Elucidating the Mechanism for Renal Olfactory Receptor 1393’s Attenuated Type 1 Diabetic Phenotype
Authors: Considine Elizabeth G. , Schiazza Alexis R. , Shepard Blythe D. 
Published: April 2020

Olfactory receptor 1393 (Olfr1393) is a G‐protein coupled receptor ectopically expressed in the murine kidney and liver that has functionality in glucose reabsorption via the sodium‐glucose linked‐transporters (Sglts). Due to the recent therapeutic advances regarding inhibition of the Sglts for both type 1 (T1D) and type 2 (T2D) diabetes, we sought to elucidate the contribution of Olfr1393 to the development and progression of the disease. Previously, we determined that Olfr1393 knockout (KO) mice exhibit improved glucose tolerance and attenuated glomerular hyperfiltration when challenged with a high fat diet (60% kcal from fat) to induce early stages of T2D as compared to their wildtype (WT) counterparts. This was linked to the reduced expression of SGLT2 within the proximal tubule of the KO mice. To determine if Olfr1393 is also involved in T1D, both KO and WT mice were challenged with low‐dose injections of Streptozotocin (STZ; 55 mg/kg BW) or vehicle control (PBS; 55 mg/kg BW) for 5 days to induce depletion of pancreatic β cells. In as little as 2 weeks, both KO and WT male STZ‐treated mice presented with hyperglycemia (2hr fasting blood glucose; WT STZ ‐ 433 ± 32.6 mg/dL, KO STZ ‐ 309 ± 22.6 mg/dL, WT V ‐ 169.7 ± 7.96 mg/dL, KO V ‐ 169.6 ± 10.9 mg/dL), although this hyperglycemia was significantly attenuated in KO mice (p < 0.005). At five weeks, this change was even more pronounced with a significant improvement in hyperglycemia noted even after an overnight fast (WT STZ ‐ 473 ± 28.35 mg/dL, KO STZ ‐ 300 ± 36.24 mg/dL). This improved phenotype is not a result of decreased sensitivity to STZ as islet cell area is similar between STZ‐treated KOs and WTs (WT STZ ‐ 4218 ± 826.5 um2, KO STZ ‐ 4913 ± 2335 um2). The improvement in blood glucose levels also correlated with a significant improvement in glucose tolerance noted in the diabetic KO mice (AUC: WT STZ ‐ 35471 ± 3279, KO STZ ‐ 2868 ± 2118; p<0.01). Notably, all improvement was seen in the male mice as STZ induced a sex dependent phenotype of T1D with female mice found to be resistant to the development of hyperglycemia (2hr fasting blood glucose; WT STZ ‐ 167.7 ± 29.16 mg/dL, KO STZ ‐ 178.0 ± 31.92 mg/dL, WT V ‐ 131.0 ± 38.59 mg/dL, KO V ‐ 144.4 ± 15.92 mg/dL). Contrary to data obtained in our T2D model, neither diabetic WT nor KO mice presented with the commonly noted diabetes‐induced hyperfiltration as measured by transdermal clearance of FITC‐sinistrin; this tracked with a lack of an alteration in glomerular area or morphology as assessed by PAS histological analysis. Additionally, we did not detect any changes in plasma electrolytes (iSTAT Chem8+) or blood pressure (via tail cuff BP‐2000 Blood Pressure Analysis System). Given the improved diabetic phenotype, efforts are currently underway to determine if loss of Olfr1393 leads to changes in the expression or localization of renal SGLT1 and/or SGLT2 in the setting of T1D. Collectively, our data has uncovered a novel regulator of glucose handling, and sheds light on how the modulation of this pathway influences the development of diabetes.Support or Funding InformationNIDDK