The impact of diabetes mellitus on endothelial dysfunction.

Coronary artery, cerebrovascular and peripheral vascular disease (PVD) are the principal causes of morbidity and mortality in type 2 diabetes mellitus (DM). (1) The augmented risk of macrovascular disease in DM is partly due to the considerably higher incidence of conventional cardiovascular risk factors, such as hypertension, obesity and dyslipidemia. (2) However, we should not forget that the pathophysiology of complications in the setting of DM is multifactorial, and in addition to the "conventional" risk factors, there are many other closely inter-related processes that develop in parallel, progress with time, and are strongly and independently associated with the risk of death on a background of DM. (1,3)

In this issue of the Southern Medical Journal, Wachtel and Frezza provide a comprehensive review of the local biologic factors that influence amputations in patients with DM. (4) This has particular inference given the impact of DM on the vascular endothelium, once thought to be a static, semipermeable monolayer of cells between the blood stream and tissues, which is now recognized to be a dynamic "organ" that plays a fundamental role in the development of atherosclerosis, thrombogenesis and fibrinolysis. (1)

What is the Possible Role of DM on the Endothelium?

Prostacyclin and nitric oxide, produced by normal endothelium, inhibit platelet activation and relax vascular smooth muscle, promoting normal blood flow. Patients with DM have reduced release of prostacyclin and nitric oxide, (1) and the chronic impairment of endothelial nitric oxide synthase activity by this mechanism may, to a certain extent, give explanation for the accelerated atherosclerosis in DM. Likewise, impaired endothelial synthesis of nitric oxide is an important feature of athero-thrombosis and can be estimated from endothelium-dependent flow-mediated dilation (FMD), and DM is independently associated with impaired FMD. (1) Diabetic patients also have decreased FMD and increased arterial stiffness compared with age- and sex-matched nondiabetic subjects, and these functional changes correlate well with the structural changes of the arteries measured by intimal medial thickness. (1) Interestingly, insulin therapy has been shown to improve endothelium-dependent and endothelium-independent vasodilatation, (1) and some newer agents like the PPAR-[gamma] agonists, now recommended for the treatment of DM, have also been shown to improve endothelial function. (1) The effects seen with such therapeutic interventions in the setting of DM demonstrates the putative link of deranged metabolic control and endothelial damage/dysfunction.

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Plasma von Willebrand factor (vWf--a marker of endothelial damage/dysfunction) levels are elevated in patients with DM. (5) This was also found to be associated with markers of increased oxidative stress and therefore reflect the severity of biochemical abnormalities, contributing to diabetic vascular disease. (1) Increased levels of vWf have also been found to be independently and significantly associated with DM in a cohort of postinfarction patients, possibly indicative of endothelial damage being causal to the increased vascular events. (1) Endothelial abnormalities in DM have been shown to be only partially influenced by contemporary, intensified multi-factorial cardiovascular risk intervention, suggesting the need for earlier and more aggressive risk factor intervention. (5)

What are the Coexisting Factors Involved in the Setting of DM?

Chronic, low-grade inflammation may be important and in the presence of pro-inflammatory stimuli, endothelial cells are activated by increasing production and expression of soluble adhesion molecules such as 1CAM-1, VCAM-l and E-selectin. (1) Vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) are mediators of angiogenesis, and recent data suggest that the balance between these growth factors may affect vascular endothelial integrity. (6) Plasma Ang-2 (but not Ang-1), like VEGF levels, have been demonstrated to be selectively elevated in patients with DM and are associated with indexes of endothelial damage/dysfunction, regardless of vascular disease. Intensive multifactorial intervention was associated with reductions in plasma VEGF, vWf, and (in patients without cardiovascular disease) Ang-2 levels, possibly reflecting an improved vascular profile with treatment. (6)

Of late, circulating endothelial cells (CECs) and endothelial progenitor cells (EPCs) have been emerging as novel biologic markers of diabetic vasculopathy. (7-9) CECs have been reported to be an ex-vivo indicator of vascular injury, and it has been demonstrated that elevated CECs are present in patients with DM, and this is independent of glucose levels or glycosylated hemoglobin, suggesting that there is ongoing vascular injury that is not directly dependent on glucose control resulting in endothelial sloughing. (7)

What is the Implication of Peripheral Vascular Disease?

