The Purinergic Landscape of Type 2 Diabetes Mellitus.

Adenosine triphosphate (ATP) is the key energy intermediate of cellular metabolic processes and a ubiquitous extracellular messenger. As an extracellular messenger, ATP acts at plasma membrane P2 receptors (P2Rs). The levels of extracellular ATP (eATP) are set by both passive and active release mechanisms and degradation processes. Under physiological conditions, eATP concentration is in the low nanomolar range but can rise to tens or even hundreds of micromoles/L at inflammatory sites. A dysregulated eATP homeostasis is a pathogenic factor in several chronic inflammatory diseases, including type 2 diabetes mellitus (T2DM). T2DM is characterized by peripheral insulin resistance and impairment of insulin production from pancreatic ß-cells in a landscape of systemic inflammation. Although various hypoglycemic drugs are currently available, an effective treatment for T2DM and its complications is not available. However, counteracting systemic inflammation is anticipated to be beneficial. The postulated eATP increase in T2DM is understood to be a driver of inflammation via P2X7 receptor (P2X7R) activation and the release of inflammatory cytokines. Furthermore, P2X7R stimulation is thought to trigger apoptosis of pancreatic ß-cells, thus further aggravating hyperglycemia. Targeting eATP and the P2X7R might be an appealing novel approach to T2DM therapy.

Increased Levels of AIM2 and Circulating Mitochondrial DNA in Type 2 Diabetes.

BACKGROUND: Chronic inflammation has critical role in Type 2 diabetes (T2D), in which IL-1ß contributes in insulin resistance and beta cell dysfunction. The activation of NLRP3 and AIM2 by endogens ligands, such as mtDNA can lead to the release of active form of IL-1ß. OBJECTIVE: To evaluate AIM2 expression and activation as well as circulating mtDNA levels in T2D patients. METHODS: AIM2 expression was analyzed by flow cytometry, it's activity was assessed by measuring in vitro release of IL-1ß induced by Poly (dA:dT), and mtDNA copy number was determined by quantitative real-time polymerase chain reaction. RESULTS: Increased percent of AIM2+ cells were detected in monocytes from patients with T2D. Moreover, increased levels of IL-1ß in monocytes cultures from T2D patients compared to healthy controls were observed. Also, association between AIM2+ cells and hyperglycemia (r=0.4385, P=0.0095) and triglycerides levels (r=0.5112, P=0.002) and waist-hip ratio (r=0.4710, P=0.0049) were detected. Likewise, the mtDNA copy number was augmented in T2D patients compared to control group. The mtDNA copies number was associated with body mass index (r=0.4231, P=0.0008) and TNF-α levels (r=0.5231, P=0.0005). In addition, increased levels of IL-12p70, TNF-a, IL-10, IL-6, IL-8 and IL-1ß were detected in a serum from T2D patients. CONCLUSION: These results suggest the involvement of AIM2 and mtDNA in the inflammatory process seen in T2D.

The presence of the 1068 G>A variant of P2X7 receptors is associated to an increase in IL-1Ra levels, insulin secretion and pancreatic ß-cell function but not with glycemic control in type 2 diabetes patients.

It has been reported that an increased function of the P2X7 purinergic receptor is associated with an increase in both insulin sensitivity and secretion. Accordingly, we explored the possible effect of the 1068 G>A polymorphism of the gene P2RX7 on glucose homeostasis and the levels of the anti-inflammatory cytokine IL-1Ra in T2D patients. The presence of the 1068 G>A polymorphism in T2D patients (n = 100) and healthy subjects (n = 100) was determined by DNA sequencing, and serum levels of IL-1Ra were measured by ELISA. Pancreatic ß-cell function, insulin resistance, blood glucose levels and glycated hemoglobin (HbA1c) were also analyzed. We detected a significant negative association between T2D and the 1068 G>A SNP (Odds ratio 0.3916, p = 0.0045). In addition, we observed that T2D patients bearing the 1068 G>A variant showed higher serum levels of IL-1Ra compared to both, patients with the GG genotype or healthy individuals (GG or G>A). Moreover, T2D patients bearing the 1068 G>A SNP showed increased insulin levels and a better pancreatic ß-cell function (p < 0.05 in both cases) compared to patients with the wild type genotype. However, the HbA1c levels, fasting glucose levels and the degree of insulin resistance were similar in T2D patients carrying or not the G>A SNP. Our results suggest that although the 1068 G>A polymorphism of the P2RX7 gene is associated with an increased ß-cell function and IL-1Ra release in T2D patients, the glycemic control is not significantly affected by the presence of this SNP.