View
226
Download
7
Category
Preview:
Citation preview
1,2Elena Barengolts MD, 2Arfana Akbar, MD, 1Irina Ciubotaru MD/PhD , 3Mark Maienschein-‐Cline and 3Zarema Arbieva, PhD
1Section of Endcrinology, Diabetes and Metabolism, University of Illinois (UIC), Chicago, IL; 2Section of Endocrinology, Jesse Brown VA Medical Center, 3Research Resource Center UIC
Background ● Peripheral blood mononuclear cells (PBMC) response to
hyperglycemia play a role in type 2 diabetes (DM2) pathogenesis.
● Vitamin D may affectPBMC response to hyperglycemia.
Methods ● Subjects: African American men (AAM) with obesity,
prediabetes and 25OHD<30ng/ml were treated with weekly 50,000IU D2 (VD) or placebo (PL) for 1 year (1).
● PBMC were from baseline (n=9) and final (n=19)visits ● Groups:
● G0 = 0min OGTT ● G60 = 60min OGTT ● LowD <15ng/ml (n=12) ● HighD >50ng/ml (n=9);
● The FDR-corrected p< 0.02 was considered significant.
Results
Objective ● To assess PBMC gene expression response to
hyperglycemia and high dose vitamin D treatment.
This work was supported in part by a Merit Review grant funded by the Department of Veterans Affairs, Jesse Brown VA Medical Center and an NIH grant number UL1RR029879
Discussion ● 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.
● The gene ontology analysis exposed differential genes primarily enriched in innate immunity, inflammation response, protein processing and insulin/adipogenesis signaling.
Values All N=28
LowD N=10
HighD N=9
P value
Age, yr 60.1 ± 5.6 56.1 ± 4.3 62.8 ± 2.8 0.01 Body wt, kg 98.2 ± 8.3 93.2 ± 8.7 102.7 ± 11.4 0.17 BMI, kg/m2 31.5 ± 3.0 29.7 ± 2.6 33.2 ± 3.2 0.07 Ba25D, ng/ml 14.3 ± 3.2 11.7 ± 3.6 14.8 ± 2.7 0.12 Fi25D 39.1 ± 27.7 21.3 ± 19.3 73.0 ± 7.8 <0.001 BaG0 97.4 ± 10.7 96.4 ± 9.9 96.8 ± 6.1 0.94 FiG0 96.1 ± 10.0 99.3 ± 11.4 89.1 ± 6.6 0.11 BaG60 170.9 ± 39.6 172.6 ± 39.2 166.6 ± 32.1 0.77 FiG60 166.5 ± 39.1 161.9 ± 37.4 159.7 ± 40.3 0.92 Ba=Baseline, Fi=Final, G0 & G60 at 0 & 60 min OGTT
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 ParPcipaPng in Vitamin D Treatment Trial
Conclusion ● 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.
Groups Gene mapping
G0 vs. G60 N=350 genes
Insulin and lipid signaling (p=2.551e-‐2) and fat adipogenesis /adipocyte differenZaZon (p=4.172e-‐2) cascades. Downregulated: IRS-‐2, PKA-‐reg. Upregulated: SOS, PPAR-‐α
LowD-‐G0 vs. HighD-‐G0 N=178 genes
Immune response (upregulated: calcineurin-‐A, IL4RA, NF-‐AT, p=2.093e-‐4) and poscranslaZonal processing of neuroendocrine pepZdes including appeZte-‐controlling pepZdes (downregulated: precursors of cholecystokinin [CCK] and oxytocin [OXT], p=2.093e-‐4).
LowD-‐G60 vs. HighD-‐G60
Comparison of LowD60 vs HighD60 showed differenZal expression of CD74 (upregulated, p=4.197e-‐2).
Global gene expression 1. Barengolts E, B. Manickam, A. Kouser, et al. Effects of high dose vitamin D repleZon on glycemic control in African American men with prediabetes and hypovitaminosis D (results of the D-‐vitamin IntervenZon in Veteran AdministraZon (DIVA) randomized clinical trial. Endocr Pract 2015;21(6):604-‐612.
Recommended