Vascular Biology of Diabetes Abdel Moniem Ibrahim Ahmed, MD Professor of Cardiovascular Physiology Cairo University Oct . 15 . 2003

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 .

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 .

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

Acute Hyperglycemia Normal Volunteers Rapid BP elevation Glucose levels trigger functional alterations in vasomotor motions Marfella et al . Am J Physiol Endocrinol Metab . 1995 , 268 : E 1167 -

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 . 1999 ; 14 (2) : 106-

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 . 1999 ; 14 (2) : 106

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 .2002 ; 15(4): 343-

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

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 .

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

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] : 744-748.

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

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 .

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

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

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 . 2001; 280: F 480-

NO scavenging (Chronic)

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 .

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 . 2001 , 108 (4) : 635

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 . 1999; 14 [Suppl 3] : 1-9

AGEs ROS NO Bioavailability Bind with their receptors RAGE (EC, VSMC, Macrophages) Quench NO activity ROS NO Bioavailability Tan et al . Diabetic Care . 2002; 25 (6): 1055

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

Oxidative-modification hypothesis Diaz et al. NEJM. 1997,337(6) : 408

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 . 2002 ; 90 : 107-

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 .

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 . 2001 ; 37 [part 2]

Proposed pathophysiological mechanisms acting during maintenance phase of ED .

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 . 2002 ; 25(6) : 1055

Clinical manifestations of diabetic nephropathy and potenial role of ED

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 .

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

Insulin Protective effects Deleterious effects (-) apoptosis (+) NO prod. (+)VEGF . (+) ET-1 . Salt - sensitive HTN * Vicent et al . TCI . 2003 , III (9) : 1373- * Ogihara et al . Diabetes . 2001 , 50 : 573-

Insulin Resistance (+) PKC in vascular tissues (-) PI-3 Kinase (-) eNOS express. Modulates vascular tone Kuboki et al Circulation . 2000 ; 101 : 676 -

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 . 2002 ; 105 : 576

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

Glycemic control (-) macrovascular & microvascular diseases (+) microvascular & macrovascular complications Glycemic control (-) macrovascular & microvascular diseases Gerich . Arch Intern Med . 2003 . 9 ; 16B (11) : 1306

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 .