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.