Role of Peroxiredoxin-6 as New Insulin and GLP-1 secretagogue agent and Peroxiredoxins as Common Soil In Type 2 Diabetes, COPD and Asthma

The reduction in the functional pancreatic beta-cell mass is one of the significant causes leading to Type 1 and Type 2 Diabetes Mellitus (T1DM and T2DM). T2DM develops from a combination of insulin resistance and defect of glucose- stimulated insulin secretion (GSIS) in pancreatic beta cells. In addition, different noxae, such as hyperglycemia, hyperlipidemia, cytokines, smoke and pollution, affect beta cell functionality. This may influence different cellular processes increasing endoplasmic reticulum stress and mitochondrial dysfunction. Oxidative and endoplasmic-reticulum stress induce beta cell dysfunction, decreasing insulin processing, activating cell apoptosis and losing the identity by dedifferentiation of pancreatic beta cells. Oxidative stress may play a pivotal role in these processes, since pancreatic beta cells have reduced classical antioxidant enzymes such as superoxide dismutase, catalase and glutathione peroxidase. Additionally, the increased production of ROS (reactive oxidative species) and RNS (reactive nitrogen species) may stimulate other dangerous cell signal, like inflammasome, increasing interleukin-1beta (IL-1beta) levels, leading to a pro-inflammatory response. This can also coexist with an impaired lung function and reduced forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) with a higher susceptibility to chronic obstructive pulmonary disease (COPD) and asthma. Patients with COPD and asthma have higher prevalence of T2DM of 18.7% and 13.5, respectively vs. 10.5% in general population. Next, higher bronchial hyperresponsiveness can be a pathophysiological mechanism associated with increased prevalence of COPD and asthma in T2DM, which can be modulated by GLP (glucagon like peptide)-1. These pathophysiological mechanisms can lead to the decline in respiratory function with a higher association between T2DM and, COPD and asthma. Peroxiredoxins (Prdxs), a recent new class of antioxidant enzymes discovered about 30 years ago, have gained more attentions. This is a family of six proteins ubiquitously expressed (pancreas and lung), divided in three different subclasses: typical 2-Cys Prdx-1 to 4, atypical 2-cys Prxd-5 and 1-cys Prdx-6. Prdxs reduce hydroperoxides and peroxynitrite, Prdx1 to Prdx4 have a more efficient antioxidant action against H2O2, whereas Prdx-5 prefers alkyl hydroperoxides and ONOO- over H2O2, Prdx-6 prefers alkyl hydroperoxides. Prdxs can reduce more than 90% of cellular peroxide and peroxynitrite. Between Prdxs, Prdx-6 acts as glutathione peroxidase, with phospholipase A2 and lysophosphatidylcholine acyl transferase activities, for this reason Prdx-6 can have a main role in the pathophysiology T2DM and lung diseases. Then, we hypothesized that in- vivo, Prdx-6 may have a hypoglycemic action and Prdxs can be new class of biomarkers.We propose to:

1. Investigate the new role of Prdx-6 as insulin and GLP-1 secretagogue in animal model of DM. We have recently obtained an Italian patent for this specific Prdx6's action (Italian Patent concession number: 102020000005467, Title:`Perossiredossina 6 o un suo Analogo Sintetico per l'uso come Ipoglicemizzante), the patent rights belong to the University of Rome Tor Vergata;
2. Analyze Prdxs as biomarkers of DM and lung dysfunction phenotype, the severity of DM and/or lung disease compared to others classical biomarkers;
3. Examine if Prdxs are biomarkers of the response to therapy in T2DM, COPD and asthma.