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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
Diabetes (New York, N.Y.), 2009-10, Vol.58 (10), p.2238-2245
GOGG, Silvia
SMITH, Ulf
JANSSON, Per-Anders
2009
Volltextzugriff (PDF)
Details
Autor(en) / Beteiligte
GOGG, Silvia
SMITH, Ulf
JANSSON, Per-Anders
Titel
Increased MAPK Activation and Impaired Insulin Signaling in Subcutaneous Microvascular Endothelial Cells in Type 2 Diabetes: The Role of Endothelin-1
Ist Teil von
Diabetes (New York, N.Y.), 2009-10, Vol.58 (10), p.2238-2245
Ort / Verlag
Alexandria, VA: American Diabetes Association
Erscheinungsjahr
2009
Quelle
MEDLINE
Beschreibungen/Notizen
Increased MAPK Activation and Impaired Insulin Signaling in Subcutaneous Microvascular Endothelial Cells in Type 2 Diabetes: The Role of Endothelin-1 Silvia Gogg , Ulf Smith and Per-Anders Jansson From the Lundberg Laboratory for Diabetes Research, Center of Excellence for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. Corresponding author: Silvia Gogg, silvia.gogg{at}medic.gu.se . Abstract 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. Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received July 17, 2008. Accepted June 15, 2009. © 2009 by the American Diabetes Association.
Sprache
Englisch
Identifikatoren
ISSN: 0012-1797, 1939-327X
eISSN: 1939-327X
DOI: 10.2337/db08-0961
Titel-ID: cdi_highwire_diabetes_diabetes_58_10_2238
Format
–
Schlagworte
Adipose Tissue - enzymology
,
Adipose Tissue - metabolism
,
Adipose Tissue - pathology
,
Adipose Tissue/enzymology/metabolism/pathology
,
Biological and medical sciences
,
Biopsy
,
Biopsy, Needle
,
Body fat
,
Cell growth
,
Diabetes
,
Diabetes Mellitus
,
Diabetes Mellitus, Type 2 - enzymology
,
Diabetes Mellitus, Type 2 - genetics
,
Diabetes Mellitus, Type 2 - pathology
,
Diabetes Mellitus, Type 2 - physiopathology
,
Diabetes. Impaired glucose tolerance
,
Endocrine pancreas. Apud cells (diseases)
,
Endocrinopathies
,
Endothelin
,
Endothelin-1 - physiology
,
Endothelium
,
Endothelium, Vascular - metabolism
,
Endothelium, Vascular - pathology
,
Enzyme Activation
,
Epithelial cells
,
Etiopathogenesis. Screening. Investigations. Target tissue resistance
,
Fibroblasts
,
Gene Expression Regulation
,
Genetic aspects
,
Humans
,
Insulin - physiology
,
Insulin Receptor Substrate Proteins - genetics
,
Insulin resistance
,
Insulin/genetics
,
Kinases
,
MEDICAL AND HEALTH SCIENCES
,
Medical sciences
,
MEDICIN OCH HÄLSOVETENSKAP
,
Microcirculation
,
Mitogen-Activated Protein Kinase Kinases - metabolism
,
Needle
,
Original
,
Phosphorylation
,
Phosphoserine - metabolism
,
Physiological aspects
,
Protein expression
,
Protein kinases
,
Proteins
,
Proto-Oncogene Proteins c-akt - metabolism
,
Receptor
,
Receptor, Insulin - genetics
,
Reference Values
,
Research design
,
Type 2 diabetes
,
Type 2/enzymology/genetics/pathology/physiopathology
,
Vascular/metabolism/pathology
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