1. Vascular Biology of Diabetes
Abdel Moniem Ibrahim Ahmed, MD
Professor of Cardiovascular Physiology
Cairo University
Oct

2. Diabetes is a Cardiovascular disease.
The concept of Endothelial Dysfunction (ED).
Mechanisms of ED in diabetes:-
Initiation ( trigger ) phase of ED:
(Hyperglycemia - induced ED)
Transition from initiation to maintenance phase of ED:
(Formation of AGEs)
Maintenance phase of ED:
(Tightly linked to accumulation of AGEs)
Hyperinsulinemia / insulin resistance and ED .

3. Diabetes is a Cardiovascular disease.
The concept of Endothelial Dysfunction.
Mechanisms of ED in diabetes:-
Initiation ( trigger ) phase of ED:
(Hyperglycemia - induced ED)
Transition from initiation to maintenance phase of ED:
(Formation of AGEs)
Maintenance phase of ED:
(Tightly linked to accumulation of AGEs)
Hyperinsulinemia / insulin resistance and ED .

4. Cardiovascular Diseases
Diabetes Mellitus
Independent major risk factor
Accelerated atherosclerosis
morbidity & mortality
(80 %)
Cardiovascular Diseases

5. Acute Hyperglycemia Normal Volunteers Rapid BP elevation
Glucose levels trigger functional alterations in vasomotor motions
Marfella et al . Am J Physiol Endocrinol Metab , 268 : E

6. Diabetic Microangiopathy
At later stages
At early stage
Reversible changes :
Capillary press .
Blood flow .
EC permeability .
Irrevesible changes :
Thickening of the basement membrane
Extracellular accumulation of proteins
Arosio et al . Ann Ital Med Int ; 14 (2) : 106-

7. Arosio et al . Ann Ital Med Int . 1999 ; 14 (2) : 106
The onset of microvascular lesions in diabetes has been preceded by endothelial dysfunction manifestations:
* ( ) in the vasodilatation response to vasoactive agents .
* Alterations in the antithrombotic properties.
Arosio et al . Ann Ital Med Int ; 14 (2) : 106

8. Pomilio et al . I pediatr Endocrinol Metab .2002 ; 15(4): 343-
In diabetic patients E N D O T H L I U M
The primary target of unbalanced glycemic control.
Involved in the pathogenesis of vascular complications.
Pomilio et al . I pediatr Endocrinol Metab ; 15(4): 343-

9. Endothelial pathophysiologic balance
Vasodilators
Nitric oxide
Prostacyclin
Endothelium derived hyperpolarizing factor
C-natriuretic peptide
Antithrombotic
Tissue type plasminogen activator
Growth inhibitors
Inflammation inhibitors
Vasoconstrictors
Endothelin-1
Angiotensin II
Endoperoxide (PGH2)
Thromboxane A2
Prothrombotic
Plasminogen activator inhibitor-1
Growth promotors
Superoxide radicals
Endothelin
Angiotenisn II
Inflammation promotors
Superoxide and other free radicals
Tumor necrosis factor-alpha

10. The concept of Endothelial Dysfunction.
Diabetes is a Cardiovascular disease.
The concept of Endothelial Dysfunction.
Mechanisms of ED in diabetes:-
Initiation ( trigger ) phase of ED:
(Hyperglycemia - induced ED)
Transition from initiation to maintenance phase of ED:
(Formation of AGEs)
Maintenance phase of ED:
(Tightly linked to accumulation of AGEs)
Hyperinsulinemia / insulin resistance and ED .

