Effect of Repetitive Glucose Spike and Hypoglycaemia on Atherosclerosis and Death Rate in Apo E-Deficient Mice.

Kenichi Nakajima,Hirotaka Watada,Yusuke Osonoi,Yoshio Fujitani,Kosuke Azuma,Tomoya Mita,Toshiyuki Takasu

doi:10.1155/2015/406394

Abstract

Epidemiological data suggest that postprandial hyperglycaemia and hypoglycaemia are potential risk factors for cardiovascular disease. However, the effects of repetitive postprandial glucose spikes, repetitive hypoglycaemia, and their combination on the progression of atherosclerosis remain largely unknown. The present study investigated the effects of rapid rises and falls in glucose, and their combination, on the progression of atherosclerosis in apolipoprotein (apo) E-deficient mice. In this study, apo E-deficient mice with forced oral administration of glucose twice daily for 15 weeks were used as a model of repetitive postprandial glucose spikes, and apo E-deficient mice given an intraperitoneal injection of insulin once a week for 15 weeks were used as a model of repetitive hypoglycaemia. In addition, we established a model of both repetitive postprandial glucose spikes and hypoglycaemia by combining the above interventions. Atherosclerosis was evaluated in all mice by oil red O staining. Administration of ipragliflozin, a selective inhibitor of sodium-glucose cotransporter 2, in the mouse model of repetitive glucose spikes inhibited the progression of atherosclerosis, whereas long-term repetitive glucose spikes, repetitive hypoglycaemia, and their combination had no significant impact on atherosclerosis. However, repetitive hypoglycaemia was associated with poor survival rate. The results showed that repetitive hypoglycaemia reduces the survival rate without associated progression of atherosclerosis in apo E-deficient mice.

Highlights

Patients with type 2 diabetes mellitus (T2DM) are at high risk of developing cardiovascular disease (CVD), which is the most frequent cause of death in these patients
While hyperglycaemia is presumed to play a significant role in the progression of atherosclerosis, several epidemiological studies have suggested that postprandial hyperglycaemia per se is an independent risk factor for developing CVD [1, 2]
We demonstrated previously that temporary hyperglycaemia induces monocyte adhesion to endothelial cells in the aorta of rats [3] and that repetitive glucose spikes enhance atherosclerotic lesions in apolipoprotein E-deficient mice [4]

Summary

Introduction

Patients with type 2 diabetes mellitus (T2DM) are at high risk of developing cardiovascular disease (CVD), which is the most frequent cause of death in these patients. While hyperglycaemia is presumed to play a significant role in the progression of atherosclerosis, several epidemiological studies have suggested that postprandial hyperglycaemia per se is an independent risk factor for developing CVD [1, 2]. In this regard, we demonstrated previously that temporary hyperglycaemia induces monocyte adhesion to endothelial cells in the aorta of rats [3] and that repetitive glucose spikes enhance atherosclerotic lesions in apolipoprotein (apo) E-deficient mice [4]. T2DM patients with glucose spikes had high oxidative stress level and endothelial dysfunction [6].

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Results

Conclusion