Download Effects of Type II diabetes on coronary vasodilation.

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
1. Aims & Hypothesis
2. Introduction
– Epidemiology of diabetes,
– Effects of hyperglycemia
– Coronary heart disease & pathological mechanisms
3. Materials & Methods
4. Results
5. Discussion & Conclusion
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
• 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%
<3%
>8%
6-8%
3-5%
High prevalence of
type II diabetes high
–associated with
increased obesity
<3%
Suboptimal
provision of health
care for diabetics
3-5%
(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)10471053
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 people
Diabetes 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
• 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
• Affects physiology
–
–
–
–
Hyperglycemia
Dehydration
Hypokalemia
Ketoacidosis
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
• 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
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
Normal
Function of
the heart
The Downward Spiral.
Myocardial
Infarction
Tissue
Recovery
Poor
Perfusion
Myocardial
Ischemia
Green = Vasodilation
Red = No Vasodilation
Reperfusion
Tissue
Necrosis &
Tissue
Damage
Cardiac
Dysfunction
Death
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
The Zucker Rat
Materials & Methods
Langendorf reperfusion apparatus...
•
•
•
•
•
Heart Rates
Coronary pressure
LVDP
Rate of ventricular systole
Rate of ventricular diastole
Results
* P < 0.05 vs Control
† P < 0.05 vs Glucose treated
Results
* P < 0.05 vs Control
† P < 0.05 vs Glucose treated
Results
Results
* P < 0.05 vs Control
† P < 0.05 vs Glucose treated
Results
*
* P < 0.05 vs Control
Results
* P < 0.05 vs Control
Results
* P < 0.05 vs Control
Results
* P < 0.05 vs Control
Results
[Nitroprusside]
* P < 0.05 vs Control
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
•
•
•
•
•
•
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.
Roselyn Rose’Meyer
Lynette Burges & Katie Crane