Controlling Glucose Handling via Renal Olfr1393 Offers Protection in a Type I Diabetic Mouse Model

Abstract

Olfactory receptor 1393 (Olfr1393) is a G‐protein coupled receptor that has vital functionality outside of its native environment in the nose. In recent reports, we have discovered that renal Olfr1393 localizes to the apical membrane of the renal proximal tubule (PT) where it aids in glucose reabsorption in both health and disease (through a diet‐induced obesity model of type II diabetes) via the sodium‐glucose co‐transporters. To identify additional roles for Olfr1393, we induced type I diabetes (T1D) in whole animal Olfr1393 wildtype (WT) and knockout (KO) male and female mice. Low dose Streptozotocin (STZ: 55 mg / kg BW) injections were administered for 5 consecutive days to deplete pancreatic β‐cells and induce insulin deficiency. Preliminary studies indicate that by 2 weeks post‐STZ, WT male mice develop hyperglycemia (2hr fasting blood glucose (mg/dl): WT diabetics – 383.3 ± 30.1 vs WT vehicle controls – 156.5 ± 24.5) and impaired glucose tolerance (area under curve in thousands (AUC) WT diabetics – 37.8 ± 5.8 vs WT vehicle – 19.8 ± 1.0). In keeping with its function in PT glucose reabsorption, compared to the diabetic WTs, KO mice have lower 2h fasting blood glucose values (Diabetic WTs: 383.3 ± 30.1 vs KOs: 272.7 ± 27.7) and improved glucose tolerance (AUC: Diabetic WTs: 37.8 ± 5.8 vs KOs – 30.1 ± 2.3). 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 present with diabetic hyperfiltration by 5 weeks post‐STZ when measured by transcutaneous elimination kinetics of FITC‐sinistrin. Efforts are currently underway to determine the glomerular damage induced by our T1D model. Collectively, this study indicates that Olfr1393‐mediated control of renal glucose handling is important for the progression of T1D, likely through the regulation of the Sglts.Support or Funding InformationNIDDKThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.