Background: β-cell dysfunction is a hallmark feature of diabetes mellitus. G protein a-subunit (Gsa) mediates receptor-stimulated intracellular cAMP production In β cells in order to increase glucose-stimulated insulin secretion, cell proliferation and survival. Growing interest in urinary metabolome has emerged as many drugs aim to improve outcomes by targeting kidney function. Given clinical significance of the Gsa pathway, we aimed to study changes of urinary metabolome as a result of Gsa deficiency.
Methods: Mice with Gsα deficiency limited to β cells (Gsa βcell-/-) were generated by mating Gsα-floxed mice with MIPcreERT mice in order to directly examine Gsα/cAMP signaling role in β cells, in a similar method to Xie et.al. Urine was collected from (Gsa βcell-/-) mice and controls and stored at -80C until processed for non-targeted metabolomics using GCMS.
Results: In a small cohort, 17 metabolites were significantly altered between the two groups (P<0.05). While pathway analysis somewhat echoed findings described in other models of diabetes (urea cycle, Malate-Aspartate shuttle, and amino acid metabolism), 4 metabolites were completely undetectable in (Gsa βcell-/-) urine including 3-Oxoglutaric acid and Methylglutarate. In addition, some changed in a different direction to what was previously described in other models of diabetes (e.g: Gsa βcell-/- mice exhibited decreased urinary adipic acid). Enrichment analysis of disease associated metabolite sets of the urine mimicked changes seen in enzymatic defects of 3-Hydroxy-3-Methylglutaryl-Coa Lyase, Kynureninase Deficiency, 2-Ketoglutarate Dehydrogenase and Wolcott-Rallison Syndrome (P<0.05).
Conclusion: Gsa pathway deficiency in β cells produced a model of diabetes with unique metabolome. Studying changes of urine metabolome after treatment with antiglycemics in the future might highlight the drugs renal impact in the setting of Gsa deficiency.
A. Ilaiwy: None. M. Capozzi: None. J.L. Brown: None. D. D’Alessio: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Intarcia Therapeutics. Research Support; Self; Ansh Labs, Eli Lilly and Company, Merck Sharp & Dohme Corp. Other Relationship; Self; Novo Nordisk A/S. J. Campbell: Research Support; Self; Eli Lilly and Company, Novo Nordisk Inc. Speaker’s Bureau; Self; Merck Sharp & Dohme Corp.