Effect of physical exercise on modulation of peroxisome proliferator-activated receptor ³ (PPAR³) and insulin-degrading enzyme (IDE) in the pancreatic islet of mice

Abstract

PPAR³ agonists increase the insulin sensitivity and are used in the treatment of type 2 diabetes mellitus (T2DM). In pancreatic islets, PPAR³ controls insulin secretion, oxidative stress, SR stress and amyloid formation. It is known that the insulin-degrading enzyme (IDE) is the main responsible for the degradation of islet amyloid polypeptide (IAPP), reducing the amyloid formation. Based on the fact that PPAR³ increases the expression of IDE in neuronal tissues and hepatocytes, we thought that PPAR³ may control IDE expression, also in pancreatic ² cells, and this enzyme could mediate some of the beneficial effects of PPAR³ in these cells. In addition, physical exercises, recommended to T2DM patients, also modulate the expression of PPAR³ in various tissues. Thus, our second hypothesis is that physical exercise could also interfere in the expression of PPAR³ in pancreatic islets and, as a consequence, PPAR³ could control the expression of IDE in this animal model. To test our first hypothesis, isolated pancreatic islets from C57BL6 mice, as well as tumoral ² cells (INS1E), will be distributed in the following groups: control group (CTL) and a group treated with rosiglitazone, which is a PPAR³ agonist (RZG). After the treatment, the expression of IDE will be assessed. If the effect of PPAR³ upon the expression of IDE is confirmed, we will analyze if IDE modulates the effects of PPAR³ in the islets and ² cells line. For this, isolated islets and INS1E cells will be distributed into the following groups: CTL, RZG, and a group treated with rosiglitazone + ML345, an IDE inhibitor (RZG+ML). Insulin secretion, islet cells survival, IAPP degradation and amyloid formation will be measured. To test if exercise regulates the expression of PPAR³, mice will be distributed in control (CTL) and exercised groups (mice trained in a treadmill 5 days a week for 1 hour during two months) (TRE). After this period, the mice will be euthanized and their islets distributed in the following groups: control (CTL), exercised (TRE), and exercised treated with GW9662, a PPAR³ antagonist (TRE+GW). Insulin secretion, islet cell survival, IAPP degradation, amyloid formation, and the gene and protein expression (Real-time RT-PCR, and Western blot, respectively) of PPAR³ and IDE will be measured. (AU)