Speaker: Kwanghyun Sohn. Advisor: Bonnie B. Punske, PhD

Abstract:

The prevalent symptoms in diabetic patients - high blood sugar, high blood pressure, and

high lipid levels – increase the incidence of coronary atherosclerosis and ischemia, when

anaerobic glucose becomes the major source for ATP generation. Insulin enhances glucose

uptake by stimulation of GLUT4 translocation to the plasma membrane. Type 2 diabetic

patients may undergo more serious ATP deficiencies by atherosclerosis and accelerated

collapse of ionic homeostasis in myocytes. The aim of this study was to test the beneficial

effects of GLUT4 and insulin on the electrical activity during hypoxia.

Hearts were isolated from wild type mice and mice with a cardiac-selective GLUT4

deficiency (G4H-/-) and Langendorff perfused. Extracellular potentials were measured around

the hearts using a custom-made cylindrical 64-electrode cage during baseline, hypoxia and

reoxygenation, with 30 minutes duration each. The maximum downstroke velocity of the

extracellular potentials recorded each electrode was normalized to baseline and averaged over

the 64 electrodes (|dVes/dtmin|na) as a parameter to measure global electrical activity. We

performed additional experimental and computational studies to support the use of

|dVes/dtmin|na as an index of sodium current activity at the moment of activation.

The results showed that at the end of hypoxia, |dVes/dtmin|na decreased to 0.21 and 0.54 in

G4H-/- and wild type hearts, respectively (p<0.05). There were overall alterations in

propagation sequence in G4H-/- hearts, but not in wild type hearts. When G4H-/- hearts were

fasted for 20 hours to remove compensation effects such as higher rate of basal glucose uptake

and higher glycogen level in myocytes, three among four hearts did not beat during hypoxia.

Insulin significantly improved values of |dVes/dtmin|na in G4H-/- hearts during hypoxia when

supplied prior to hypoxia, but there was no insulin effect when supplied at the beginning of

hypoxia.

This study showed the critical role of GLUT4 in sustaining the proper electrical activity

during hypoxia. Results of this study implied that the protective role of insulin for G4H-/-

hearts resulted from increased glycogen levels before hypoxia rather than enhanced glucose

uptake during hypoxia, and suggested the possibility that both insulin resistance and frequent

incidence of arrhythmias in diabetics may be related to downregulated GLUT4 translocation.

This study also proved that |dVes/dtmin|na can be a useful index of sodium current activity at the

moment of activation.