The aim of the present study was to investigate the role of GV (glycaemic variability) in diabetic vascular complications and to explore the molecular pathways modulated by glycaemic ‘swings’. We developed a murine model. A total of 30 diabetic mice received once daily basal insulin administration plus two oral boluses of glucose solution (GV group, named ‘V’) and 30 diabetic mice received once daily basal insulin plus two oral boluses of saline solution (stable hyperglycaemia group, named ‘S’) for a period of 30 days. Glycaemia was measured eight times daily to detect GV. Finally, postischaemic vascularization, induced by hindlimb ischaemia 30 days after diabetes onset, was evaluated. We found that GV was significantly different between S and V groups, whereas no significant difference in the mean glycaemic values was detected. Laser Doppler perfusion imaging and histological analyses revealed that the ischaemia-induced angiogenesis was significantly impaired in V mice compared with S group, after ischaemic injury. In addition, immunostaining and Western blot analyses revealed that impaired angiogenic response in V mice occurred in association with reduced VEGF (vascular endothelial growth factor) production and decreased eNOS (endothelial nitric oxide synthase) and Akt (also called protein kinase B) phosphorylation. In conclusion, we describe a murine model of GV. GV causes an impairment of ischaemia-induced angiogenesis in diabetes, likely to be independent of changes in average blood glucose levels, and this impaired collateral vessel formation is associated with an alteration of the VEGF pathway.
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Research Article|
August 22 2011
Glycaemic variability affects ischaemia-induced angiogenesis in diabetic mice
Federico Biscetti;
Federico Biscetti
1
*Laboratory of Vascular Biology and Genetics, Department of Medicine, A. Gemelli University Hospital, Catholic University School of Medicine, Rome, Italy
Correspondence: Dr Federico Biscetti (email [email protected]).
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Dario Pitocco;
Dario Pitocco
1
*Laboratory of Vascular Biology and Genetics, Department of Medicine, A. Gemelli University Hospital, Catholic University School of Medicine, Rome, Italy
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Giuseppe Straface;
Giuseppe Straface
†Vascular Medicine and Atherothrombosis Laboratory, Department of Experimental Medicine, Sapienza University of Rome, Polo Pontino, Italy
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Francesco Zaccardi;
Francesco Zaccardi
*Laboratory of Vascular Biology and Genetics, Department of Medicine, A. Gemelli University Hospital, Catholic University School of Medicine, Rome, Italy
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Raimondo de Cristofaro;
Raimondo de Cristofaro
‡Department of Internal Medicine, Haemostasis Research Center, Catholic University School of Medicine, Rome, Italy
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Paola Rizzo;
Paola Rizzo
*Laboratory of Vascular Biology and Genetics, Department of Medicine, A. Gemelli University Hospital, Catholic University School of Medicine, Rome, Italy
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Stefano Lancellotti;
Stefano Lancellotti
‡Department of Internal Medicine, Haemostasis Research Center, Catholic University School of Medicine, Rome, Italy
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Vincenzo Arena;
Vincenzo Arena
§Department of Pathology, Catholic University School of Medicine, Rome, Italy
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Egidio Stigliano;
Egidio Stigliano
§Department of Pathology, Catholic University School of Medicine, Rome, Italy
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Tittania Musella;
Tittania Musella
*Laboratory of Vascular Biology and Genetics, Department of Medicine, A. Gemelli University Hospital, Catholic University School of Medicine, Rome, Italy
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Giovanni Ghirlanda;
Giovanni Ghirlanda
*Laboratory of Vascular Biology and Genetics, Department of Medicine, A. Gemelli University Hospital, Catholic University School of Medicine, Rome, Italy
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Andrea Flex
Andrea Flex
*Laboratory of Vascular Biology and Genetics, Department of Medicine, A. Gemelli University Hospital, Catholic University School of Medicine, Rome, Italy
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Publisher: Portland Press Ltd
Received:
February 01 2011
Revision Received:
July 01 2011
Accepted:
July 05 2011
Accepted Manuscript online:
July 05 2011
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2011 Biochemical Society
2011
Clin Sci (Lond) (2011) 121 (12): 555–564.
Article history
Received:
February 01 2011
Revision Received:
July 01 2011
Accepted:
July 05 2011
Accepted Manuscript online:
July 05 2011
Citation
Federico Biscetti, Dario Pitocco, Giuseppe Straface, Francesco Zaccardi, Raimondo de Cristofaro, Paola Rizzo, Stefano Lancellotti, Vincenzo Arena, Egidio Stigliano, Tittania Musella, Giovanni Ghirlanda, Andrea Flex; Glycaemic variability affects ischaemia-induced angiogenesis in diabetic mice. Clin Sci (Lond) 1 December 2011; 121 (12): 555–564. doi: https://doi.org/10.1042/CS20110043
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