title: Tofogliflozin, a novel sodium-glucose co-transporter 2 inhibitor, improves renal and pancreatic function in db/db mice.
abstract: OBJECTIVE
  Although inhibition of renal sodium-glucose co-transporter 2 (SGLT2) has a stable glucose-lowering effect in patients with type 2 diabetes, the effect of SGLT2 inhibition on renal dysfunction in type 2 diabetes remains to be determined. To evaluate the renoprotective effect of SGLT2 inhibition more precisely, we compared the effects of tofogliflozin (a specific SGLT2 inhibitor) with those of losartan (an angiotensin II receptor antagonist) on renal function and beta-cell function in db/db mice.
  
  
  METHODS
  The effects of 8-week tofogliflozin or losartan treatment on renal and beta-cell function were investigated in db/db mice by quantitative image analysis of glomerular size, mesangial matrix expansion and islet beta-cell mass. Blood glucose, glycated Hb and insulin levels, along with urinary albumin and creatinine were measured
  
  
  RESULTS
  Tofogliflozin suppressed plasma glucose and glycated Hb and preserved pancreatic beta-cell mass and plasma insulin levels. No improvement of glycaemic conditions or insulin level was observed with losartan treatment. Although the urinary albumin/creatinine ratio of untreated db/db mice gradually increased from baseline, tofogliflozin or losartan treatment prevented this increase (by 50-70%). Tofogliflozin, but not losartan, attenuated glomerular hypertrophy. Neither tofogliflozin nor losartan altered matrix expansion.
  
  
  CONCLUSIONS
  Long-term inhibition of renal SGLT2 by tofogliflozin not only preserved pancreatic beta-cell function, but also prevented kidney dysfunction in a mouse model of type 2 diabetes. These findings suggest that long-term use of tofogliflozin in patients with type 2 diabetes may prevent progression of diabetic nephropathy.
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Nagata
authors.forename: T
authors.initials: T
authors.lastname: Fukuzawa
authors.forename: M
authors.initials: M
authors.lastname: Takeda
authors.forename: M
authors.initials: M
authors.lastname: Fukazawa
authors.forename: T
authors.initials: T
authors.lastname: Mori
authors.forename: T
authors.initials: T
authors.lastname: Nihei
authors.forename: K
authors.initials: K
authors.lastname: Honda
authors.forename: Y
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Y
authors.initials: Y
authors.lastname: Kawabe
mesh_terms: D000419:Albuminuria / Q000378:metabolism / Q000517:prevention & control; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D005260:Female; D005960:Glucosides / Q000494:pharmacology*; D006442:Glycated Hemoglobin / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D019808:Losartan / Q000494:pharmacology; D051379:Mice; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013997:Time Factors
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001559:Benzhydryl Compounds; D015415:Biomarkers; D001786:Blood Glucose; D005960:Glucosides; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D019808:Losartan; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C490299:Slc5a2 protein, mouse; C575086:6-((4-ethylphenyl)methyl)-3',4',5',6'-tetrahydro-6'-(hydroxymethyl)spiro(isobenzofuran-1(3H),2'-(2H)pyran)-3',4',5'-triol
keywords: beta-cell loss; nephropathy; sodium-glucose co-transporter inhibitor; tofogliflozin