Preliminary analysis of immune activation in early onset type 2 diabetes

Abstract

IntroductionFirst 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).MethodsSerum 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.ResultsYouth 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.ConclusionThese 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.

Leptin but not adiponectin is related to type 2 diabetes mellitus in obese adolescents

“…Also Mendelian randomization studies do not support a causal role for reduced circulating adiponectin levels in T2DM (46). Studies reporting decreased adiponectin levels in T2DM in adults (17,24,47,48) or children (15,18,(31)(32)(33)(34)49) were based on normal weight controls and not age-, gender-, and BMI-matched controls as in our study explaining the difference to our study.…”

“…Several clinical studies have demonstrated that hypoadiponectinemia correlates with the development of T2DM (17,(24)(25)(26), but the causal directions of these associations are unclear. In manifest T2DM, some studies have reported reduced adiponectin concentrations in adults (16,17,(22)(23)(24)(27)(28)(29)(30) and children with T2DM (15,18,(31)(32)(33)(34), whereas others reported no difference in adiponectin levels between obese humans with and without T2DM (18,31).…”

Circulating cell-free mitochondrial DNA as the probable inducer of early endothelial dysfunction in the prediabetic patient

“…Previous evidence indicates that the innate immune response, where TLRs play a central role, is impaired in diabetic patients. Some reports have shown the relevance of TLR4 in the development of DM2 in the induction of the synthesis of TNF-α and IL-1β and by inhibiting the insulin signaling pathways (Rempel et al, 2013). Another TLR, previously associated with the pathology of DM2, is TLR3.…”

Gingipain R1 and lipopolysaccharide from Porphyromonas gingivalis have major effects on blood clot morphology and mechanics

“…Type diabetes (T2DM) is also associated with bacterial translocation via the gut [23][24][25]. LPS presence has also been noted in the central nervous system of patients with Alzheimer's disease (AD) [26][27][28] or in their blood [29], and blood of T2DM [30,31], Parkinson's disease (PD) [29], sepsis [32,33], Rheumatoid Arthritis [34] and psoriasis vulgaris [35].…”