Impaired coronary microcirculation in type 2 diabetic patients is associated with elevated circulating regulatory T cells and reduced number of IL-21R⁺ T cells.
BACKGROUND
Low-grade systemic inflammation is considered to participate in the progression of type 2 diabetes (T2D) and in diabetic complications.


METHODS
To determine if circulating leukocytes were abnormally regulated in T2D patients, 8-color flow-cytometry (FACS) analysis was performed in a cross-sectional study of 37 T2D patients and 16 controls. Data obtained from the FACS analysis were compared to coronary flow reserve (CFR), assessed by Rb(82)-PET-imaging, to uncover inflammatory signatures associated with impaired CFR.


RESULTS
Presence of T2D was associated with T cell attenuation characterized by reduced overall T cell, Th17, IL-21R(+), Treg's and TLR4(+) T cells, while the monocyte population showed enhanced TLR4 expression. Further, our data revealed reduced M1-like CD11c expression in T2D which was associated with impaired CFR. In contrast, we show, for the first time in T2D, increased TLR4 expression on CD8 T cells, increased Treg cell number and Treg maturation and reduced IL-21R expression on CD8 T cells to be functionally associated with impaired CFR.


CONCLUSIONS
Our demonstration that HbA1c inversely correlates to several T cell populations suggests that T cells may play disease modulating roles in T2D. Further, the novel association between impaired CFR and regulatory T cells and IL-21R(+) T cells imply an intricate balance in maintaining tissue homeostasis in vascular diabetic complications.
Department of Diabetic Complications, Steno Diabetes Center, Niels Steensens Vej 1, 2820, Gentofte, Denmark. bjos@steno.dk.
Bernt Johan
BJ
von Scholten
Diabetes Complications Research, Novo Nordisk A/S, Måløv, Denmark.|Department of New Haemophilia, Novo Nordisk A/S, Gentofte, Denmark.|Baxalta Inc, Medical Affairs, Tobaksvej 2, 2860, Søborg, Denmark.
Alexander
A
Rosendahl
Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet, Copenhagen, Denmark.
Philip
P
Hasbak
Diabetes Complications Research, Novo Nordisk A/S, Måløv, Denmark.
Regine
R
Bergholdt
Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet, Copenhagen, Denmark.
Andreas
A
Kjaer
Department of Diabetic Complications, Steno Diabetes Center, Niels Steensens Vej 1, 2820, Gentofte, Denmark.|University of Copenhagen, Copenhagen, Denmark.|Aarhus University Denmark, Aarhus, Denmark.
Peter
P
Rossing
Department of Diabetic Complications, Steno Diabetes Center, Niels Steensens Vej 1, 2820, Gentofte, Denmark.
Tine W
TW
Hansen
D000328:Adult; D000368:Aged; D003324:Coronary Artery Disease / Q000150:complications / Q000503:physiopathology*; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000503:physiopathology*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000503:physiopathology; D053738:Interleukin-21 Receptor alpha Subunit / Q000276:immunology; D008297:Male; D008833:Microcirculation / Q000502:physiology*; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology
C508117:IL21R protein, human; D053738:Interleukin-21 Receptor alpha Subunit
Cardiovascular disease; Coronary flow reserve; Coronary microcirculation; Flow-cytometry (FACS) analysis; Inflammation; Monocyte sub-populations; Peripheral blood; Type 2 diabetes