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October 14, 2014
8:00 AM - 10:00 AM
Room Hall B1-Area C
Acute Hyperglycemia Diminishes Cardioprotective Effects of High Dose Insulin in the Ischemic Rat Heart
Yosuke Nakadate, M.D., Hiroaki Sato, M.D., Takeshi Oguchi, M.D., Tamaki Sato, M.D., Kazuha Mitsui, M.D., Takashi Matsukawa, M.D.
University of Yamanashi, Yamanashi, Japan

It is reported that not only diabetes but also the acute hyperglycemia abolishes ischemic preconditioning effects (1, 2). On the other hand, our previous study demonstrated that high dose insulin has cardiac preconditioning effects and this advantage is related to the activation of phosphatidylinositol 3-kinase/Akt signaling pathway (3). However, the effect of hyperglycemia on the insulin induced preconditioning is still unclear. We hypothesized that hyperglycemia diminishes preconditioning effects of high dose insulin in the ischemic rat heart.


With Animal Investigation Committee approval, thirty hearts were excised from rats (weighing 300g) under sodium pentobarbital anesthesia. The hearts were perfused with a Langendorff system at constant pressure. A thin latex balloon was inserted into the left ventricle through the mitral valve for continuous monitoring of left ventricular (LV) pressure. After stabilization (baseline), the hearts were randomly assigned to one of three groups as follows (each group: n=10). Three groups were perfused with different solution for 20 minutes before onset of 15 minutes no-flow ischemia; 1) the insulin and normal glucose group (InsG100): received Krebs-Henseleit (KH) buffer containing 0.5U/L insulin and 100 mg/dl glucose, 2) the insulin and high glucose group (InsG600): received KH solution containing 0.5 U/L insulin and 600 mg/dl glucose, 3) the high glucose group (G600): received KH buffer with 600 mg/dl glucose. To rule out the effects of osmotic pressure, 27.5mmol/L of mannitol was added to KH solution in the InsG100 group. Afterwards, no-flow ischemia was induced for 15 minutes, followed by reperfusion for 20 min in each group. Only during ischemic period, the heart was paced at 222 beats⁄min. Measurements of heart rate, coronary flow and maximum of left ventricular derivative of pressure development (dP/dt max) were recorded. Myocardial p-Akt contents at the end of reperfusion were assayed by ELISA technique. Statistical analysis was performed using an analysis of variance, followed by the Bonferroni post-hoc test. Two-sided P values less than 0.05 were considered statistically significant.


After reperfusion, LV dP/dt max in the InsG600 group was significantly reduced, compared with the InsG100 group (Fig. 1). The myocardial p-Akt level in the InsG600 group was significantly lower than in the InsG100 group. The p-Akt level in the InsG600 group was significantly higher than in the G600 group (Fig 2).


Acute hyperglycemia diminishes cardioprotective effects of insulin in the ischemic rat heart. Acute hyperglycemia decreases p-Akt and p-Akt suppression is probably leading to contractile myocardial dysfunction.

1. Am J Physiol Heart Circ Physiol. 2000 Apr;278(4):H1218-24.

2. Am J Physiol. 1998; 275: 721-5.

3. Anesthesiology 2012 Annual Meeting, A1254

Figure 1
Figure 2

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