Type 2 diabetes and cardiovascular disease
Christopher D. Byrne FRCPath FRCP PhD
Professor of Endocrinology & Metabolism
Director of Wellcome Trust Clinical Research Facility
Southampton University Hospitals Trust
Impact of diabetes on the average annual age-adjusted incidence/1,000 cardiovascular events in men and
women aged 45-74 years from the Framingham study
Men Women
Diabetes Control Diabetes Control
Cardiovascular disease 39.1 19.1 27.2 10.2Cardiovascular mortality 17.4 8.5 17.0 3.6Coronary heart disease 24.8 14.9 17.8 6.9Congestive heart failure 7.6 3.5 11.4 2.2Claudication 12.6 3.3 8.4 1.3Stroke 4.7 1.9 6.2 1.7
Kannel WB, McGee DL, JAMA 1979; 241: 2035 - 2038.
CHD mortality in type 2 diabetes
No DM type 2 DM
MI no MI MI no MI
(n=69) (n=1304) (n=169) (n=890)
% events (p.a.)
fatal/non-fatal MI 3.0 0.5* 7.8# 3.2**
fatal/non-fatal stroke 1.2 0.3* 3.4# 1.6**
CV death 2.6 0.3* 7.3# 2.5**
*p<0.001 prior MI versus no prior MI no DM#p<0.001 prior MI versus no prior MI DM**p<0.001 DM versus no DM Haffner et al NEJM 1998 339: 229-234
STABLE ATHEROSCLEROTIC PLAQUE
fibrous cap(smooth muscle cells & matrix)
lipid core
adventitia
endothelial cellsintimal smooth muscle cells
(repair phenotype)
medial smooth muscle cells(contractile phenotype)
adventitia
lipid corelipid core
UNSTABLE CORONARY ARTERY DISEASE
Accumulation of modified lipid
Endothelial cell activation
Inflammatory cell migration
Inflammatory cell activation
Smooth muscle cell recruitment
Proliferation and matrix synthesis
Fibrous cap formation
Plaque rupture
Platelet aggregation
Thrombosis
Smooth musclecell apoptosis
Matrix degradation
PATHOGENESIS OF ATHEROSCLEROSIS
Growthfactors
Growthfactors
Insulinresistance
-celldysfunction
Type 2diabetes
Adapted from: Beck-Nielson H et al. J Clin Invest 1994;94:1714–1721 and Saltiel AR, Olefsky JM. Diabetes 1996;45:1661–1669
What is Type 2 diabetes?
A progressive metabolic disordercharacterised by:
Insulin resistance and insulinhypersecretion precede type 2 diabetes
Insulin Insulin Macrovascularsensitivity secretion disease
30% 50% 50%
50% 70–100% 40%
70% 150% 10%
100% 100%
Adapted from: Beck-Nielsen H, Groop LC. J Clin Invest 1994;94:1714–1721
IGT
Impaired glucose
metabolism
Normal glucose metabolism
Type 2 diabetes
Clinical indicators ofthe Insulin Resistance Syndrome
• + Insulin resistance
• + Type 2 diabetes or IGT
• + Dyslipidaemia ( TG, LDLc, HDLc)
• + Central obesity
• + Hypertension
• + Hyperinsulinaemia (initially)
• + Atherosclerosis
DeFronzo RA, Ferrannini E. Diabetes Care 1991;14(3):173–194
Glucose uptake in insulin-resistant subjects: impaired in patients with type 2 diabetes
Adapted from Baron AD. Am J Physiol 1994;267:E187–E202
Serum insulin (pmol/L)
Who
le-b
ody
gluc
ose
upta
ke(µ
mol
/m2 /
min
)3,000
1,500
1,000
500
0
2,000
2,500
10 100 1,000 10,000 100,000
Lean
Obese
Type 2 diabetes
Pancreatic -cell Insulin resistance
Liver
HYPERGLYCAEMIA
Islet -cell degranulationReduced insulin content
Muscle(PKC Adipose tissue
Decreased glucose transport& activity (expression) of GLUT-4
Increased lipolysis
Elevated plasma NEFA
+ -
Low plasmainsulin
Increased glucose output
ElevatedTNF
Insulin resistance and -cell dysfunctionproduce hyperglycaemia in type 2 diabetes
Modified from: Turner N, Clapham JC. Prog Drug Res 1998;51:34–94
Why is the prevalence of insulin resistance increasing?
Health Survey for England:Cardiovascular disease 1998
• 16 - 24 year age group
• ~50% overweight BMI > 25kg/m2
or obese BMI > 30kg/m2
• 17% men and 21% women are obese
NB: increased from 14% men and 17% women - 1994
Relative risk of death due to cardiovascular disease according to BMI among non-smoking women aged 30 to 55 years
0.0
1.0
2.0
3.0
4.0
5.0
Manson, J.E. et al. New England Journal of Medicine 1995; 333: 677-85.
