Senior Research Associate
My major interest is in a field of diabetes. For the last ten years we are working on the problem of the role of major antioxidant enzymes in glucose homeostasis. Glucose homeostasis, which is critical to an organism`s viability, is under tight insulin control. Malfunction of this system leads to metabolic disease - diabetes. The islets of Langerhans, the main structures involved in the regulation of insulin homeostasis, have been shown to be very vulnerable to oxidative stress. Therefore, oxidative stress might influence insulin homeostasis, and antioxidants, as well as antioxidant enzymes, might be implicated in the regulation of insulin metabolism. Therefore it is very important to evaluate the role of antioxidant enzymes in pancreatic insulin homeostasis.
My research focuses on the interrelationships between insulin resistance, diabetes development and the role of antioxidant systems in these processes. We investigated the implication of an antioxidant enzyme, Se-dependent cellular glutathione peroxidase 1 (GPX1) in the development of insulin resistance and obesity in a GPX1 overexpressing (OE) mouse model. Pancreatic beta cells are considered low in antioxidant capacity and susceptible to oxidative stress. Consequently, oxidative injury of beta cells has become a new etiological focus of diabetes and insulin resistance. Indeed, insulin metabolism in insulin producing or secreting cells is impaired by elevated intracellular reactive oxygen species (ROS), and the impairments are partially alleviated by overexpressing antioxidant enzymes. However, overexpressing antioxidant proteins in animals, either specifically in pancreatic beta cells or ubiquitously in various tissues, has produced highly variable or even negative phenotypes. Most striking, we have observed a spontaneous development of hyperglycemia, hyperinsulinemia, insulin resistance, and obesity in mice that overexpress GPX1, a major intracellular antioxidant
While the physiological relevance of our paradoxical finding was shown by a strong
correlation between erythrocyte GPX1 activity increases and insulin resistance in gestational
diabetic women, our initial study did not sort out the metabolic sequence of the phenotype in OE
mice. It remained unclear whether hyperinsulinemia and insulin resistance in the OE mice were caused by or largely confounded by obesity. Because obesity may be eliminated or controlled by diet restriction it is logical to examine whether obesity in the OE mice can be prevented by restricted feeding, and whether their impaired insulin metabolism is independent of obesity.
Subsequently, we conducted a series of experiments to test: 1) whether hyperinsulinemia in the OE mice was attributed to elevated beta cell mass, insulin synthesis, mitochondrial potential, and glucose stimulated insulin secretion (GSIS) in islets; 2) whether the OE islet phenotype was related to PDX1 and UCP2 expression; and 3) whether the deregulation of PDX1 and UCP2 by GPX1 overexpression was mediated by ROS scavenging, acetylation of H3 and H4 histone in the PDX1 promoter, and alterations of JNK, AKT, and PTP-1B. Our data indicate that hyperinsulinemia in the OE mice was associated with an upregulated PDX1 and a down regulated UCP2 in islets, and hyperacetylation of H3 and H4 histone in the PDX1 promoter in response to GPX1 overexpression was a novel regulatory mechanism for this key transcriptional factor in vivo.
A second large project I am involved in explores the role of GPX1 and superoxide dismutase 1 (SOD1) in glucose and insulin metabolism using GPX1 knockout, SOD1 knockout, and double knockout mouse models. Here, to specifically address questions about the unique role
of antioxidant enzymes in pancreas, we are planning to generate pancreas specific GPX1 and
SOD1 knockout mouse models.
Animals in Biomedical Research (AS 3980)
From Food to Medicine (AS 1160)