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Role of PC-1 in the etiology of insulin resistance
I D Goldfine1, B A Maddux, J F Youngren
1Department of Medicine, Mount Zion Medical Center, University of California San Francisco 94143-1616, USA. idg@itsa.ucsf.edu
Abstract:
Defects in insulin receptor tyrosine kinase activity have been demonstrated in tissues from insulin resistant subjects, but mutations in the insulin receptor gene are rare. Therefore, other molecules that are capable of modulating the insulin receptor most likely play a major role in insulin resistance. In cultured fibroblasts from an insulin resistant patient with Type 2 diabetes, we first identified membrane glycoprotein PC-1 as an inhibitor of the insulin receptor tyrosine kinase activity. PC-1 is overexpressed in fibroblasts from other insulin resistant subjects, both with and without Type 2 diabetes. PC-1 is a large class II exoprotein whose function is unknown. Studies in muscle and fat of insulin resistant subjects two primary tissues for insulin activation, reveal that elevated levels of PC-1 are inversely correlated with decreased insulin action both in vivo and in vitro. Transfection and expression of PC-1 in cultured cells demonstrate that overexpression of PC-1 produces impairments in insulin receptor tyrosine kinase activity, and the subsequent cellular responses to insulin. These studies indicate, therefore, that PC-1 is a major factor in the etiology of insulin resistance, and is a potential new therapeutic target for anti-diabetic therapy.
Insights
Membrane glycoprotein PC-1 inhibits insulin receptor activity, contributing to insulin resistance. Elevated PC-1 levels are linked to reduced insulin action, suggesting PC-1 as a therapeutic target for diabetes.
Area of Science:
- Biochemistry
- Molecular Biology
- Endocrinology
Background:
- Insulin resistance is linked to impaired insulin receptor tyrosine kinase activity, but gene mutations are rare.
- Other molecules modulating insulin receptor function likely play a significant role in insulin resistance.
- The function of membrane glycoprotein PC-1, a class II exoprotein, was previously unknown.
Purpose of the Study:
- To identify molecules involved in insulin resistance.
- To investigate the role of membrane glycoprotein PC-1 in insulin receptor function and insulin resistance.
Main Methods:
- Cultured fibroblasts from insulin-resistant patients were used to identify PC-1.
- PC-1 expression levels were analyzed in fibroblasts, muscle, and fat tissues.
- PC-1 was transfected and expressed in cultured cells to assess its impact on insulin receptor activity and cellular responses.
Main Results:
- Membrane glycoprotein PC-1 was identified as an inhibitor of insulin receptor tyrosine kinase activity.
- PC-1 is overexpressed in insulin-resistant subjects and inversely correlated with insulin action in vivo and in vitro.
- Overexpression of PC-1 in cultured cells impaired insulin receptor tyrosine kinase activity and insulin signaling.
Conclusions:
- PC-1 is a significant factor in the etiology of insulin resistance.
- PC-1 represents a potential therapeutic target for anti-diabetic therapies.