Abstract
Activation of innate immunity and low-grade inflammation contributes to hyperglycemia and an onset of Type 2 Diabetes Mellitus (T2DM). Interleukin-2 (IL-2), leptin, High Mobility Group Box-1 (HMGB-1), and increased glucose concentrations are mediators of these processes also by modulating peripheral blood mononuclear cells (PBMCs) response. The aim of this study was to investigate if HMGB-1 and IL-2 turn on PBMCs and their leptin secretion. In isolated human PBMCs and their subpopulations from healthy individuals and naïve T2DM patients, leptin release, pro-inflammatory response and Toll-like Receptors (TLRs) activation was measured. After treatment with IL-2 and HMGB1, NK (Natural Killer) have the highest amount of leptin secretion, whilst NK-T have the maximal release in basal conditions. TLR4 (TAK242) and/or TLR2 (TLR2-IgA) inhibitors decreased leptin secretion after IL-2 and HMGB1 treatment. A further non-significant increase in leptin secretion was reported in PBMCs of naive T2DM patients in response to IL-2 and HMGB-1 stimulation. Finally, hyperglycemia or hyperinsulinemia might stimulate leptin secretion from PBMCs. The amount of leptin released from PBMCs after the different treatments was enough to stimulate the secretion of IL-1β from monocytes. Targeting leptin sera levels and secretion from PBMCs could represent a new therapeutic strategy to counteract metabolic diseases such as T2DM.
Highlights
High Mobility Group Box1 (HMGB1) incubation did not lead to interferon-γ (IFN-γ) release from peripheral blood mononuclear cells (PBMCs); on the contrary, IL-2 stimulation induced the secretion of IFN−γ with a further significant increase when combined with HMGB1 (p < 0.05) (Figure 1C), as already reported [27]
We confirmed that PBMCs can secrete leptin after pro-inflammatory stimuli [47], and the highest secretion levels of leptin were obtained from NK-T cells, in particular in response to high glucose concentrations
PBMCs treated with IL-2 and HMGB1, a pro-inflammatory stimulus, led to a significant increase of leptin secretion
Summary
Type 2 Diabetes mellitus (T2DM) is a metabolic disorder where chronic low gradeinflammation and the activation of the innate immunity contribute to the pathogenesis of insulin resistance and pancreatic β cell failure [1]. Inflammation impact on T2DM pathophysiology is even more evident since pro-inflammatory mediators like interleukin1β (IL-1β) and tumor necrosis factor-α (TNF-α) mediate glucotoxicity effect on pancreatic β-cell dysfunction and increase insulin resistance levels [2,3]. T2DM might be considered as an inflammatory disorder, where high nutrient intake may lead to lipid overflow and overload, triggering the activation of the innate immunity, through the toll-like receptors (TLRs) system [4]. The activation of the innate immunity is implicated in the pathogenesis of insulin resistance and T2DM, triggering the TLR systems [7,8]. T2DM and T1DM patients have higher blood concentrations of TLR ligands with higher activation of the TLR system [11]
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