Effective glycaemic control critically determines insulin cardioprotection against ischaemia/reperfusion injury in anaesthetized dogs.
OBJECTIVE
Experimental evidence has shown significant cardioprotective effects of insulin, whereas clinical trials produced mixed results without valid explanations. This study was designed to examine the effect of hyperglycaemia on insulin cardioprotective action in a preclinical large animal model of myocardial ischaemia/reperfusion (MI/R).


RESULTS
Anaesthetized dogs were subjected to MI/R (30 min/4 h) and randomized to normal plasma insulin/euglycaemia (NI/NG), normal-insulin/hyperglycaemia (NI/HG), high-insulin/euglycaemia (HI/NG), and high-insulin/hyperglycaemia (HI/HG) achieved by controlled glucose/insulin infusion. Endogenous insulin production was abolished by peripancreatic vessel ligation. Compared with the control animals (NI/NG), hyperglycaemia (NI/HG) significantly aggravated MI/R injury. Insulin elevation at clamped euglycaemia (HI/NG) protected against MI/R injury as evidenced by reduced infarct size, decreased necrosis and apoptosis, and alleviated inflammatory and oxidative stress (leucocyte infiltration, myeloperoxidase, and malondialdehyde levels). However, these cardioprotective effects of insulin were markedly blunted in hyperglycaemic animals (HI/HG). In vitro mechanistic study in neonatal rat cardiomyocytes revealed that insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and Akt was significantly attenuated by high glucose, accompanied by markedly increased IRS-1 O-GlcNAc glycosylation following hypoxia/reoxygenation. Inhibition of hexosamine biosynthesis with 6-diazo-5-oxonorleucine abrogated high glucose-induced O-GlcNAc modification and inactivation of IRS-1/Akt as well as cell injury.


CONCLUSIONS
Our results, derived from a canine model of MI/R, demonstrate that hyperglycaemia blunts insulin protection against MI/R injury via hyperglycaemia-induced glycosylation and subsequent inactivation of insulin-signalling proteins. Our findings suggest that prevention of hyperglycaemia is critical for achieving maximal insulin cardioprotection for the ischaemic/reperfused hearts.
Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Qiujun
Q
Yu
Department of Cardiology, Hospital of Shaanxi Provincial Corps of Chinese People's Armed Police Forces, Xi'an, China.
Ning
N
Zhou
Department of Physiology, Fourth Military Medical University, Xi'an, China.
Ying
Y
Nan
Department of Geriatrics, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
Lihua
L
Zhang
Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Yan
Y
Li
Department of Clinical Laboratory Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Xiaoke
X
Hao
Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Lize
L
Xiong
Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
Wayne Bond
WB
Lau
Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
Xin L
XL
Ma
Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China fgao@fmmu.edu.cn wanghc@fmmu.edu.cn.
Haichang
H
Wang
Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China Department of Physiology, Fourth Military Medical University, Xi'an, China fgao@fmmu.edu.cn wanghc@fmmu.edu.cn.
Feng
F
Gao
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D004195:Disease Models, Animal; D004285:Dogs; D006943:Hyperglycemia / Q000188:drug therapy* / Q000378:metabolism; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D017202:Myocardial Ischemia / Q000378:metabolism / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D017207:Rats, Sprague-Dawley
D001786:Blood Glucose; D007328:Insulin; D051057:Proto-Oncogene Proteins c-akt
Cardioprotection; Dog; Hyperglycaemia; Insulin; Myocardial ischaemia/reperfusion