Kidney Week

Abstract: SA-OR028

Effects of Sodium Glucose Cotransporter 2 Deletion on Bone and Mineral Metabolism

Session Information

• Diabetic Kidney Disease: Mechanisms, Models, and Modulators - II
  October 27, 2018 | Location: 5A, San Diego Convention Center
  Abstract Time: 05:54 PM - 06:06 PM

Category: Diabetic Kidney Disease

• 601 Diabetic Kidney Disease: Basic

Authors

• Gerber, Claire, Northwestern University, Chicago, Illinois, United States

Claire Gerber, PhD, MPH



• David, Valentin, Northwestern University - Feinberg School of Medicine, Chicago, Illinois, United States

Valentin David,

• Quaggin, Susan E., Northwestern University, Chicago, Illinois, United States

Susan E. Quaggin,

• Martin, Aline, Northwestern University, Chicago, Illinois, United States

Aline Martin,

• Isakova, Tamara, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States

Tamara Isakova,

Background

Type 2 diabetes mellitus (T2DM) and chronic kidney disease are associated with an increased risk of developing bone and mineral metabolism abnormalities. A new class of glucose-lowering agents, sodium-glucose cotransporter 2 (SGLT2) inhibitors, promotes urinary glucose excretion and improves renal and cardiovascular outcomes in patients with T2DM. However, SGLT2 inhibitors are associated with increased risk of bone fractures. Because loss of SGLT2 function may decreases urinary phosphate, we hypothesize that inhibition of SGLT2 induces mineral metabolism alterations that could contribute to increased bone fragility.

Methods

Slc5a2 nonsense mutation in Sweet Pee (SP) mice results in total loss of SGLT2 function in proximal tubules. To understand the effects of loss of SGLT2 function on mineral metabolism, urine and serum was collected from fasted wild type (WT) and SP mice. Levels of fractional excretion of calcium and phosphate; serum phosphate, calcium, PTH, 1,25(OH)₂D, and FGF23 were evaluated at 15 and 25 weeks. To determine the longitudinal impact of loss of SGLT2 function on bone metabolism, bone architecture, remodeling, and mineralization was assessed in SP mice and WT mice at 15 and 25 weeks of age.

Results

At 25 weeks, SP mice showed significantly decreased body weight compared to WT mice (21.6±3.8 vs 25.1±2.9 g, p<0.05). Consistently, femoral length was significantly shorter in SP mice compared to WT mice (14.1±0.4 vs 14.5±0.2 mm, p<0.05). Overall renal function was not impaired in SP mice compared to WT mice (blood urea nitrogen: 18±4 vs 21±5 mg/dL, NS). Fasted SP mice did not show modification of fractional excretion of calcium. Serum calcium, PTH, and 1,25(OH)₂D levels were similar between WT and SP mice at 15 and 25 weeks. Fractional excretion of phosphate was significantly higher at 25 weeks in SP mice compared to WT (5.5±2.0 vs 2.5±1.9 %, p<0.05), despite unchanged levels of FGF23. SP mice had reduced cortical bone mineral density, compared to WT mice at 25 weeks (1240±16 vs 1264±14 mg/cm³, p<0.05).

Conclusion

These results suggest that loss of SGLT2 function in the absence of T2DM may contribute to bone fragility. Future studies are required to determine how loss of SGLT2 function impacts bone fragility in T2DM.

Funding

• NIDDK Support