11. IMPAIRED VASORELAXATION
Hyperglycemia Advanced Glycosylation End Products Oxidized Lipoproteins Insulin Resistance
INCREASED
PROTHROMBOTIC
ACTIVITY
Leukocyte
adhesion molecules &
chemoattractants
Cell surface
procoagulant
activity
Altered junctions
& transport
EDRF
PGI2
Expression of
growth factors &
mitogens
INCREASED
PERMEABILITY
& TRAPPING of LDL
IMPAIRED VASORELAXATION
(VASOSPASM)
INCREASED
LEUKOCYTE
RECRUITMENT
SMC MIGRATION,
PROLIFERATION &
ECM PRODUCTION

12. Goligorsky et al . Hypertension .2001, 37 [part2] : 744-748.
“ EC - dependent vasorelaxation ( flow - mediated dilatation )by using echo Doppler has remained the gold standard in assessing endothelial function & dysfunction .”
Goligorsky et al . Hypertension .2001, 37 [part2] :

13. Endothelial Nitric Oxide Production
GTP VSMc c GMP SM relaxation
(+) Guanylyl cyclase
TARGET CELLS
(SMC, EC, PLATELETS)
[NO/EDRF]
LSS
Growth Factors
Acetylcholine
(other mediators)
LSS
L-arg
[Ca+2, IP3]
ecNOS
ecNOS
L-arginine
citrulline
ACUTE
CHRONIC

14. Mechanisms of ED in diabetes:-
Diabetes is a Cardiovascular disease.
The concept of Endothelial Dysfunction.
Mechanisms of ED in diabetes:-
Initiation ( trigger ) phase of ED:
(Hyperglycemia - induced ED)
Transition from initiation to maintenance phase of ED:
(Formation of AGEs)
Maintenance phase of ED:
(Tightly linked to accumulation of AGEs)
Hyperinsulinemia / insulin resistance and ED .

15. Goligorsky et al . Hypertension .2001; 37 [part2] : 744
Proposal consequence ( transient & cumulative) of hyperglycmic episodes on vascular wall .
Goligorsky et al . Hypertension .2001; 37 [part2] : 744

16. “ The ED initiation events is linked to scavenging of NO by glucose ( NO bioavailability ) during transient episodes of hyperglycemia ”

17. Acute Hypertensive response
(-) Vasorelaxation 15 min. after hyperglycemia
NO Bioavailability
(+) Platelet reactions prothrmbotic activity
(+) (MN) leukocyte chemotaxis & activation
(+) Express . of leukocyte - CAMs
(+) VSMC migration & proliferation
Acceleration of Atherosclerosis
Brodsky et al . Am J Physiol Renal Physiol ; 280: F 480-

18. NO scavenging
(Chronic)

19. Mechanisms of ED in diabetes:-
Diabetes is a Cardiovascular disease.
The concept of Endothelial Dysfunction.
Mechanisms of ED in diabetes:-
Initiation ( trigger ) phase of ED:
(Hyperglycemia - induced ED)
Transition from initiation to maintenance phase of ED:
(Formation of AGEs)
Maintenance phase of ED:
(Tightly linked to accumulation of AGEs)
Hyperinsulinemia / insulin resistance and ED .

20. ROS + NO Acute Hyperglycemia NO Bioavailability In healthy subjects
(+)
Mitochondrial superoxide (O2.-) production
ROS + NO
Peroxynitrites
(ineffective)
Plasma nitrotyrosine (marker of oxid . Stress )
NO Bioavailability
Marfella et al . JCI , 108 (4) : 635

21. Hyperglycemia in Diabetes
Tissue
deposition
Hyperglycemia in Diabetes
Aging
Ambient glucose
Non-enzymatic reaction
Primary amino acid groups on protein
Maillard
reaction
Amadoric products
Dehydration
Fragmentation
AGEs in the Sub-EC Compartment
Friedman . Nephrol Dial Transport ; 14 [Suppl 3] : 1-9

22. AGEs ROS NO Bioavailability Bind with their receptors RAGE
(EC, VSMC, Macrophages)
Quench NO activity
ROS
NO Bioavailability
Tan et al . Diabetic Care ; 25 (6): 1055

