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While inflammation is beneficial for insulin secretion during homeostasis, its transformation adversely affects β cells and contributes to diabetes. However, the regulation of islet inflammation for maintaining glucose homeostasis remains largely unknown. Here, we identified pericytes as pivotal regulators of islet immune and β cell function in health. Islets and pancreatic pericytes express various cytokines in healthy humans and mice. To interfere with the pericytic inflammatory response, we selectively inhibited the TLR/MyD88 pathway in these cells in transgenic mice. The loss of MyD88 impaired pericytic cytokine production. Furthermore, MyD88-deficient mice exhibited skewed islet inflammation with fewer cells, an impaired macrophage phenotype, and reduced IL-1β production. This aberrant pericyte-orchestrated islet inflammation was associated with β cell dedifferentiation and impaired glucose response. Additionally, we found that Cxcl1, a pericytic MyD88-dependent cytokine, promoted immune IL-1β production. Treatment with either Cxcl1 or IL-1β restored the mature β cell phenotype and glucose response in transgenic mice, suggesting a potential mechanism through which pericytes and immune cells regulate glucose homeostasis. Our study revealed pericyte-orchestrated islet inflammation as a crucial element in glucose regulation, implicating this process as a potential therapeutic target for diabetes.

Abstract Disclosure: A. Moscona-Nissan: None. D. Marrero-Rodríguez: None. S. Andonegui-Elguera: None. E.S. Luna-Ávila: None. F. Martínez-Mendoza: None. S. Vela-Patiño: None. I. Ramírez-Ramos: None. S. Hinojosa-Alvarez: None. J. Hernandez-Perez: None. R.A. Chavez-Santoscoy: None. S. Mercado-Medrez: None. K.S. León-Wu: None. R. De Miguel Ibanez: None. M. Mercado: None. K. Taniguchi-Ponciano: None. A. Ferreira-Hermosillo: None. MODY misdiagnosis remains widespread, existing remarkable variability within genetic variants across populations. While diagnostic tools are based on Caucasian cohorts, Whole Exome Sequencing (WES) studies are needed to identify new genes in non-Caucasians, as up to 77% of patients do not harbor variants of significance in MODY-known genes. In Latino populations, no WES studies have explored MODY’s genomic landscape beyond its canonical genes. We carried WES in 51 participants: 17 patients with MODY, 17 with type 2 diabetes (T2DM) and 17 healthy controls (HC) at a Mexican tertiary care center. MODY diagnosis followed Exeter criteria (score ≥36%) in subjects with minimal or no insulin use. Clinical and genomic data were analyzed, comparing the SNV landscape across groups using Maftools in R, and performing enrichment analyses. We compared genetic variant frequencies of MODY 1-14 and additional genes associated with MODY in other populations using Chi-squared test. Canonical MODY genes used for routine genetic diagnosis showed low discrimination utility, having variants similar frequencies between MODY, T2DM and HC in the Mexican population. We propose 14 candidate genes with variants distinguishing MODY from T2DM and HC, as we detected variants in genes as MAP2K, TPTE, SYT15, PEX5, KCNJ12, KTM2C, OR2A1, RIMBP3, TRIM49C, AQP12B, OR51A4, RIMBP3B, ZNF717, and SUSD2 in 75-100% of MODY cases while absent in T2DM and HC. In MAP2K3, we detected variants c.281G>T (p.Arg94Leu), c.286C>T (p.Arg96Trp), c.304C>T (p.Gln102Ter), and c.164G>C (p.Arg55Thr) in 100% of MODY cases but in none of T2DM/HC cases. In KCNJ12, variant c.128G>A (p.Arg43His) was found in 100% of MODY but 0% of T2DM/HC cases. In TPTE, variants c.1156A>G (p.Lys386Glu) and c.1445A>C (p.Tyr482Ser) were detected in 100% and 94% of MODY cases, respectively, while absent in T2DM/HC. Regarding PEX5, a splicing variant was found in 94% of MODY cases while in 0% of T2DM/HC. Enrichment analysis revealed involvement of the mentioned genes in synaptic vesicle trafficking, insulin/IGF pathway-mitogen activated protein kinase/MAPK cascade, and insulin/IGF pathway-protein kinase B/AKT signaling cascade. This is the first WES study in a MODY Latino population, analyzing beyond canonical genes. Besides improving our understanding of glycemic regulation pathways, candidate genes could serve as diagnostic biomarkers for MODY in Latinos, enabling accurate diagnosis and implementation of personalized therapies for patients. Presentation: Monday, July 14, 2025

Background: Pituitary adenomas (PA) are the second most common tumor in the central nervous system and have low counts of mutated genes. Splicing occurs in 95% of the coding RNA. There is scarce information about the spliceosome and mRNA-isoforms in PA, and therefore we carried out proteomic and transcriptomic analysis to identify spliceosome components and mRNA isoforms in PA. Methods: Proteomic profile analysis was carried out by nano-HPLC and mass spectrometry with a quadrupole time-of-flight mass spectrometer. The mRNA isoforms and transcriptomic profiles were carried out by microarray technology. With proteins and mRNA information we carried out Gene Ontology and exon level analysis to identify splicing-related events. Results: Approximately 2000 proteins were identified in pituitary tumors. Spliceosome proteins such as SRSF1, U2AF1 and RBM42 among others were found in PA. These results were validated at mRNA level, which showed up-regulation of spliceosome genes in PA. Spliceosome-related genes segregate and categorize PA tumor subtypes. The PA showed alterations in CDK18 and THY1 mRNA isoforms which could be tumor specific. Conclusions: Spliceosome components are significant constituents of the PA molecular machinery and could be used as molecular markers and therapeutic targets. Splicing-related genes and mRNA-isoforms profiles characterize tumor subtypes.