Date of Award

6-2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Medical Education

First Advisor

Chris Ho\<,arth

Second Advisor

Murat Oz

Third Advisor

Ernest Adeghate

Abstract

Type 2 diabetes mellitus accounts for more than 90% of cases of diabetes mellitus. Cardiovascular diseases are the major causes of morbidity and mortality in diabetic patients. A variety of diastolic and systolic dysfunction have been reported. The severity of the abnormality depends on the patients’ age and diabetes duration. The aim of the study was to investigate the age-dependent, exercise and pharmacological intervention on electromechanical function of the heart in the Goto-Kakizaki (GK) type 2 diabetic rat. mRNA expression was assessed in ventricular muscle with real-time RT-PCR. Ventricular myocytes shortening, intracellular Ca2+ transport and L-type Ca2+ current were measured with video edge detection, fluorescence photometry and whole cell patch clamp techniques, respectively. In vivo biotelemetry was used to measure the electrocardiogram. In young GK (8-10 weeks) rat, mRNA expression of Atpla3, Cacna1h, Scn1b and Hcn2 were upregulated and Slc9al, Hcn4, Kcna2/4 and Kcnj2 were downregulated. Amplitude of ventricular myocytes shortening and intracellular Ca2+ transient were unaltered, time to peak shortening was prolonged and time to half decay of the Ca2+ transient was shortened in GK myocytes. Physical exercise is well established as a valuable form of non-pharmacological therapy. Experiments were performed in GK and control (10-11 months) following 2-3 months of treadmill exercise training. Expression of mRNA encoding Tpm2, Gja4, Atp1b1, Cacna1g, Cacnb2, Hcn2, Kcna3 and Kcnel were upregulated and Gjal, Kcnj2 and Kcnk3 were downregulated in hearts of sedentary GK rats compared to sedentary controls. Gjal, Cav3 and Kcnk3 were upregulated and Hcbn2 was down-regulated in heart of exercise trained GK controls, Amplitude of ventricular myocytes shortening, Ca2+ transients and L-type Ca2+ current were not significantly altered.

The effects of the anti-diabetic drug Pioglitazone on ventricular myocytes shortening and Ca2+ transport in addition to electrocardiogram were also investigated. Pioglitazone (0.1-10) μM reduced the amplitude of shortening in ventricular myocytes from GK and control rats. Pioglitazone reduced the amplitude of the Ca2+ transient end modest reductions in L-type Ca2+ current in GK and control myocytes. Heart rate in GK rats reduced. Although Pioglitazone reduced blood glucose in GK rats it had little effect on heart electrocardiogram.

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