23. AGE - RAGE interaction is a potential source for cell-mediated oxidation & lipid peroxidation

24. Oxidative-modification hypothesis
Diaz et al. NEJM ,337(6) : 408

25. Hyperglycemia NO Bioavailability Protein kinase C (PKC) activation
Glucose – induced O2.-
Mitochondrial O2.-over
Diacylglycerol (DAG)
Protein kinase C (PKC) activation
(-) PI3 kinase- mediated eNOS(+)
(+) NAD(P) H oxidase
ROS
NO Bioavailability
Beckman et al . Circ Res ; 90 : 107-

26. Mechanisms of ED in diabetes:-
Diabetes is a Cardiovascular disease.
The concept of Endothelial Dysfunction.
Mechanisms of ED in diabetes:-
Initiation ( trigger ) phase of ED:
(Hyperglycemia - induced ED)
Transition from initiation to maintenance phase of ED:
(Formation of AGEs)
Maintenance phase of ED:
(Tightly linked to accumulation of AGEs)
Hyperinsulinemia / insulin resistance and ED .

27. AGEs Consume EC-derived NO Functional NO deficiency Deficiency of
Quench NO Activity
Functional NO deficiency
Deficiency of
Angiogenic response
(+) fibroblast proliferation
Extracellular matrix & physico-chemical changes
Collagen -to- collagen cross linking & tissue rigidity
Vascular Complications of Diabetes
Goligorsky et al . Hypertension ; 37 [part 2]

28. Proposed pathophysiological mechanisms acting during maintenance
phase of ED .

29. Tan et al . Diabetic care . 2002 ; 25(6) : 1055
(+)
(+)
Induction of TGF - b “chemotactic factor”
AGEs
NF- kB (+)
VSMC migration
( ) ET-1 prod.
Atherosclerosis
(+)
Hyperglycemia
Tan et al . Diabetic care ; 25(6) : 1055

30. Clinical manifestations of diabetic nephropathy and potenial role of ED

31. Hyperinsulinemia/insulin resistance and ED .
Diabetes is a Cardiovascular disease.
The concept of Endothelial Dysfunction.
Mechanisms of ED in diabetes:-
Initiation ( trigger ) phase of ED:
(Hyperglycemia - induced ED)
Transition from initiation to maintenance phase of ED:
(Formation of AGEs)
Maintenance phase of ED:
(Tightly linked to accumulation of AGEs)
Hyperinsulinemia/insulin resistance and ED .

32. Metabolic Syndrome Cluster of Metabolic & CV Abnormalities Endothelium
Insulin Resistance
Endothelium
Target of Insulin’s action on vasomotility
Common dominator

33. Insulin Protective effects Deleterious effects (-) apoptosis
(+) NO prod.
(+)VEGF .
(+) ET-1 .
Salt - sensitive HTN
* Vicent et al . TCI , III (9) : * Ogihara et al . Diabetes , 50 : 573-

34. Insulin Resistance (+) PKC in vascular tissues
(-) PI-3 Kinase
(-) eNOS express.
Modulates vascular tone
Kuboki et al Circulation ; 101 : 676 -

35. O2.- ED Vit. C Hyperinsulinemia (-) EC- dependent VD (+) E T-1
Prolonged exposure
(-) EC- dependent VD
(+) ED
Vit. C
O2.-
(Antioxidant)
(+) NAD(P) H oxidase express .
(+) E T-1
Arcaro et al . Circulation ; 105 : 576

36. Conclusion
Diabetes is a chronic vascular disease in which disordered glucose homeostasis triggers endothelial dysfunction of every organ, deriving, in part, from vascular disturbance.

37. Glycemic control (-) macrovascular & microvascular diseases
(+) microvascular & macrovascular complications
Glycemic control
(-) macrovascular & microvascular diseases
Gerich . Arch Intern Med ; 16B (11) : 1306

38. Conclusion
Understanding the mechanism(s) by which acute hyperglycemia induces ED in DM may lead to secondary preventive strategies to reduce CV morbidity and mortality in this highly prevalent disease .