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Increased MAPK activation and impaired insulin signaling in subcutaneous microvascular endothelial cells in type 2 diabetes: the role of endothelin-1

Gogg, Silvia, 1962 (author)
Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine
Smith, Ulf, 1943 (author)
Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine
Jansson, Per-Anders, 1961 (author)
Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine
 (creator_code:org_t)
2009
2009
English.
In: Diabetes. - 1939-327X. ; 58:10, s. 2238-45
  • Journal article (peer-reviewed)
Abstract Subject headings
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  • OBJECTIVE: To establish a method for isolation and culture of subcutaneous microvascular endothelial cells (MVEC) from small human tissue biopsies to compare gene and protein expression of insulin signaling molecules in MVEC from insulin-resistant and healthy control subjects. RESEARCH DESIGN AND METHODS: Stromavascular cells from subcutaneous needle biopsies of type 2 diabetic and control subjects were expanded in culture and the endothelial cells selected with magnetic immune separation. Western blots and RT-PCR were used for protein and gene expression assays. RESULTS: At least 99% of the expanded primary MVEC could be characterized as endothelial cells. The expression of insulin receptors was low, but insulin increased tyrosine phosphorylation of both the insulin receptor and insulin receptor substrate (IRS)-1 and activated protein kinase B (PKB). The IRS-1 protein expression was reduced and the serine phosphorylation of PKB in response to insulin attenuated whereas basal and insulin-stimulated phosphorylation of extracellular signal-related kinase (ERK)1/2 was increased in type 2 diabetes MVEC. Endothelin (ET)-1 mRNA levels were significantly higher in type 2 diabetes cells. The addition of ET-1 increased the phosphorylation of mitogen-activated protein kinase (MAPK), an effect antagonized by the MEK-1 inhibitor PD98059. Furthermore, the endothelin ET(A) and ET(B) receptor antagonists BQ123 and BQ788 decreased basal MAPK activity in type 2 diabetes MVEC and prevented the ET-1-induced activation. CONCLUSIONS: We developed a system for isolation and culture of human MVEC from small needle biopsies. Our observations support the concept of "selective" insulin resistance, involving IRS-1 and the PI3kinase pathway, as an underlying factor for a dysregulated microvascular endothelium in type 2 diabetes. Our data also support a role of ET-1 for the increased MAPK activity seen in nonstimulated type 2 diabetes MVEC.

Keyword

Adipose Tissue/enzymology/metabolism/pathology
Biopsy
Needle
Diabetes Mellitus
Type 2/enzymology/genetics/pathology/*physiopathology
Endothelin-1/*physiology
Endothelium
Vascular/metabolism/pathology
Enzyme Activation
Gene Expression Regulation
Humans
Insulin/*physiology
Insulin Receptor Substrate Proteins/genetics
Microcirculation
Mitogen-Activated Protein Kinase Kinases/*metabolism
Phosphoserine/metabolism
Proto-Oncogene Proteins c-akt/metabolism
Receptor
Insulin/genetics
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Gogg, Silvia, 19 ...
Smith, Ulf, 1943
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