Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 694-701 |
| Number of pages | 8 |
| Journal | Nature Clinical Practice Endocrinology and Metabolism |
| Volume | 2 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 27 2006 |
| Externally published | Yes |
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Keywords
- E-NPP1
- Genetics
- Insulin receptor
- Insulin resistance
- PC-1
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism
- Endocrinology
Cite this
Mechanisms of disease : Ectonucleotide pyrophosphatase phosphodiesterase 1 as a 'gatekeeper' of insulin receptors. / Abate, Nicola; Chandalia, Manisha; Di Paola, Rosa; Foster, Daniel W.; Grundy, Scott M.; Trischitta, Vincenzo.
In: Nature Clinical Practice Endocrinology and Metabolism, Vol. 2, No. 12, 27.12.2006, p. 694-701.Research output: Contribution to journal › Article
}
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 - Article
VL - 2
SP - 694
EP - 701
JO - Nature Reviews Endocrinology
JF - Nature Reviews Endocrinology
SN - 1759-5029
IS - 12
ER -