Role of Protein Tyrosine Phosphatase 1B in Hepatocyte-Specific Insulin and Growth Factor Signaling

Abstract

Insulin resistance in major insulin target tissues such as liver, adipose tissues, and skeletal muscle is a key pathogenic feature of type 2 diabetes mellitus (T2DM). Among them, the liver plays a major role in controlling blood glucose homeostasis through the balance between glucose utilization and storage (Int J Biochem Cell Biol 36:753–758, 2004; Diabetologia 44:983–991, 2001). The molecular mechanism underlying hepatic insulin resistance is not completely understood; however, it is believed to involve impairment of the insulin receptor (IR) signaling network. A number of epidemiologic and clinical studies have shown a close association between nonalcoholic fatty liver disease (NAFLD) and chronic hepatitis C virus (HCV) infection and insulin resistance (N Engl J Med 346:1221–1231, 2002; Diabetologia 48:634–642, 2005; J Hepatol 44:253–261, 2006; N Engl J Med 345:41–52, 2001). Therefore, one of the challenges facing researchers in the field is the selection of therapeutic targets against hepatic insulin resistance among components of the insulin signaling cascade. In this chapter, we will focus on the regulation of hepatic insulin signaling by protein tyrosine phosphatase 1B (PTP1B) since many studies during the last decade have revealed that PTP1B is a critical node of the insulin signaling cascade and, therefore, its inhibition is of promise for alleviating insulin resistance and T2DM. On the other hand, since receptor tyrosine kinase (RTK)-mediated signaling is also negatively modulated by PTP1B, particularly in the liver, we will also review the impact of the inhibition of PTP1B in the context of cell proliferation and survival.