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 PC-1 (membrane [corrected] glycoprotein plasma cell antigen 1; also termed [corrected] ectonucleotide pyrophosphatase phosphodiesterase 1 or ENPP1) [corrected] is either overexpressed or overactive in muscle, adipose tissue, fibroblasts, and other tissues of insulin-resistant individuals, both nondiabetic and diabetic. Moreover, PC-1 (ENPP1) overexpression [corrected] in cultured cells in vitro and in transgenic mice in vivo, [corrected] 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 in the alpha-subunit to activation of tyrosine kinase activation in the beta-subunit. When PC-1 is overexpressed, it inhibits insulin [corrected]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 [corrected] 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.
Goldfine
Ira D
ID
Department of Medicine and Diabetes Center, University of California San Francisco, San Francisco, California 94143, USA. ira.goldfine@ucsf.edu
Maddux
Betty A
BA
Youngren
Jack F
JF
Reaven
Gerald
G
Accili
Domenico
D
Trischitta
Vincenzo
V
Vigneri
Riccardo
R
Frittitta
Lucia
L
D000818:Animals; D048909:Diabetes Complications; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D014644:Genetic Variation; D006801:Humans; D007333:Insulin Resistance; D009765:Obesity / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D011085:Polycystic Ovary Syndrome; D011110:Polymorphism, Genetic; D020836:Protein Structure, Quaternary; D011755:Pyrophosphatases / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D011972:Receptor, Insulin / Q000502:physiology
D011972:Receptor, Insulin; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases