Date of Award

3-2014

Document Type

Thesis

Degree Name

Master of Science in Medical Sciences (MSMS)

Department

Medical Education

First Advisor

Professor Chri Howarth

Second Advisor

Professor Ernest Adeghate

Third Advisor

Doctor Nicola King

Abstract

Diabetes Mellitus (DM) is currently the fastest growing disease in the world. The prevalence of DM has increased worldwide and is expected to double within 20 years. The UAE is ranked 15th worldwide, with 18.98% of the UAE population living with diabetes. Six Middle East North Africa (MENA) region countries – Bahrain, Egypt, Kuwait, Oman, Saudi Arabia, and United Arab Emirates (UAE) - are among the world’s 10 highest for prevalence of diabetes and impaired glucose tolerance. This represents a huge cost to society in terms of morbidity and mortality, and economically through lost productivity and cost burden on the healthcare system. In 2009 mortality linked to DM constituted 75% percent of the deaths among UAE nationals and 31% among non-nationals. The Goto-Kakizaki (GK) rat is one of the best characterized genetic animal models of T2DM. A variety of contractile dysfunctions, associated with alterations in intracellular Ca2+, have been demonstrated in GK rat heart. The consumption of sugar-sweetened beverages has been linked to the rising rates of obesity which in turn is a risk factor for development of T2DM.

In these experiments, GK and Control rats received either normal drinking water or drinking water containing sucrose (100-400Mm) for either 6 or 8 months. After 6 months of dietary intervention the amplitude of ventricular myocytes shortening and Ca2+ transient were not significantly altered in either GK or control rats. After 8 months, amplitude of shortening was decreased in Control/Sucrose and in GK/Sucrose rats compared to Control and GK rats respectively. Interestingly, the amplitude of the Ca2+ transient was increased in myocytes from Control/Sucrose and decreased in GK/Sucrose compared to Control and GK rats.

Expression of genes encoding a range of ventricular muscle proteins were also investigated in ventricular tissue after 8 months of dietary intervention. Genes encoding cardiac muscle proteins (Myh7, Mybpc3, My11, My13, My1pf), intercellular proteins (Gja4), cell membrane transport (Atp1b1), calcium channels (Cacna1c, Cacnc1g, Cacnb1), potassium channels (Kcnj11) were upregulated in GK compared to control rats. Genes encoding potassium channels (Kcnb1) were decreased in GK compared to Control rats. Genes encoding cardiac muscle proteins (Myh6, Mybpc3, Tnn2), intercellular proteins (Gja1, Gja4), intracellular Ca2+ transport (Atp2a1, Ryr2), cell membrane transport (Atp1a2, Atp1b1), potassium channel (Kcnj2, Kcnj8) proteins were upregulated in Control/Sucrose compared to control rats. Genes encoding cardiac muscle proteins (Myh7) were downregulated in Control/Sucrose compared to Control rats. Genes encoding cardiac muscle protein (Myh7), potassium channel (Kenj11) proteins were downregulated in GK/Sucrose compared to Control rats.

In conclusion, sucrose-enriched diets altered dietary habits in GK and control rats and exacerbated diabetic status in GK rats. Subtle changes in expression of genes encoding a variety of ventricular muscle proteins are associated with changes in ventricular myocyte shortening and intracellularCa2+ transport in ventricular myocytes from GK T2DM and Control rats fed a sucrose-enriched diet.

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