The role of membrane glycoprotein plasma cell antigen 1 ectonucleotide pyrophosphatase phosphodiesterase 1 in the pathogenesis of insulin resistance and related abnormalities

Insulin resistance is a major feature of most patients with type 2 diabetes mellitus (T2D). A number of laboratories have observed that membrane glycoprotein plasma cell antigen 1 (PC-1) [ ectonucleotide pyrophosphatase phosphodiesterase 1] is either overexpressed or overactive in muscle, adipose tissue, fibroblasts, and other tissues of insulin-resistant individuals, both nondiabetic and diabetic. Moreover, in cultured cells in vitro and in transgenic mice in vivo, PC-1 overexpression impairs insulin stimulation of insulin receptor (IR) activation and downstream signaling. PC-1 binds to the connecting domain of the IR alpha-subunit that is located in residues 485-599. The connecting domain transmits insulin binding the alpha- subunit to activation of tyrosine kinase activation in the beta- subunit. When PC-1 is overexpressed, it inhibits insulin-induced IR beta- subunit tyrosine kinase activity. In addition, a polymorphism of PC-1 ( K121Q) in various ethnic populations is closely associated with insulin resistance, T2D, and cardio-and nephrovascular diseases. The product of this polymorphism has a 2- to 3-fold increased binding affinity for the IR and is more potent than the wild-type PC-1 protein ( K121K) in inhibiting the IR. These data suggest therefore that PC-1 is a candidate protein that may play a role in human insulin resistance and T2D by its overexpression, its overactivity, or both.