TY - JOUR
T1 - Mechanisms of disease
T2 - Ectonucleotide pyrophosphatase phosphodiesterase 1 as a 'gatekeeper' of insulin receptors
AU - Abate, Nicola
AU - Chandalia, Manisha
AU - Di Paola, Rosa
AU - Foster, Daniel W.
AU - Grundy, Scott M.
AU - Trischitta, Vincenzo
PY - 2006/12/27
Y1 - 2006/12/27
N2 - Insulin resistance is pathogenic for type 2 diabetes and cardiovascular disease. Several inhibitors of insulin signaling have a role in human insulin resistance. The transmembrane glycoprotein ectonucleotide pyrophosphatase phosphodiesterase 1 (E-NPP1; also known as plasma cell membrane glycoprotein PC-1) interacts with the insulin receptor and inhibits subsequent signaling by decreasing its Β-subunit autophosphorylation. E-NPP1 is overexpressed in skeletal muscle, adipose tissue and cultured skin fibroblasts of insulin-resistant individuals who are not yet obese or diabetic, which indicates that excessive E-NPP1 expression is an early, intrinsic defect in human insulin resistance. Genetic studies also support a primary role of E-NPP1 in insulin resistance. Among other variants, a missense polymorphism, Lys121Gln, has been described.The Gln121 variant is a stronger inhibitor than Lys121 of insulin receptor function, and is associated with insulin resistance, type 2 diabetes and both cardiovascular and nephrovascular complications in diabetic patients. E-NPP1 is measurable in human serum, where it might represent a valuable biomarker of insulin resistance, but its relationship to tissue and systemic insulin resistance remains to be thoroughly elucidated. Understanding the mechanisms that regulate E-NPP1 expression and/or function might render this protein a new target for strategies to treat and prevent type 2 diabetes and cardiovascular disease.
AB - Insulin resistance is pathogenic for type 2 diabetes and cardiovascular disease. Several inhibitors of insulin signaling have a role in human insulin resistance. The transmembrane glycoprotein ectonucleotide pyrophosphatase phosphodiesterase 1 (E-NPP1; also known as plasma cell membrane glycoprotein PC-1) interacts with the insulin receptor and inhibits subsequent signaling by decreasing its Β-subunit autophosphorylation. E-NPP1 is overexpressed in skeletal muscle, adipose tissue and cultured skin fibroblasts of insulin-resistant individuals who are not yet obese or diabetic, which indicates that excessive E-NPP1 expression is an early, intrinsic defect in human insulin resistance. Genetic studies also support a primary role of E-NPP1 in insulin resistance. Among other variants, a missense polymorphism, Lys121Gln, has been described.The Gln121 variant is a stronger inhibitor than Lys121 of insulin receptor function, and is associated with insulin resistance, type 2 diabetes and both cardiovascular and nephrovascular complications in diabetic patients. E-NPP1 is measurable in human serum, where it might represent a valuable biomarker of insulin resistance, but its relationship to tissue and systemic insulin resistance remains to be thoroughly elucidated. Understanding the mechanisms that regulate E-NPP1 expression and/or function might render this protein a new target for strategies to treat and prevent type 2 diabetes and cardiovascular disease.
KW - E-NPP1
KW - Genetics
KW - Insulin receptor
KW - Insulin resistance
KW - PC-1
UR - http://www.scopus.com/inward/record.url?scp=33845397703&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33845397703&partnerID=8YFLogxK
U2 - 10.1038/ncpendmet0367
DO - 10.1038/ncpendmet0367
M3 - Review article
C2 - 17143316
AN - SCOPUS:33845397703
VL - 2
SP - 694
EP - 701
JO - Nature Reviews Endocrinology
JF - Nature Reviews Endocrinology
SN - 1759-5029
IS - 12
ER -