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Effects of high caloric diet on insulin secretion and the activity of NAD(P)H oxidase in pancreatic islets from gp91 phox Knockout mice

Grant number: 13/12702-0
Support type:Regular Research Grants
Duration: December 01, 2013 - November 30, 2015
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Principal researcher:Angelo Rafael Carpinelli
Grantee:Angelo Rafael Carpinelli
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Assoc. researchers:Patrícia Riva Patrício

Abstract

Pancreatic islets are mostly composed of insulin secreting cells (B cells) whose function is modulated by the plasma concentration of nutrients including glucose, which recognized as the major insulin secretagogue. Metabolic disorders, obesity and insulin resistance are characterized by an imbalance in glucose homeostasis and the deficiency in the secretion and / or action of this hormone. Such disorders may be caused by the intake of high-calorie foods that induce high serum concentration of fatty acids (FA), which leads to lipid accumulation in the tissues and thus insulin resistance, hyperinsulinemia, hyperglycemia and B cell damage due to the accumulation of fatty acids metabolites. In parallel, the increase in plasma glucose concentration causes disturbances that have been attributed to channeling of this substrate towards alternative metabolic pathways associated with excessive formation of advanced glycation end products (AGEs) and reactive oxygen species (ROS). Increased circulating AGEs are associated with complications of diabetes mellitus (DM) and even with the onset of the disease. The excessive formation of ROS results in oxidative stress, which is also associated to the loss of function of pancreatic B cells. A source of cellular ROS production is the activation of the enzyme nicotinamide adenine dinucleotide phosphate oxidase (NAD(P)H oxidase) which is expressed in pancreatic B cells. Thus, the imbalance of glucose homeostasis is correlated with the increased production of ROS and AGEs. So far, little is known about the mechanisms involved in the deleterious effects of AGEs on the functionality of pancreatic islets and the possible activation of the enzyme NAD(P)H oxidase by these agents to increase ROS production, as it is known to occur in other tissues. The aim of this study is to induce in wild and gp91 (active site of NAD(P)H oxidase) knockout mice the glycemic imbalance by treating the animals with high-fat diets plus sucrose. In this model, where the production of AGEs is increased, we intend to evaluate the production of ROS and the expression and activity of NAD(P)H oxidase in pancreatic B cells and the possible modulation of this activity by AGEs. (AU)

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