Reversal of diabetes-induced rat graft transplant coronary artery disease by metformin.
BACKGROUND
Induction of diabetes in rat heterotopic heart transplantation models leads to an accelerated form of severe transplant coronary artery disease (TxCAD). We undertook this study to determine whether treatment of diabetes with metformin would favorably affect TxCAD.


METHODS
Heterotopic abdominal heart transplantation was performed in rat isograft and allograft models. After transplantation, diabetes was induced with streptozotocin. Fifty percent of the animals received metformin at 500 mg/kg twice daily. We quantitatively assessed TxCAD using histologic sections of harvested hearts at 30 and 60 days with computer-assisted morphometry. We compared vessels in the first tertile of the area distribution with vessels in the last tertile.


RESULTS
Fasting glucose levels in metformin-treated animals were 161 +/- 45 mg/dl compared with 400 +/- 120 mg/dl (p < 0.05) in untreated rats. Treatment with metformin led to decreased diabetes-induced TxCAD in the larger vessels. This effect was sustained during the study course in the isografts but not in the allografts. Treatment with metformin did not prevent progression of TxCAD in the smaller vessels at 60 days.


CONCLUSIONS
Metformin reduced luminal occlusion and severe TxCAD in the larger vessels but did not alter the course of TxCAD in the smaller vessels. These results may have therapeutic implications for patients.
Cantin
Bernard
B
Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California 94305-5406, USA.
Zhu
Dening
D
Wen
Peizhong
P
Panchal
Shyam N
SN
Dai
Xiaohong
X
Gwathmey
Judith K
JK
Reaven
Gerald M
GM
Valantine
Hannah A
HA
D000617:Aminoglycosides; D000818:Animals; D000900:Anti-Bacterial Agents; D003327:Coronary Disease / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D004195:Disease Models, Animal; D016027:Heart Transplantation; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008687:Metformin / Q000627:therapeutic use*; D051381:Rats; D013997:Time Factors
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D007004:Hypoglycemic Agents; D008687:Metformin