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This secondary analysis of a randomized clinical trial investigates the relative effectiveness and safety of the sodium-glucose cotransporter-2 inhibitor dapagliflozin for Black and White patients with chronic kidney disease (CKD) in North and South America.

Phytochemical investigation of the aerial parts of Eryngium caeruleum led to the isolation of two new source flavone glycosides (1 and 2). The structures of these compounds were determined with the help of one- and two-dimensional (1D- and 2D-) NMR techniques including 1H-NMR, 13C-NMR, HMQC, HMBC, 1H- 1H COSY, and NOESY experiments. The compounds were studied for their in vitro aldose reductase (ALR1 and ALR2) and glucosidase (α and β) inhibitory activities, and antiglycation potential. Both the compounds showed higher inhibition potential against ALR1 than ALR2. Compound 2 showed three fold higher potency against ALR2 than the reference drug Sorbinil. In silico studies were performed to understand the binding mechanism of these compounds to aldose reductase .

Abstract Disclosure: E.J. Louwagie: None. J.N. Diego: None. C.S. Farooqi: None. M.M. Kamal: None. As prescriptions for sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and the novel agent tirzepatide continue to increase, a rare yet serious condition has emerged: euglycemic ketoacidosis (EKA). EKA is a life-threatening condition similar to diabetic ketoacidosis, except diagnosis is more challenging because patients present with normal to slightly elevated blood glucose levels. Tirzepatide is a novel dual agonist at GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors and is approved for treatment of diabetes and weight loss. Here, we describe a unique case in which a young male patient placed on both an SGLT2 inhibitor and tirzepatide developed EKA. The patient’s diagnosis was delayed, and he required treatment and monitoring in an intensive care unit. Clinicians should be aware of this rare yet potentially fatal complication as well as potential risk factors. Presentation: Monday, July 14, 2025

Abstract Disclosure: M.T. Otunla: None. We recently showed that kidney-specific glucose transporter 2 knockout (Ksp-Glut2 KO) mice exhibit glycosuria and have an overactive hypothalamic-pituitary-adrenal (HPA) axis. This observation suggests a potential crosstalk between elevated glycosuria and stress-related comorbidities, particularly in the context of currently used SGLT2 inhibitors. To investigate the mechanism underlying the HPA axis dysregulation in renal Glut2 KO mice we performed single nucleus RNA sequencing on renal tissue, analyzed their behavior (light/dark box, elevated plus maze, forced swim, open field, and hot plate tests), induced acute and chronic stress using a physical restraint and measured their corticosterone levels. RNA sequencing revealed that the Fkbp5 gene, which has been implicated in contributing to stress-associated psychiatric disorders, diabetes and obesity, was differentially expressed in the renal tissues of Glut2 KO mice. Specifically, it was significantly upregulated in the endothelial cells and downregulated in the proximal tubules of the kidneys. The qPCR analysis showed that the Glut2 KO mice exhibited decreased Fkbp5 expression in the skeletal muscle (100.0±12.19 vs 36.7±5.1, p<0.05) and increased expression in the liver (100.0±20.5 vs 226.7±11.2, p<0.05). This result suggests tissue-specific alterations in glucocorticoid signaling. Moreover, renal Glut2 KO mice had higher levels of plasma corticosterone at baseline (36.6±7.0 vs 48.7±8.7 ng/ml control vs experimental), after acute stress (153.7±18.4 vs 243.3±12.0 ng/ml) and following chronic stress (199.5±9.7 vs 262.0±14.4 ng/ml). The behavioral tests demonstrated that renal Glut2 KO mice had lower frequency of entry into the light side arena (56.5±5.1 vs 46.2±3.0 control vs experimental) along with a reduced mean activity in the Forced Swim Test (0.57±0.19 vs 0.13±0.01, p<0.05), suggesting an impairment in stress-handling capacity. In addition, the KO mice exhibited a lower frequency of entry into the closed arms (13.0±2.0 vs 7.6±1.4, p<0.05) and spent more time in the closed arms (167.0±19.5 vs 236.0±15.2, p<0.05), indicating a preference for the enclosed, safer areas, consistent with increased anxiety-like behavior. The experimental mice also showed reduced motivation or increased depression-like behavior as evidenced by a higher average percentage and a longer cumulative duration of inactivity. Finally, the Glut2 KO mice showed lower latency (10.7±0.9 vs 7.8±0.3, p=0.0114) to react during the hot plate test, indicating their hypersensitivity to pain. In summary, our findings identify Fkbp5 as a critical mediator of HPA axis dysregulation in renal Glut2 KO mice, linking renal glycosuria to stress-associated behaviors. These results have important implications for the use of SGLT2 inhibitors, particularly in individuals with preexisting neurological disorders. Presentation: Monday, July 14, 2025