Tofogliflozin, a novel sodium-glucose co-transporter 2 inhibitor, improves renal and pancreatic function in db/db mice.

Abstract

BACKGROUND AND PURPOSE:

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.

EXPERIMENTAL APPROACH:

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

KEY 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 AND IMPLICATIONS:

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: T Nagata, T Fukuzawa, M Takeda, M Fukazawa, T Mori, T Nihei, K Honda, Y Suzuki, Y Kawabe
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 170 Issue 3 Pg. 519-31 (Oct 2013) ISSN: 1476-5381 [Electronic] England
• PMID: 23751087 (Publication Type: Comparative Study, Journal Article)
• Copyright: © 2013 The British Pharmacological Society.

Chemical References

• Angiotensin II Type 1 Receptor Blockers
• Benzhydryl Compounds
• Biomarkers
• Blood Glucose
• Glucosides
• Glycated Hemoglobin A
• Hypoglycemic Agents
• Insulin
• Slc5a2 protein, mouse
• Sodium-Glucose Transporter 2
• Sodium-Glucose Transporter 2 Inhibitors
• Losartan
• 6-((4-ethylphenyl)methyl)-3',4',5',6'-tetrahydro-6'-(hydroxymethyl)spiro(isobenzofuran-1(3H),2'-(2H)pyran)-3',4',5'-triol

Topics

• Albuminuria (metabolism, prevention & control)
• Angiotensin II Type 1 Receptor Blockers (pharmacology)
• Animals
• Benzhydryl Compounds (pharmacology)
• Biomarkers (blood)
• Blood Glucose (drug effects, metabolism)
• Diabetes Mellitus, Type 2 (complications, drug therapy, metabolism, physiopathology)
• Diabetic Nephropathies (etiology, metabolism, physiopathology, prevention & control)
• Disease Models, Animal
• Female
• Glucosides (pharmacology)
• Glycated Hemoglobin (metabolism)
• Hypoglycemic Agents (pharmacology)
• Insulin (blood)
• Insulin-Secreting Cells (drug effects, metabolism, pathology)
• Kidney (drug effects, metabolism, pathology, physiopathology)
• Losartan (pharmacology)
• Mice
• Sodium-Glucose Transporter 2 (metabolism)
• Sodium-Glucose Transporter 2 Inhibitors
• Time Factors