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Insulin-like growth factor I receptors are more abundant than insulin receptors in human micro- and macrovascular endothelial cells
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
2004 (English)In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, Vol. 286, E896-E901 p.Article in journal (Refereed) Published
Abstract [en]

Micro- and macroangiopathy are major causes of morbidity and mortality in patients with diabetes. Our aim was to characterize IGF-I receptor (IGF-IR) and insulin receptor (IR) in human micro- and macrovascular endothelial cells. Cultured human dermal microvascular endothelial cells (HMVEC) and human aortic endothelial cells (HAEC) were used. Gene expression was measured by quantitative real-time RT-PCR and receptor protein by ligand-binding assay. Phosphorylation of IGF-IR ß-subunit was analyzed by immunoprecipitation and Western blot. Glucose metabolism and DNA synthesis was assessed using [3H]glucose and [3H]thymidine incorporation, respectively. We detected gene expression of IGF-IR and IR in HAEC and HMVEC. IGF-IR gene expression was severalfold higher than that of IR. The specific binding of 125I-IGF-I was higher than that of 125I-insulin in HAEC and HMVEC. Insulin and the new, long-acting insulin analog glargine interacted with the IGF-IR with thousand- and hundred-fold less potency than IGF-I itself. Phosphorylation of the IGF-IR ß-subunit was shown in HAEC for IGF-I (10-8 M) and insulin (10-6 M) and in HMVEC for IGF-I and glargine (10-8 M, 10-6 M). IGF-I 10-7 M stimulated incorporation of [3H]thymidine into DNA, and 10-9–10-7 M also the incorporation of [3H]glucose in HMVEC, whereas glargine and insulin had no significant effects at 10-9–10-7 M. Human micro- and macrovascular endothelial cells express more IGF-IR than IR. IGF-I and high concentrations of glargine and insulin  ctivates the IGF-IR. Glargine has a higher affinity than insulin for the IGF-IR but probably has no effect on DNA synthesis at concentrations reached in vivo.

Place, publisher, year, edition, pages
2004. Vol. 286, E896-E901 p.
Keyword [en]
Human endothelial cells, receptor, insulin, glargine
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-12552DOI: 10.1152/ajpendo.00327.2003OAI: oai:DiVA.org:liu-12552DiVA: diva2:1690
Available from: 2008-09-15 Created: 2008-09-15 Last updated: 2009-08-17
In thesis
1. Expression and function of IGF-I and insulin receptors in human micro- and macrovascular cells
Open this publication in new window or tab >>Expression and function of IGF-I and insulin receptors in human micro- and macrovascular cells
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Insulin-like growth factor and insulin are phylogenetically closely related polypeptides and have large structural and biological similarities. Low circulating insulin-like growth factor-I (IGF-I), diabetes as well as insulin resistance have been implicated in the pathogenesis of cardiovascular disease, but the mechanisms involved are still not clear. Furthermore, little is known about direct effects of insulin-like growth factor-I (IGF-I) and insulin on human micro- and macrovascular cells.

In these studies we investigated the expression and function of insulin-like growth factor-I receptors (IGF-IR) and insulin receptors (IR) in human micro- and macrovascular endothelial cells and in human coronary artery smooth muscle cells.

Our results showed expression of both IGF-IR and IR in human dermal microvascular (HMVEC), aortic (HAEC) umbilical vein (HUVEC) and coronary artery (HCAEC) endothelial cells as well as in human coronary artery smooth muscle cells (HASMC). The gene expression of IGF-IR was several times more abundant than that of IR. Ligand binding studies confirmed that the IGF-IR was severalfold more abundant than the IR. It also demonstrated that insulin and glargine interacted with the IGF-IR with thousand- and hundredfold, respectively, less potency than IGF-I itself. The presence of IGF-IR and IR proteins and activation of their β-subunits was revealed by immunoprecipitation and Western blot analysis in human macrovascular endothelial cells and in coronary artery smooth muscle cells. At physiological concentrations (≤10-9 M) IGF-I and insulin activated their cognate receptors. The presence of hybrid IR/IGF-IR was shown through detection of the β-subunit for IGF-IR and IR on the same membrane by Western blot after immunoprecipitation with specific antibodies against either IGF-IR or IR, implying coprecipitation of the IGF-IR β-subunit and the IR β-subunit. The inability of physiological concentrations of insulin to phosphorylate IR β-subunit immunoprecipitated with IGF-IR antibodies and that IGF-I at physiological concentration activates the IR β-subunit is another evidence for the presence of the hybrid IR/IGF-IR. At physiological concentrations (≤10-9 M) IGF-I stimulated DNA synthesis and glucose incorporation into human coronary artery smooth muscle cells (HCASMC) and DNA synthesis in microvascular endothelial cells (HMVEC), but not in human macrovascular endothelial cells (HCAEC or HUVEC). No effect of insulin was found. Although physiological concentrations of insulin (≤10-9 M) were able to activate IR, insulin had no biological effects on the vascular cells studied. A possible explanation is that the insulin receptor signalling is too attenuated due to the presence of hybrid IR/IGF-IR and low number of IR expressed in the cells studied. Regarding the safety in the use of glargine, we show that glargine has 10-fold higher affinity for IGF-IR than human insulin. However, the glargine concentrations obtained in vivo during diabetes treatment is too low to affect the IGF-IR.

In conclusions our studies provide experimental evidence that human micro- and macrovascular endothelial and vascular smooth muscle cells express both IGF-IR and IR. Our in vitro data suggest that the cells studied are sensitive to IGF-I, but insensitive to insulin and this is due to the preponderance of IGF-IR and presence of hybrid IR/IGF-IR.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2008. 89 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1045
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-12558 (URN)978-91-7393-972-0 (ISBN)
Public defence
2008-03-14, Berzeliussalen (hus 463, ingång 65), Hälsouniversitet, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2008-09-15 Created: 2008-09-15 Last updated: 2009-08-21Bibliographically approved

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Chisalita, Simona IoanaArnqvist, Hans J.

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Chisalita, Simona IoanaArnqvist, Hans J.
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Cell BiologyFaculty of Health SciencesDepartment of Acute Internal MedicineDepartment of Endocrinology and Gastroenterology UHL
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American Journal of Physiology. Endocrinology and Metabolism
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