Research Project
10219830
SUMMARY/ABSTRACT Beta cell failure, microvascular endothelial cell dysfunction, fibrosis, and calcification are clinically significant problems in type 2 diabetic (T2D) patients because they cause myocardial infarction, stroke, peripheral artery disease, retinopathy, nephropathy, cardiomyopathy, and wound healing delay. However, the detrimental mechanisms responsible for these pathologies in T2D are not completely understood. Current therapies for T2D neither halt nor reverse beta cell failure, endothelial cell dysfunction, nor the tissue complications. Therefore, there is a critical need for the identification of mechanism-based, treatable targets to improve beta cell and microvascular function, to reduce fibrosis and calcification, and to limit the abnormalities of multiple tissues and organs in T2D. Cytokine and adipokine secretion is increased in T2D, which affects beta cell and microvascular function and structure. Specifically, the level of the pro- inflammatory cytokine interleukin-12 (IL-12) is increased in adolescent and adult T2D patients. However, it is unknown whether the inhibition of IL-12 protects beta cell and microvascular function, thereby reducing fibrosis and calcification in multiple organs. Furthermore, the mechanism by which increased IL-12 might cause these pathologies is unknown. The premise is that IL-12 administration to non-obese mice leads to diabetes, liver toxicity and fibrosis, kidney damage, and atherosclerosis, supporting a detrimental role of IL- 12 in diabetes, and multiple tissues and organs damage. We hypothesize that increased IL-12 in T2D mice causes beta cell dysfunction, hyperglycemia, insulin resistance, microvascular endothelial cell dysfunction, fibrosis, and calcification through inflammation, endoplasmic reticulum (ER) stress, and autophagy mechanisms. To test the hypothesis, we proposed the following aims: Aim #1: IL-12 causes beta cell and endothelial cell dysfunction, fibrosis, and calcification in T2D. We will assess whether IL-12-induced pathology in T2D can be abrogated using genetic deletion of IL-12 or neutralizing IL- 12 antibody; Aim #2: IL-12 induces pancreatic islet inflammation in T2D. We will examine if genetic deletion of IL-12 or neutralizing IL-12 antibody in T2D mice attenuates the inflammation in pancreatic islets, and subsequently improves beta cell and endothelial cell function, and reduces fibrosis and calcification; Aim #3: IL-12 induced beta and endothelial cell dysfunction, fibrosis, and calcification are dictated by an ER stress mechanism in T2D. We will illustrate the mechanisms in beta cells and endothelial cells whereby IL-12 leads to beta cell and endothelial cell dysfunction, fibrosis and calcification in T2D; Aim #4: IL-12 induced beta cell and endothelial cell dysfunction, fibrosis, and calcification are driven by an autophagy mechanism in T2D. We will elucidate the mechanisms in beta cells and endothelial cells whereby IL-12 leads to beta cell and endothelial cell dysfunction, fibrosis, and calcification in T2D.
