Insulin restores gestational diabetes mellitus-reduced adenosine transport involving differential expression of insulin receptor isoforms in human umbilical vein endothelium

Westermeier, Francisco, Salomon, Carlos, Gonzalez, Marcelo, Puebla, Carlos, Guzman-Gutierrez, Enrique, Cifuentes, Fredi, Leiva, Andrea, Casanello, Paola and Sobrevia, Luis (2011) Insulin restores gestational diabetes mellitus-reduced adenosine transport involving differential expression of insulin receptor isoforms in human umbilical vein endothelium. Diabetes, 60 6: 1677-1687. doi:10.2337/db11-0155


Author Westermeier, Francisco
Salomon, Carlos
Gonzalez, Marcelo
Puebla, Carlos
Guzman-Gutierrez, Enrique
Cifuentes, Fredi
Leiva, Andrea
Casanello, Paola
Sobrevia, Luis
Title Insulin restores gestational diabetes mellitus-reduced adenosine transport involving differential expression of insulin receptor isoforms in human umbilical vein endothelium
Journal name Diabetes   Check publisher's open access policy
ISSN 0012-1797
1939-327X
Publication date 2011
Sub-type Article (original research)
DOI 10.2337/db11-0155
Open Access Status
Volume 60
Issue 6
Start page 1677
End page 1687
Total pages 11
Place of publication Alexandria, VA, United States
Publisher American Diabetes Association
Language eng
Formatted abstract
Objective: To determine whether insulin reverses gestational diabetes mellitus (GDM)-reduced expression and activity of human equilibrative nucleoside transporters 1 (hENT1) in human umbilical vein endothelium cells (HUVECs).

Research Design and Methods: Primary cultured HUVECs from full-term normal (n = 44) and diet-treated GDM (n = 44) pregnancies were used. Insulin effect was assayed on hENT1 expression (protein, mRNA, SLC29A1 promoter activity) and activity (initial rates of adenosine transport) as well as endothelial nitric oxide (NO) synthase activity (serine1177 phosphorylation, L-citrulline formation). Adenosine concentration in culture medium and umbilical vein blood (high-performance liquid chromatography) as well as insulin receptor A and B expression (quantitative PCR) were determined. Reactivity of umbilical vein rings to adenosine and insulin was assayed by wire myography. Experiments were in the absence or presence of L-NG-nitro-L-arginine methyl ester (L-NAME; NO synthase inhibitor) or ZM-241385 (an A2A-adenosine receptor antagonist).

Results: Umbilical vein blood adenosine concentration was higher, and the adenosine- and insulin-induced NO/endothelium-dependent umbilical vein relaxation was lower in GDM. Cells from GDM exhibited increased insulin receptor A isoform expression in addition to the reported NO-dependent inhibition of hENT1-adenosine transport and SLC29A1 reporter repression, and increased extracellular concentration of adenosine and NO synthase activity. Insulin reversed all these parameters to values in normal pregnancies, an effect blocked by ZM-241385 and L-NAME.

Conclusions: GDM and normal pregnancy HUVEC phenotypes are differentially responsive to insulin, a phenomenon where insulin acts as protecting factor for endothelial dysfunction characteristic of this syndrome. Abnormal adenosine plasma levels, and potentially A 2A-adenosine receptors and insulin receptor A, will play crucial roles in this phenomenon in GDM.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collection: UQ Centre for Clinical Research Publications
 
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