PVD is a threatening complication of DM and as EPCs are involved in neovasculogenesis and maintenance of vascular homeostasis, their impairment may have a role in the pathogenesis of diabetic vasculopathy, as decreased EPCs have been directly related to PVD severity (ankle-brachial pressure index), and flow cytometry studies have demonstrated EPC function to be altered in diabetic subjects with PVD, further strengthening the pathogenetic role of EPC dys-regulation in diabetic vasculopathy. (8,9) Of note, reduced EPC levels correlated inversely with glucose levels, and patients with ischemic foot lesions had the lowest levels of EPCs. Hence, depletion of circulating EPCs in patients with DM may be implicated in the pathogenesis of peripheral vascular complications. (8,9)

PVD can compromise the blood supply to the lower limb with amputation being necessary in severe cases. Reduced blood flow may be due to arterial occlusive disease or constriction of skeletal microvessels with the resultant ischemia causing pain, tissue damage, ulceration and gangrene. (10) These events are associated with endothelial damage or dysfunction: endothelin-1 has been implicated as a mediator via its constrictor, proinflammatory and proliferative actions, and raised plasma and tissue levels of this peptide have been described in various ischemic conditions, including PVD. (10)

In conclusion, abnormalities in endothelial cell morphology and function are now recognized features of DM, and diminished endothelium-dependent relaxation and enhanced endothelium-dependent contraction have been described. Thus, endothelial dysfunction, the initial step of the atherosclerotic process, can be reversible to a considerable extent and therefore, major efforts should be made to control not only hyperglycemia, but also the other risk factors for cardiovascular disease, (11,12) to prevent the onset of all the processes that eventually lead the patient with DM to premature death, (13) especially so in view of the prothrombotic risk of DM. (14)

References

1. Varughese GI, Tomson J, Lip GY. Type 2 diabetes mellitus: a cardiovascular perspective. Int J Clin Pract 2005;59:798-816.

2. Varughese GI, Patel JV, Lip GY. Blood pressure control in the setting of diabetes mellitus: new targets, new hope for improvement? J Hum Hypertens 2006;20:635-637.

3. Varughese GI, Lip GY. Hypertension in patients with type-II diabetes: relation to urinary albumin excretion, endothelial function and inflammation. J Hum Hypertens 2005;19:421-424.

4. Wachtel MS, Frezza EE. Local biological factors that influence amputations in diabetic patients. South Med J 2006;100:158-161.

5. Lim HS, Chong AY, Freestone B, et al. The effect of multi-factorial intervention on plasma von Willebrand factor, soluble E-selectin and tissue factor in diabetes mellitus: implications for atherosclerotic vascular disease. Diabet Med 2005;22:249-255.

6. Lim HS, Blann AD, Chong AY, et al. Plasma vascular endothelial growth factor, angiopoietin-1, and angiopoietin-2 in diabetes: implications for cardiovascular risk and effects of multifactorial intervention. Diabetes Care 2004;27:2918-2924.

7. McClung JA, Naseer N, Saleem M, et al. Circulating endothelial cells are elevated in patients with type 2 diabetes mellitus independently of HbA(1)c. Diabetologia 2005;48:345-350.

8. Fadini GP, Sartore S, Albiero M, et al. Number and function of endothelial progenitor cells as a marker of severity for diabetic vasculopathy. Arterioscler Thromb Vase Biol 2006;26:2140-2146.

9. Fadini GP, Miorin M, Facco M, et al. Circulating endothelial progenitor cells are reduced in peripheral vascular complications of type 2 diabetes mellitus. J Am Coll Cardiol 2005;45:1449-1457.

10. Tsui JC, Dashwood MR. A role for endothelin-1 in peripheral vascular disease. Curr Vase Pharmacol 2005;3:325-332.

11. Varughese GI, Patel JV, Lip GY, et al. Novel concepts of statin therapy for cardiovascular risk reduction in hypertension. Curr Pharm Des 2006;12:1593-1609.

12. Varughese GI, Scarpello JH. The role of deranged glucose metabolism. Arch Intern Med 2006;166:1784-1785.

13. Avogaro A, Fadini GP, Gallo A, et al. Endothelial dysfunction in type 2 diabetes mellitus. Nutr Metab Cardiovasc Dis 2006;16 (Suppl 1):S39-45.

14. Varughese GI, Patel JV, Tomson J, et al. The prothrombotic risk of diabetes mellitus in atrial fibrillation and heart failure. J Thromb Haemost 2005;3:2811-2813.

George Iype Varughese, MRCP

From the Department of Diabetes & Endocrinology, University Hospital of North Staffordshire, Stoke-on-Trent, United Kingdom.

Reprint requests to Dr. G. I. Varughese, MRCP (Ireland); MRCP (UK), Specialist Registrar in Diabetes & Endocrinology, Department of Diabetes & Endocrinology, c/o Ward 61--The Metabolic Unit, University Hospital of North Staffordshire, Stoke-on-Trent ST4 6QG, United Kingdom. Email: [e-mail]