title: Preliminary analysis of immune activation in early onset type 2 diabetes.
abstract: BACKGROUND
  First Nations and other Aboriginal children are disproportionately affected by cardiometabolic diseases, including type 2 diabetes (T2D). In T2D, the disruption of insulin signalling can be driven by pro-inflammatory immunity. Pro-inflammatory responses can be fueled by toll-like receptors (TLR) on immune cells such as peripheral blood mononuclear cells (PBMC, a white blood cell population). TLR4 can bind to lipids from bacteria and food sources activating PBMC to produce cytokines tumour necrosis factor (TNF)-α and interleukin (IL)-1β. These cytokines can interfere with insulin signalling. Here, we seek to understand how TLR4 activation may be involved in early onset T2D. We hypothesized that immune cells from youth with T2D (n = 8) would be more reactive upon TLR4 stimulation relative to cells from age and body mass index (BMI)-matched controls without T2D (n = 8).
  
  
  METHODS
  Serum samples were assayed for adipokines (adiponectin and leptin), as well as cytokines. Freshly isolated PBMC were examined for immune reactivity upon culture with TLR4 ligands bacterial lipopolysaccharide (LPS, 2 and 0.2 ng/ml) and the fatty acid palmitate (200 µM). Culture supernatants were evaluated for the amount of TNF-α and IL-1β produced by PBMC.
  
  
  RESULTS
  Youth with T2D displayed lower median serum adiponectin levels compared to controls (395 vs. 904 ng/ml, p < 0.05). PBMC isolated from youth with and without T2D produced similar levels of TNF-α and IL-1β after exposure to the higher LPS concentration. However, at the low LPS dose the T2D cohort exhibited enhanced IL-1β synthesis relative to the control cohort. Additionally, exposure to palmitate resulted in greater IL-1β synthesis in PBMCs isolated from youth with T2D versus controls (p < 0.05). These differences in cytokine production corresponded to greater monocyte activation in the T2D cohort.
  
  
  CONCLUSIONS
  These preliminary results suggest that cellular immune responses are exaggerated in T2D, particularly with respect to IL-1β activity. These studies aim to improve the understanding of the biology behind early onset T2D and its vascular complications that burden First Nations people.
authors.affiliation: OOH-QUIN Immunology Laboratory, Section of Hepatology, Department of Internal Medicine, Manitoba Institute of Child Health, Winnipeg, Canada. julia.rempel@med.umanitoba.ca
authors.forename: Julia D
authors.initials: JD
authors.lastname: Rempel
authors.forename: Juliet
authors.initials: J
authors.lastname: Packiasamy
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Dean
authors.forename: Jonathon
authors.initials: J
authors.lastname: McGavock
authors.forename: Alyssa
authors.initials: A
authors.lastname: Janke
authors.forename: Mark
authors.initials: M
authors.lastname: Collister
authors.forename: Brandy
authors.initials: B
authors.lastname: Wicklow
authors.forename: Elizabeth A C
authors.initials: EA
authors.lastname: Sellers
mesh_terms: D052242:Adiponectin / Q000097:blood; D000293:Adolescent; D000367:Age Factors; D015992:Body Mass Index; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology*; D005260:Female; D006801:Humans; D007111:Immunity, Cellular; D007198:Indians, North American / Q000706:statistics & numerical data; D053583:Interleukin-1beta / Q000097:blood; D020738:Leptin / Q000097:blood; D008297:Male; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D052242:Adiponectin; D053583:Interleukin-1beta; D020738:Leptin; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha
keywords: TLR4; early onset type 2 diabetes; interleukin 1beta