Abstract 2080 Heavy Metals, Heavy Breathing: The Effects of Cadmium Chloride on Protein Kinase Signaling in Lung Epithelial Cells

The development of type 2 diabetes (T2D) is largely dependent on the maintenance of pancreatic islet function and mass.Sexual dimorphism in T2D is evident in many areas, such as pathophysiology, treatment, and prevention.Mitogen-activated protein kinase phosphatase-2 (MKP-2) have a distinct role in the regulation of cell proliferation and development of metabolic disorders.However, whether there is causal relationship between MKP-2 and diabetes onset is unclear.The aim of this study is to determine the role of MKP-2 in the development of hyperglycemia and diabetes and the impact on pancreatic islet mass.The role of MKP-2 in the regulation of glucose metabolism and pancreatic islet function was investigated in vivo using MKP-2 global knockout mice.Here, we show that female mice with whole-body deletion of MKP-2 exhibit hyperglycemia in multiple low dose of streptozotocin (STZ) mouse models.In comparison, both male MKP-2 wild type and knockout mice were hyperglycemic.Consistent with the hyperglycemia, female MKP-2 deficient mice exhibited reduced islet size.Under T2D conditions, MKP-2 deficient mice display enhanced pancreatic JNK and ERK phosphorylation that is associated with downregulation of genes important for pancreatic islet development and function, Pdx-1 and MafA.Furthermore, we found impaired metabolic flux in adipose tissue that is consistent with hyperglycemia and dysfunctional pancreas.MKP-2 deletion results in reduced Akt activation that is associated with increased adiposity and insulin resistance in female MKP-2 KO mice.These studies demonstrate a critical role of MKP-2 in development of T2D diabetes in vivo.This suggests that MKP-2 may have a genderspecific role in diabetes development.This discovery raises the possibility that postmenopausal prevention of T2D may benefit from activation of MKP-2 activity in islet cells.