Abstract
Type 2 diabetes mellitus is a severe public health issue worldwide. It displays a harmful effect on different organs as the eyes, kidneys and neural cells due to insulin resistance and high blood glucose concentrations. To date, the available treatments for this disorder remain limited. Several reports have correlated obesity with type 2 diabetes. Mainly, dysfunctional adipocytes and the regulation of high secretion of inflammatory cytokines are the crucial links between obesity and insulin resistance. Several clinical and epidemiological studies have also correlated the onset of type 2 diabetes with inflammation, which is now indicated as a new target for type 2 diabetes treatment. Thus, it appears essential to discover new drugs able to inhibit the secretion of proinflammatory adipocytokines in type 2 diabetes. Adipocytes produce inflammatory cytokines in response to inflammation or high glucose levels. Once activated by a specific ligand, CXCR1 and CXCR2 mediate some cytokines’ effects by activating an intracellular signal cascade once activated by a specific ligand. Therefore, it is conceivable to hypothesize that a specific antagonist of these receptors may ameliorate type 2 diabetes and glucose metabolism. Herein, differentiated 3T3-L1-adipocytes were subjected to high glucose or inflammatory conditions or the combination of both and then treated with ladarixin, a CXCR1/2 inhibitor. The results obtained point towards the positive regulation by ladarixin on insulin sensitivity, glucose transporters GLUT1 and GLUT4, cytokine proteome profile and lipid metabolism, thus suggesting ladarixin as a potentially helpful treatment in type 2 diabetes mellitus and obesity.
Highlights
Adipocyte characterization was corroborated by Western blotting analysis of pre-adipocyte factor 1 (Pref-1), adipose tissue fatty acid-binding protein, peroxisome proliferator-activated receptor-gamma (PPARγ) and GLUT4. aP2 is a carrier protein for fatty acids primarily expressed in adipocytes and macrophages
Once the model was established, cells were treated with different concentrations of ladarixin (1–50 μM) for 72 h and cells viability was evaluated by Cytotox Green Assay; the results showed that the concentrations tested were not toxic (Figure A1A,B)
Having found that High glucose cells (HG) dramatically downregulated GLUT4 expression and that this effect was reverted by Ladarixin treatment, we investigated the effect of HG on the expression of GLUT1 which, together with GLUT4, constitutes one of the two predominant isoforms of the glucose transporter expressed in 3T3-L1 adipocytes
Summary
Obesity is related with an increased risk of insulin resistance and several metabolic complications, including type 2 diabetes mellitus (T2D) [1,2]. The prevalence of obesity and obesity-related diseases including type 2 diabetes, cardiovascular disorders and metabolic syndrome has significantly risen in the past 20 to 30 years [3]. The primary function of AT is to stimulate the uptake of both glucose and fatty acids after feed in response to insulin signalling [6]. These functions are impaired during the initiation and progression of obesity. GLUT4 is upregulated in differentiated adipocytes and matures as GLUT1 (glucose transporter type 1, non-insulin-responsive) is downregulated [10,11]. Adiponectin expression raises 3 to 4 days post-differentiation and is believed to be a late marker of mature adipocytes [14,15]
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