Type 1 (T1) and type 2 (T2) diabetes mellitus (DM), along with their accompanying hyperglycemia, are associated with a multitude of comorbidities, including the development of diabetic kidney disease and nonalcoholic steatohepatitis. Although the hallmarks of these metabolic disorders have been well‐characterized in population and animal studies, it is becoming increasingly apparent that DM manifests itself differently in men and women. Epidemiological studies indicate that men are at higher risk of developing T2DM than pre‐menopausal women, suggesting that estrogen may serve a protective role in the development of the disorder. Sex differences have also been observed in animal models of DM where females tend to resist diabetic induction and have trouble attaining the hyperglycemic threshold, resulting in a heavy reliance on male preclinical models. Previously, we used streptozotocin (STZ; 55mg/kg BW) to induce T1DM in both male and female C57BL/6 mice to characterize their development of diabetic comorbidities. While male mice developed robust hyperglycemia (threshold was 2‐hour fasting glucose > 230 mg/dL) compared to their vehicle controls, the female mice were unaffected by STZ treatment (Schiazza et al. 2021). It has been found that estrogen receptor (ER) signaling has anti‐apoptotic activity; thus, we hypothesized that this signaling pathway may be offering protection from STZ challenge. To test this, male and female C57BL/6 mice were implanted with slow release pellets of either tamoxifen (1.25mg over 60 days) or its active metabolite, 4‐hydroxytamoxifen (4OH; 0.6mg over 21 days), to modulate ER signaling. Following implantation, mice were challenged with STZ or vehicle (citrate buffer; 55 mg/kg BW) for 5 consecutive days. Two weeks following the last injection, two hour fasting blood glucose measurements were collected. While tamoxifen failed to induce persistent hyperglycemia or impaired glucose tolerance (likely due to the low circulating levels of 4OH as measured by mass spectrometry), implantation of 4OH promoted appreciable hyperglycemia in both males and females indicating that ER signaling does have an anti‐diabetic role in both sexes (Males: 4OH Vehicle ‐ 185 ± 4.95 mg/dL, Placebo STZ ‐ 450 ± 11.6 mg/dL, 4OH STZ ‐ 575 ± 4.95 mg/dL; Females: 4OH vehicle ‐ 178 ± 3.50 mg/dL, Placebo STZ ‐ 330 ± 8.22 mg/dL, 4OH STZ ‐ 436 ± 4.65 mg/dL). Given the effectiveness of ER modulation, we next aimed to understand the downstream effects that 4OH has on both the kidney and liver. TaqMan qPCR for > 90 ER‐regulated genes was performed on cDNA isolated from all treatment groups. Initial analysis revealed that 4OH treatment modulates membrane dynamics with differential expression observed in genes associated with caveolin and lipid rafts. We also observed changes in genes regulating cellular iron handling. Efforts are currently underway to confirm these changes at both the gene and protein level, and to understand the global impact that ER modulation may have on DM. Collectively, these data have implications both fo...

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.