High-dose metformin (420mg/kg daily p.o.) increases insulin sensitivity but does not affect neointimal thickness in the rat carotid balloon injury model of restenosis.
Our laboratory has shown that insulin's effect to decrease neointimal thickness after arterial injury is greatly diminished in insulin resistant conditions. Thus, in these conditions, a better alternative to insulin could be to use an insulin sensitizing agent. Metformin, the most commonly prescribed insulin sensitizer, has a cardiovascular protective role. Therefore, the objective of this study was to investigate the potential benefit of metformin on neointimal area after arterial injury in a rat model of restenosis.



Rats fed with either normal or high fat diet and treated with or without oral metformin (420mg/kg daily) underwent carotid balloon injury. Effects of metformin on clamp-determined insulin sensitivity, vessel AMPK (AMP-activated protein kinase) phosphorylation (activation marker) and neointimal area were evaluated.



Metformin increased insulin sensitivity, but did not affect neointimal thickness in either the normal fat or high fat diet-fed rats. Furthermore, metformin activated AMPK in uninjured but not in injured vessels. Similarly, 10mmol/L metformin inhibited proliferation and activated AMPK in smooth muscle cells of uninjured but not injured vessels, whereas 2mmol/L metformin did not have any effect.



In rats, metformin does not decrease neointimal growth after arterial injury, despite increasing whole body insulin sensitivity.
Department of Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
June
J
Guo
Department of Pharmacology and Therapeutics, Children's Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada R3E 3P4.
Troy J
TJ
Pereira
Department of Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
Prasad
P
Dalvi
Department of Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
Lucy Shu Nga
LSN
Yeung
Department of Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
Nathan
N
Swain
Department of Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
Danna M
DM
Breen
Department of Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
Loretta
L
Lam
Department of Pharmacology and Therapeutics, Children's Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada R3E 3P4.
Vernon W
VW
Dolinsky
Department of Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8; Department of Medicine, University of Toronto, Toronto, Ontario, Canada M5S 1A8; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada M5S 1A8; Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada M5S 1A8. Electronic address: adria.giacca@utoronto.ca.
Adria
A
Giacca
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure; D020212:Carotid Artery Injuries / Q000188:drug therapy*; D059168:Carotid Intima-Media Thickness; D016893:Carotid Stenosis / Q000188:drug therapy*; D049109:Cell Proliferation / Q000187:drug effects; D059305:Diet, High-Fat / Q000009:adverse effects; D004106:Dilatation; D015309:Glucose Clamp Technique; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007333:Insulin Resistance; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D007004:Hypoglycemic Agents; D008687:Metformin; D055372:AMP-Activated Protein Kinases
AMPK; Angioplasty; Insulin resistance; Metformin; Neointima