Elucidating the role of renal olfactory receptor 1393 in female Type 1 diabetic mice

Diabetes mellitus is a condition arising from the inability to sufficiently produce or respond to insulin, thus manifesting glucose intolerance. We previously identified an olfactory receptor (Olfr1393), which is localized in the renal proximal tubule where glucose is reabsorbed by Sglt1 and Sglt2. Inhibition of these transporters have therapeutic value by decreasing glucose reabsorption and promoting glycosuria to enable improved glucose homeostasis in patients with diabetes. On a normal chow diet, whole-animal Olfr1393 knockout (KO) mice are euglycemic yet present with glycosuria and improved glucose tolerance (Shepard et al 2016). While this phenotype was observed in both male and female mice, the female KOs presented with more robust glycosuria (p=0.03) and a significant reduction in SGLT1 total cellular membrane expression (p=0.04). Recently, we found that when administered low-dose models of Streptozotocin (STZ)—an alkylating agent that depletes pancreatic β cells thereby mimicking Type 1 diabetes—male Olfr1393 KO mice exhibit an improved diabetic phenotype. However, in keeping with other published reports, we found that the wildtype (WT) and KO female mice were unaffected by STZ treatment. This resistance to STZ has been explained by the anti-apoptotic activity of estrogen receptor signaling that protects pancreatic beta islet cells from chemical-induced damage. To overcome this, slow-release pellets containing 4-hydroxytamoxifen (4OH)—an estrogen receptor modulator in pancreatic beta islet cells—were implanted in both male and female C57BL/6J mice three days prior to STZ challenge (55 mg/kg body weight for 5 consecutive days). Using this method, we were able to successfully induce diabetes in the female mice (female fasting blood glucose - 4OH vehicle: 178 ± 3.50 mg/dL; placebo STZ: 330 ± 8.22 mg/dL; 4OH STZ: 436 ± 4.65 mg/dL). We also noted that 4OH-treated male mice exhibited a more robust diabetic phenotype (male fasting blood glucose - 4OH vehicle: 185 ± 4.95 mg/dL; placebo STZ: 450 ± 11.6 mg/dl; 4OH STZ: 575 ± 4.95 mg/dl). With the successful induction of diabetes in female mice, we have used the same method to test the hypothesis that Olfr1393 female KO mice are protected from the development of diabetes and kidney damage. Female Olfr1393 WT and KO mice were administered 4OH pellet implantations followed by STZ-treatment. Preliminary data suggests that loss of Olfr1393 does indeed attenuate, but does not eliminate, the development of hyperglycemia (2-hour fasting blood glucose values - female WT: 368 mg/dL; female KO: 247.5 mg/dL). Future study will determine if the loss of Olfr1393 also protects against diabetes-induced glomerular hyperfiltration and altered renal blood flow. NIDDK, Yale O'Brien Center This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.