Abstract: PP14-1

CD74 and Oxytocin-Related Networks Link Hyperglycemia and Vitamin D to Type 2 Diabetes Pathogenic Mechanisms: Data from PBMC Transcriptome Analysis of African American Men with Prediabetes Participating in Vitamin D Treatment Trial

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Abstract


Background: Emerging evidence links peripheral blood mononuclear cells (PBMC) with low-grade inflammation and insulin resistance. Vitamin D affects low-grade inflammation and insulin resistance as well. Objective: To assess PBMC transcriptome response to acute glucose challenge and high dose vitamin D treatment. Methods: African American men (AAM) with obesity, prediabetes and hypovitaminosis D were treated with weekly 50,000IU ergocalciferol (VD) or placebo (PL) for 1 year (1). The PBMCs were collected at final visit for 0min and 60min of oral glucose tolerance test (OGTT). view more

Background: Emerging evidence links peripheral blood mononuclear cells (PBMC) with low-grade inflammation and insulin resistance. Vitamin D affects low-grade inflammation and insulin resistance as well. Objective: To assess PBMC transcriptome response to acute glucose challenge and high dose vitamin D treatment. Methods: African American men (AAM) with obesity, prediabetes and hypovitaminosis D were treated with weekly 50,000IU ergocalciferol (VD) or placebo (PL) for 1 year (1). The PBMCs were collected at final visit for 0min and 60min of oral glucose tolerance test (OGTT). The global transcriptional profiling of PBMCs was compared between the groups as follows: 1) 0min (G0) vs 60min (G60) of OGTT (n=28); 2) G0 and low 25OHD50ng/ml (HighD0, n=9); 3) G60 and LowD (LowD60, n=12) vs G60 and HighD (HighD60, n=9). The FDR-corrected p< 0.02 was considered significant.  Results: AAM (n=28) average age, BMI, and A1C were: 60 years, 32 kg/m2, and 6.1%, respectively. The number of genes with observed differential expression was as follows: 1) G0 vs G60 350 genes, 2) LowD0 vs HighD0 178 genes, 3) LowD60 vs HighD60 41 genes. The pathway map comparison of G0 vs G60 revealed differentials for insulin and lipid signaling (p=2.551e-2) and fat adipogenesis /adipocyte differentiation (p=4.172e-2) cascades. These pathways showed downregulation of IRS-2 and PKA-reg and upregulation of SOS and PPAR-+. Comparison of LowD0 vs HighD0 showed differences in genes of immune response (upregulated: calcineurin-A, IL4RA, NF-AT, p=2.093e-4) and posttranslational processing of neuroendocrine peptides including appetite-controlling peptides (downregulated: precursors of cholecystokinin [CCK] and oxytocin [OXT], p=2.093e-4). Comparison of LowD60 vs HighD60 showed differential expression of CD74 (upregulated, p=4.197e-2). Conclusions: The interaction between acute hyperglycemia (produced by OGTT) and high serum 25OHD level (produced by VD treatment) resulted in upregulation of CD74 gene in PBMCs. This novel finding suggested CD74 role in DM2 pathogenesis. In animal models CD74, the macrophage inhibitory factor (MIF) receptor, affected DM1 and pancreatic cancer development. There were no studies connecting CD74 to DM2 or vitamin D status. The data on differential expression of precursor genes for CCK and OXT was novel as well. This data linking immune/inflammatory response to the neuroendocrine system supported CCK and OXT importance in DM2 development. Overall, the gene ontology analysis exposed differential genes primarily enriched in innate immunity, inflammation response, protein processing and insulin/adipogenesis signaling. The patterns of expressed genes offered an insight into DM2 pathogenic networks. Further studies are needed to validate these results and evaluate observed pathways as therapeutic targets and/or biomarkers for risk prediction.

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