Type 1 Diabetes Mellitus (T1D) is an incurable disease, progression and negative complications of which may be only delayed, but not completely cured. A group of beneficial compounds, called antioxidants, recently was shown to be implicated in possible protective role in diabetes. We will investigate the involvement of GPX1 in protection of the organism from environmental factors, capable of triggering the onset of T1D.

More than one million of Americans suffer from Type 1 Diabetes Mellitus (T1D) and its complications. The progress of T1D is characterized by pancreatic islet beta-cells destruction, loss of glycemic control and following metabolic deregulation of whole organism. A harmful role of reactive oxygen species (ROS) as a result of autoimmune/inflammatory response in T1D is well documented. In contrary, a possible primary influence of ROS on T1D development is not yet well studied. It was shown that selenium-dependent glutathione peroxidase (GPX1) is implicated in insulin metabolism, reinforcing the need to address the question of the role of GPX1 in etiology of T1D in comprehensive and systematic manner. The question of T1D development as a result of an outrageous ROS generation triggered by outer factors, its link with generation of autoimmune response and the role of GPX1 in this process will be addressed. Two mouse models will be used in these studies: GPX1 knockout (GPX1 KO) and GPX1 overexpressing (GPX1 OE). The following specific aims will be addressed: 1) whether acute and moderate alloxan (ALX) or streptozotocin (STZ)-induced T1D is associated with oxidative stress and its relation with autoimmune responses; 2) whether GPX1 is involved in reducing the incidence of experimentally induced T1D; 3) whether transcriptional control of T1D genes is mediated through chromatin histone acetylation and is it dependant on the level of oxidative stress in islet beta-cells.

We have prepared and submitted a manuscript about the mechanisms of GPX1 overexpression induced obesity: Diet restriction eliminated obesity and other phenotypes but not hyperinsulinemia in OE mice. These mice had greater pancreatic ß cell mass (> 2-fold) and pancreatic insulin content (40%) than the WT, along with an enhanced mitochondria membrane potential and glucose–stimulated insulin secretion in islets. With a diminished ROS production, the OE islets displayed hyperacetylation of H3 and H4 histone in the PDX1 promoter, elevated PDX1 mRNA and protein, and decreased UCP2 mRNA and protein. Hyperinsulinemia was a hallmark or a primary effect of GPX1 overexpression. This hallmark was attributed to a deregulated insulin synthesis and secretion associated with seemingly beneficial changes in functional expression of PDX1 and UCP2 in islets.

Type 2 diabetes mellitus has become a major threat to public health and is, therefore, a very active area of biomedical research. Insulin resistance and islet beta-cell dysfunction are major factors involved in the development of this devastating disease. Unveiling the role of one of the major antioxidant enzyme, GPX1, in glucose and insulin homeostasis is a significant contribution to the basic knowledge, which can be used to delay or alleviate consequences of chronic hyperglycemia.

Diabetes