Effects of the SGLT2 inhibitor ipragliflozin on various diabetic symptoms and progression of overt nephropathy in type 2 diabetic mice.

Diabetic nephropathy is the leading cause of end-stage renal disease and is associated with high-cardiovascular risk and significant morbidity and mortality. The recent development of sodium-glucose cotransporter (SGLT) 2 inhibitors offers a new antidiabetic therapy via enhanced glucose excretion; however, the beneficial effect of these drugs on the development of type 2 diabetic overt nephropathy is still largely unclear. We examined the therapeutic effects of the SGLT2 inhibitor ipragliflozin on various diabetic symptoms and the progression of nephropathy in uninephrectomized type 2 diabetic mice, which exhibit not only typical diabetic symptoms, such as impaired insulin secretion, glucose intolerance, hyperglycemia, and obesity, but also overt nephropathy with decline in renal function. Diabetes was induced by intraperitoneal administration of nicotinamide (1000 mg/kg) and streptozotocin (150 mg/kg) to uninephrectomized high-fat diet-fed mice. Ipragliflozin (0.1-3 mg/kg) was orally administered to diabetic mice once daily for 4 weeks. Repeated administration of ipragliflozin improved diabetic symptoms, such as hyperglycemia and insulin resistance, via an increase in urinary glucose excretion. In addition, ipragliflozin attenuated albuminuria/proteinuria and the decline in renal function, and improved renal injury, including glomerulosclerosis and interstitial fibrosis. Our results demonstrate that ipragliflozin improves various diabetic symptoms and delays development of diabetic nephropathy. Therefore, SGLT2 inhibitors could constitute a novel therapeutic target for the treatment of type 2 diabetes with overt nephropathy.