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Abstract: FR-PO211

Renal Olfactory Receptor 1393 Contributes to the Development and Progression of Type 1 Diabetes

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Schiazza, Alexis R., Georgetown University, Washington, District of Columbia, United States
  • Considine, Elizabeth G., Georgetown University, Washington, District of Columbia, United States
  • Shepard, Blythe D., Georgetown University, Washington, District of Columbia, United States
Background

Olfactory receptor 1393 (Olfr1393) is a G-protein coupled receptor with vital functionality outside of its native environment of the nose. Recently, we determined that this receptor is expressed in the renal proximal tubule where it aids in glucose reabsorption via the sodium-glucose co-transporters (Sglts). We also found that Olfr1393 is linked to the progression of type II diabetes in a diet-induced obesity mouse model. As Sglt inhibitors have emerged as a novel therapeutic option for type I diabetes (T1D), we sought to extrapolate the role of renal Olfr1393 in the context of this metabolic disorder.

Methods

To induce T1D in whole-animal Olfr1393 wildtype (WT) and knockout (KO) mice, low dose injections of Streptozotocin (STZ; 55 mg/kg BW) or vehicle control were administered for 5 consecutive days to deplete pancreatic β-cells and induce insulin deficiency in both male and female mice. Progression of diabetes was tracked by measuring 2 hour fasting blood glucose and glucose tolerance via intraperitoneal glucose tolerance tests at 2, 5, and 12 weeks post-STZ injections. Glomerular filtration rate was determined using transdermal measurement of FITC-Sinistrin and urinalysis was performed by dipstick.

Results

STZ administration induced phenotypes of hyperglycemia and impaired glucose tolerance in male, but not female, Olfr1393 WT mice. Notably, these diabetic phenotypes were significantly attenuated in the Olfr1393 KO males by 2 weeks post-STZ injection and the differences became more pronounced after 5 weeks. This improvement was accompanied with a reduction in proteinuria, glycosuria, and hemoglobinuria. No significant differences were detected in insulin sensitivity between diabetic WT and KO mice. One hallmark of T1D is the development of glomerular hyperfiltration; notably, neither diabetic WT nor KO mice presented with hyperfiltration 12 weeks post-STZ.

Conclusion

Collectively, this study indicates that diabetic phenotypes are attenuated in Olfr1393 KO mice suggesting that Olfr1393-mediated glucose handling is important for the progression of T1D. Efforts are currently underway to determine the expression and activity of the renal Sglts in the setting of T1D to elucidate the mechanism by which Olfr1393 contributes to the diabetic phenotype.

Funding

  • NIDDK Support