Abstract: TH-PO669

PBI-4050 Prevents Diabetic Nephropathy and Protects β-Cells in NOD Mice: A Model of Type 1 Diabetes

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

  • Gagnon, Lyne, Prometic BioSciences Inc., Laval, Quebec, Canada
  • Hince, Kathy, Prometic BioSciences Inc., Laval, Quebec, Canada
  • Sarra-Bournet, François, Prometic BioSciences Inc., Laval, Quebec, Canada
  • Tremblay, Mikaël, Prometic BioSciences Inc., Laval, Quebec, Canada
  • Cloutier, Marie-Pier, Prometic BioSciences Inc., Laval, Quebec, Canada
  • Létourneau, Sylvie, Prometic BioSciences Inc., Laval, Quebec, Canada
  • Laurin, Pierre, Prometic BioSciences Inc., Laval, Quebec, Canada
  • Grouix, Brigitte, Prometic BioSciences Inc., Laval, Quebec, Canada
  • Leblond, Francois A., Prometic BioSciences Inc., Laval, Quebec, Canada
Background

PBI-4050, a novel first-in-class orally active antifibrotic compound, which is currently in a phase II clinical trial, significantly reduced glycated hemoglobin (HbA1c) after 12 and 24 weeks of treatment in patients with type 2 diabetes and metabolic syndrome with elevated HbA1c despite anti-hyperglycemic treatment. PBI-4050 also reduced biomarkers associated to kidney injury. In the present study, we examined whether PBI-4050 may prevent diabetic nephropathy in NOD mice, a model of type 1 diabetes.

Methods

NOD/ShiLtJ female mice (8 weeks of age) received vehicle (water) or PBI-4050 (200 mg/kg/day) by daily gastric gavage for 23 weeks.

Results

In kidney, PBI-4050 protects against lesions by reducing glomerular volume and mesangial cross sectional area. Furthermore, tubular lesions were absent in PBI-4050-treated mice. Tubular dystrophy as PAS granular accumulation was constantly present in proximal tubules of NOD control mice and was completely abrogated by treatment with PBI-4050. Mice treated with PBI-4050 did not develop diabetes. OGTT was also normalized in PBI-4050 treated mice. Despite a reduced number of islets compared to non-diabetic mice, NOD mice treated with PBI-4050 maintained normoglycemia and showed a 30% reduction in the number of islets with grade 4 lesions.

Conclusion

This data suggests that PBI-4050 prevents diabetic nephropathy and complete destruction of β-cells and islets in type 1 diabetes model.

Funding

  • Commercial Support