Effects of type ii diabetes on coronary vasodilation
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Effects of Type II diabetes on coronary vasodilation. By Matthew Cozier Research Project 3003MSC Supervisor: Roselyn Rose'Meyer Lab partners; Lynette Burges & Katie Crane. Overview. Aims & Hypothesis Introduction Epidemiology of diabetes, Effects of hyperglycemia

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Effects of type ii diabetes on coronary vasodilation
Effects of Type II diabetes on coronary vasodilation.

  • By Matthew CozierResearch Project 3003MSC

  • Supervisor: Roselyn Rose'Meyer

  • Lab partners; Lynette Burges & Katie Crane


Overview
Overview

  • Aims & Hypothesis

  • Introduction

    • Epidemiology of diabetes,

    • Effects of hyperglycemia

    • Coronary heart disease & pathological mechanisms

  • Materials & Methods

  • Results

  • Discussion & Conclusion


Hypothesis
Hypothesis

Type II diabetes affects the mechanism of ischemia induced vasodilation, and potentiates the risk of coronary heart disease.

(Cozier et al., 2008)


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


Introduction
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


Worldwide mortality of diabetes

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


Diabetes epidemiology projections
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.


Type ii diabetes
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.


The pathobiology of diabetes type ii
The pathobiology of diabetes Type II

  • Affects physiology

    • Hyperglycemia

    • Dehydration

    • Hypokalemia

    • Ketoacidosis


The pathobiology of diabetes type ii1
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.


Mechanisms of ischemia induced vasodilation
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;


Mechanisms of ischemia induced vasodilation1
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


The downward spiral
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


Materials methods
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



Materials methods1
Materials & Methods

Langendorf reperfusion apparatus...

  • Heart Rates

  • Coronary pressure

  • LVDP

  • Rate of ventricular systole

  • Rate of ventricular diastole



Results
Results

* P < 0.05 vs Control

† P < 0.05 vs Glucose treated


Results1
Results

* P < 0.05 vs Control

† P < 0.05 vs Glucose treated



Results3
Results

* P < 0.05 vs Control

† P < 0.05 vs Glucose treated


Results4
Results

*

* P < 0.05 vs Control


Results5
Results

* P < 0.05 vs Control


Results6
Results

* P < 0.05 vs Control


Results7
Results

* P < 0.05 vs Control


Results8
Results

[Nitroprusside]

* P < 0.05 vs Control


Conclusions
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.


Future directions
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.


Thankyou

Roselyn Rose’Meyer

Lynette Burges & Katie Crane


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