0015, Japan.
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Ueta
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ishihara
authors.forename: Yukio
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Akira
authors.initials: A
authors.lastname: Oku
authors.forename: Masao
authors.initials: M
authors.lastname: Nawano
authors.forename: Takuya
authors.initials: T
authors.lastname: Fujita
authors.forename: Akira
authors.initials: A
authors.lastname: Saito
authors.forename: Kenji
authors.initials: K
authors.lastname: Arakawa
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002254:Carbonates / Q000627:therapeutic use*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D003929:Diabetic Neuropathies / Q000378:metabolism / Q000517:prevention & control*; D004032:Diet; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D005960:Glucosides / Q000627:therapeutic use*; D006943:Hyperglycemia / Q000188:drug therapy* / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D009004:Monosaccharide Transport Proteins / Q000037:antagonists & inhibitors*; D051381:Rats; D011919:Rats, Inbred Strains; D017208:Rats, Wistar; D012964:Sodium / Q000378:metabolism; D051269:Sodium-Glucose Transporter 1; D013997:Time Factors
chemical_list: D002254:Carbonates; D004791:Enzyme Inhibitors; D005960:Glucosides; D008562:Membrane Glycoproteins; D009004:Monosaccharide Transport Proteins; C495676:Slc5a1 protein, rat; D051269:Sodium-Glucose Transporter 1; C121396:T 1095; D012964:Sodium; D005947:Glucose