Body mass index (kg/m2)
Rel
ativ
e ri
sk o
f de
ath
P<0.001
Relative risk of type 2 diabetes according to BMI in US women aged 30 to 55 years
0102030405060708090
100
Body mass index (kg/m2)
Age
-adj
uste
d re
lativ
e ris
k
Colditz GA et al. Annals of Internal Medicine 1995; 122: 481-86.
Why does obesity cause type 2 diabetes?
• high levels of free fatty acids found in obese or overweight patients, interfere with
glucose metabolism
Mechanisms of insulin resistance linking fatty acid and glucose metabolism
Increased adipocyte lipolysis (central obesity)
FFAs
acetyl CoA (cellular)
hepaticgluconeogenesis
NADH/NAD citrate
glycogen synthase
pyruvate dehydrogenase
plasmaglucose
glucose transport
hexokinase glucose 6-P
phosphofructokinase
glycogen content
Differences between visceral and subcutaneous fat
Visceral fat Subcutaneous fat
6-20% of total body fat 80% of total body fat
Greater number of smaller cells Smaller number of large cells with richer blood supply with poorer blood supply
Intra-abdominal with direct Extra-abdominal drainage to portal vein
Greater catecholamine-induced Reduced catecholamine-induced lipolysis lipolysis
Reduced insulin inhibition of Increased insulin inhibition of lipolysis lipolysis
How can the impact of diabetes and metabolic syndrome
to cause vascular disease be reduced?
TM
© 1999 Professional Postgraduate Services®
UKPDS: Intensive Blood-Glucose vs ConventionalTreatment in Patients With Type 2 Diabetes
RR=relative risk.PVD=peripheral vascular disease.
UKPDS Group. Lancet. 1998;352:837-853.
Any diabetes-related end point 0.88 (0.79–0.99) 0.029
Diabetes-related deaths 0.90 (0.73–1.11) 0.34
All-cause mortality 0.94 (0.80–1.10) 0.44
MI 0.84 (0.71–1.00) 0.052
Stroke 1.11 (0.81–1.51) 0.52
Amputation or death from PVD 0.65 (0.36–1.18) 0.15
Microvascular disease 0.75 (0.60–0.93) 0.0099
Favors Favors Log-rank RR (95% CI) intensive conventional P value
Clinical End Point0.1 1 10
TM
© 1999 Professional Postgraduate Services®
Any diabetes-related end point 0.76 (0.62–0.92) 0.0046
Diabetes-related deaths 0.68 (0.49–0.94) 0.019
All-cause mortality 0.82 (0.63–1.08) 0.17
MI 0.79 (0.59–1.07) 0.13
Stroke 0.56 (0.35–0.89) 0.013
Peripheral vascular disease 0.51 (0.19–1.37) 0.17
Microvascular disease 0.63 (0.44–0.89) 0.0092
UKPDS: Tight Blood Pressure Control vs LessTight Control in Patients With Type 2 Diabetes
RR=relative risk.
UKPDS Group. BMJ. 1998;317:703-713.
RR for Favors Favors tight control tight less tight P
(95% CI) control control value
Clinical End Point10.1 10
August 1999
How can insulin resistance be How can insulin resistance be reduced?reduced?
How can insulin resistance be How can insulin resistance be reduced?reduced?
LifestyleLifestyleWeight reduction - optimum BMI in Weight reduction - optimum BMI in Caucasians?Caucasians?Increasing levels of energy expenditureIncreasing levels of energy expenditure
MedicationMedicationMetformin & GlitazonesMetformin & Glitazones
LifestyleLifestyleWeight reduction - optimum BMI in Weight reduction - optimum BMI in Caucasians?Caucasians?Increasing levels of energy expenditureIncreasing levels of energy expenditure
MedicationMedicationMetformin & GlitazonesMetformin & Glitazones
Reduction in risk of various clinical endpoints with metformin (n=342) compared with a conventional policy
in overweight patients (BMI=31) with type 2 diabetes
Clinical endpoint Risk reduction p value
Any diabetes-related endpoint 32% 0.002
Diabetes-related deaths 42% 0.017
All-cause mortality 36% 0.011
Myocardial infarction 39% 0.010
Data taken from UK Prospective Diabetes Study (UKPDS) group. Lancet 1998; 352: 854-65.
How does activation of PPAR enhance insulin action and normalise blood glucose?
Glitazoneand insulin
PPAR
Pre-adipocyte
Adipocyte
Increaseddifferentiation
Reversal of TNF-inducedinsulin resistance
Increased insulin sensitivity and capacity for glucose
disposal/lipid storage
Reduced lipolysis and free fatty
acid availability
Skeletal muscle
Liver
Euglycaemia
Increasedglucose disposal
Reducedhepatic glucose output
PPAR
GLUT-4
TG & PKC
Treatment with glitazones
Diagnosis
Diet and Exercise
Sulphonylurea
HbA1c > 7%
Can’t use Metformin
Metformin
HbA1c > 7%
Obese
Add Glitazone
HbA1c > 7%
OverweightNormal weight
Combination therapy?
PPAR gamma andPPAR alpha agonists
Future challenges for type 2 diabetes management
Glucose control
Adverse experiences
ComplicationsDrug
interactions
-cell function
Insulin resistance
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