Type 2 diabetes is a serious global public health threat and the leading cause of end-stage renal disease. Almost 40% of patients with type 2 diabetes will go on to develop chronic kidney disease (CKD). Given that the pathogenesis of diabetic kidney disease and other long-term complications is linked to long-standing hyperglycemia, one of the greatest challenges for treatment of diabetes is maintaining blood glucose levels within the normal range. New therapeutic strategies aimed at improving blood glucose levels and reducing the risks of long-term complications are constantly being developed. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are glucose-lowering oral drugs that offer nephroprotection and improved cardiovascular outcomes, as seen in early clinical trials. SGLT2 is highly expressed in the renal proximal tubules. SGLT2 inhibitors regulate blood glucose levels by reducing the reabsorption of filtered glucose back into the capillaries surrounding the renal tubules. This consequently increases glucose in the tubular lumen leading to a rise in urinary glucose excretion. However, use of a certain class of SGLT2 inhibitors has been associated with an increased risk of fractures. It is essential to determine the risks associated with SGLT2 inhibitors as this may affect their use in the clinic. The goal of our research proposal is to evaluate the effects of SGLT2 inhibition on bone and mineral metabolism by utilizing a novel mouse model. The Sweet Pee mice have a nonsense mutation in the Slc5a2 gene that results in total loss of SGLT2 function in proximal tubules. We will use the Sweet Pee mice to investigate the longitudinal effects of loss of SGLT2 function in mice with and without type 2 diabetes and CKD. Preliminary data from Sweet Pee mice demonstrate glucosuria, hypercalciuria, and growth retardation in non-challenged states. Use of SGLT2 inhibitors has also been linked to decreased urinary phosphate losses and increased serum phosphate levels. We propose that the hyperphosphatemia and hypercalciuria may promote elevations in parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23). Elevation of these hormones may contribute to altered bone remodeling and bone demineralization. We believe that our proposed study will generate novel mechanistic insights that are urgently needed to advance the clinical development of SGLT2 inhibitors in T2DM. Our long term goal is to leverage the Sweet Pee mice to determine the impact of loss of SGLT2 function on renal and cardiovascular systems and to define the mechanisms for these effects in a model of T2DM and CKD.
|Effective start/end date||10/1/17 → 12/31/19|
- ASN Foundation for Kidney Research (ASN foundation 04/13/2017)