Effects of Type II diabetes on coronary vasodilation.

1. Effects of Type II diabetes on coronary vasodilation. • By Matthew CozierResearch Project 3003MSC • Supervisor: Roselyn Rose'Meyer • Lab partners; Lynette Burges & Katie Crane

2. Overview • Aims & Hypothesis • Introduction • Epidemiology of diabetes, • Effects of hyperglycemia • Coronary heart disease & pathological mechanisms • Materials & Methods • Results • Discussion & Conclusion

3. Hypothesis Type II diabetes affects the mechanism of ischemia induced vasodilation, and potentiates the risk of coronary heart disease. (Cozier et al., 2008)

4. Aims • To measure • Coronary vasodilatory mechanisms • Fasting blood glucose levels, • Blood pressure, • Heart and body weight, • Coronary flow rate • Potassium levels in adipose and skeletal muscle tissues.Between groups consisting of male Wistar rats with or without 3 weeks dietary intervention of 5% glucose, and age-matched Zucker obsese rats

5. Introduction • Diabetes Melitus (DM) is a 'metabolic syndrome'. • DM associated with the onset & progression of coronary heart disease (CHD)† • Accounts for 10% of the global expenditure of health care.* † Hanley AJ, Williams K, Stern MP, Haffner SM (2002): Homeostasis model assessment of insulin resistance in relation to the incidence of cardiovascular disease: the San Antonio Heart Study. Diabetes Care 25: 1177–1184, 2002. * Diabetes Atlas. Gan D, Ed. Brussels, Belgium, International Diabetes Federation, 2003

6. 3-5% 6-8% 6-8% 3-5% High prevalence of type II diabetes high –associated with increased obesity 3-5% Suboptimal provision of health care for diabetics Worldwide mortality of diabetes <3% >8% <3% (Wild et al., 2000) Wild SH., Roglic G., Green a., Sicree R., King H., Global Prevalence of Diabetes. Estimates for the year 2000 and projections for 2030. Diabetes Care 27;(5)1047-1053

7. Diabetes Epidemiology & Projections • Worldwide by 2010; 218.3 Million people 97% will have Type II Diabetes. 2 out of 3 patients with type II diabetes will suffer from cardiovascular disease... 141.9 Million peopleDiabetes is the greatest risk factor for CHD* * de Courten M, Zimmet P (1997) Screening for non-insulin-dependent diabetes mellitus: where to draw the line. Diabet Med 14: 95±98 Danaei G., Lawes C.M., Vander Hoorn S., et al., Global and regional mortality from ischaemic heart disease and stroke attribute to higher-than-optimum blood glucose concentration: Comparative risk assessment. Lancet. 2006; 368:1651-1659.

8. Type II Diabetes • Resistance to insulin and hyperglycemia. • Attributed to obesity, poor diet and lack of exercise. • Progresses from a state of ’pre-diabetes.’ • Pre-diabetes; Similar symptoms exist – yet glucose levels considered sub-acute • Signs & Symptoms; • increased thirst, • increased hunger, • fatigue, • increased urination, especially at night, • weight loss, blurred vision, • sores that do not heal.

9. The pathobiology of diabetes Type II • Affects physiology • Hyperglycemia • Dehydration • Hypokalemia • Ketoacidosis

10. The pathobiology of diabetes Type II • Affects cell biology • Cell metabolism → produciton of O2 radicals • Cell signalling - intracellular signalling cascades. • Cell function (tissue specific)‏ • -->> Vasodilatory mechanisms << --Cardiovascular complications.

11. Mechanisms of ischemia induced Vasodilation • 2 main Pathways • NO induced • Nitric oxide is derived from many tissues end product of arginine catabolism, catalysed by NOS. Mechanism of Action. NO → NO receptor → cGMP → PKG → Relaxation of Smooth muscle. Nitroprusside - NO receptor Agonists;

12. Mechanisms of ischemia induced Vasodilation • Adenosine Mediated • Adenosine is the end product of ATP dephosphorylation Adenosine → A2 Adenosine Receptors → cAMP → PKA → K-ATP channel activation → Hyperpolarisation of the cell membrane → vasodilation. A link between metabolic state of the heart and function of the cardiac vasculature. NECA; Adenosine Analogue Diazoxide; K-ATP channel opener

13. The Downward Spiral. Normal Function of the heart Tissue Recovery Myocardial Infarction Poor Perfusion Reperfusion Bad Myocardial Ischemia Tissue Necrosis & Tissue Damage Death Green = Vasodilation Red = No Vasodilation Cardiac Dysfunction Much Badness

14. Materials & Methods • Animal Models; • 12 Male Wistar Rats • 6 Control • 6 rats Glucose treated - fed upon a diet consisting of 5% • 6 Male Zucker obese Rats

15. The Zucker Rat

16. Materials & Methods Langendorf reperfusion apparatus... • Heart Rates • Coronary pressure • LVDP • Rate of ventricular systole • Rate of ventricular diastole

17. Here Come the Results...

18. Results * P < 0.05 vs Control † P < 0.05 vs Glucose treated

19. Results * P < 0.05 vs Control † P < 0.05 vs Glucose treated

20. Results

21. Results * P < 0.05 vs Control † P < 0.05 vs Glucose treated

22. Results * * P < 0.05 vs Control

23. Results * P < 0.05 vs Control

24. Results * P < 0.05 vs Control

25. Results * P < 0.05 vs Control

26. Results [Nitroprusside] * P < 0.05 vs Control

27. Conclusions • Both glucose treated and Zucker obese rats are pre-diabetic. • Insulin resistance observed • Hyperglycemia • Exhibited some degree of resistance to the diazoxide, NECA and nitroprusside. • Type II diabetes attenuates the coronary vasodilatory response to myocardial ischemia. • May explain the reduced recovery rates in those suffering from both diabetes and cardiovascular heart disease. All aims have been achieved; experiment successful.

28. Future Directions • Determine how diabetes affects the actions of endogenous and exogenous vasodilatory compounds • Determine the diabetic rat hearts sensitivity to numerous vasoconstrictors, and new drugs that have not yet been considered such as glibenclamide. • Identify how the body handles potassium in type II diabetes and determine how this may impact upon vasodilation. • Use the Zucker lean rats may as a more suitable candidate for further experimentation in order to reduce genetic variability between populations and yield more precise data. • Take advantage of novel methods of observing the ‘energetics’ of the heart in order to observe the effects of diabetes at a metabolic level. • Investigate protein modification and levels of expression in myocytes, vascular endothelium and many other cell types isolated from rats with II diabetes.

29. Thankyou Roselyn Rose’Meyer Lynette Burges & Katie Crane