Beneficial Effect Of T‐1095, A Selective Inhibitor Of Renal Na⁺–Glucose Cotransporters, On Metabolic Index And Insulin Secretion In Spontaneously Diabetic Gk Rats

Abstract

1. To investigate the pharmacological effects of T-1095, this novel derivative of phlorizin was administered to GK rats for 8 weeks. T-1095 treatment significantly lowered plasma glucose and glycosylated haemoglobin (HbA1c) levels, but did not significantly affect bodyweight. 2. T-1095 treatment did not affect 3.3 mmol/L glucose-induced insulin secretion in the isolated perfused pancreas of GK rats. 3. The peak insulin release in T-1095-treated GK rats was significantly higher during the first phase than in untreated GK rats (3-4 min after beginning 16.7 mmol/L glucose perfusion). The total amount of insulin secreted during the first phase in T-1095-treated GK rats was significantly higher than in untreated GK rats (35.3 +/- 1.4 vs. 27.3 +/- 2.5 ng in T-1095-treated compared with untreated rats, respectively). 4. During the second phase, insulin release in T-1095-treated GK rats was somewhat higher than in untreated GK rats (7-30 min after beginning 16.7 mmol/L glucose perfusion). The total amount of insulin secreted during the second phase in T-1095-treated GK rats was significantly higher than in untreated GK rats (88.2 +/- 6.1 vs. 68.1 +/- 5.7 ng, respectively). 5. The total amount of insulin secreted during perfusion in T-1095-treated GK rats was significantly higher than in untreated GK rats (123.5 +/- 7.3 vs. 95.4 +/- 7.7 ng, respectively). 6. These data show that the metabolic indices, plasma glucose and HbA1c levels and insulin secretion are significantly improved by T-1095 treatment in GK rats, which are spontaneously diabetic rats, suggesting its usefulness as a novel oral therapeutic antidiabetic agent.

Remogliflozin Etabonate, in a Novel Category of Selective Low-Affinity Sodium Glucose Cotransporter (SGLT2) Inhibitors, Exhibits Antidiabetic Efficacy in Rodent Models

“…In this sense, this SGLT2 inhibitor offers some advantages over existing antidiabetic drugs such as sulfonylureas, biguanides, ␣-glucosidase inhibitors, and thiazolidinediones. Multiple studies on T-1095 have demonstrated its beneficial effects on postprandial hyperglycemia, FPG, GHb, insulin resistance, ␤-cell function, and diabetic complications (nephropathy and neuropathy) in diabetic rodent models (Adachi et al, 2000;Nawano et al, 2000;Oku et al, 2000;Arakawa et al, 2001;Nunoi et al, 2002;Ueta et al, 2005;Fujimoto et al, 2006). We suppose that remogliflozin etabonate may also be useful for a wide range of diabetic conditions, and it can be beneficial for the treatment of diabetes when used in combination with a number of antidiabetic drugs.…”

Phlorizin: a review

“…Chronic treatment with T-1095 reduces glucose and glycohemoglobin levels, lowers insulin and triglyceride levels, normalizes whole body and muscle GLUT 4 content, and decreases hepatic glucose production [62]. They also describe a number of renal effects of T-1095 in animal models of diabetes, including delay in the development of microalbuminuria, normalization of renal GLUT 2 levels, restoration of normal kidney weight and epithelial vacuolation [63][64][65][66].…”

Development of the Renal Glucose Reabsorption Inhibitors: A New Mechanism for the Pharmacotherapy of Diabetes Mellitus Type 2

“…19 The O-glycoside 3a (T-1095A) exhibited sufficiently promising potency, selectivity, and in vivo efficacy when administered orally, if protected from intestinal glucosidases, that it entered clinical trials as the methyl carbonate prodrug 3b (T-1095). [20][21][22] The report from Wyeth that administration of 4-benzylpyrazolones 4, such as 4a (WAY-123783), could induce a glucosuric response in mice prompted investigations at Kissei and Bristol-Myers Squibb that independently led to the realization that in vivo glucosylation of 4 must occur to generate a series of potent SGLT2 inhibitors 5. 23 Subsequently, merging of structures 3 and 5 and truncation of the tether joining the two aryl rings of phlorizin from three carbons to one carbon by chemists at Bristol-Myers Squibb and Kissei independently led to disclosure of O-glucosides of o-benzylphenols 6 as a second potent series of SGLT2 inhibitors ( Figure 3).…”

“…[18][19][20][21][22]26 The in vivo profile of 16 suggests that C-glucoside based inhibitors are no different. When administered at 0.1-1.0 mg/kg to normal and diabetic rats, 16 dose- dependently increased glucosuria, resulting in urinary glucose excretion of up to 1.0 g/day without causing hypoglycemia.…”