Mechanisms of Vascular Dysfunction in Diabetes Mellitus Lynette Pittman, RN, Nurse Clinician, Heart Health Services, Calgary Health Region

Mechanisms of Vascular Dysfunction in Diabetes Mellitus Lynette Pittman, RN, Nurse Clinician, Heart Health Services, Calgary Health Region By 2020 cardiovascular disease (CVD) will dominate all other causes of deaths and surpass infectious disease as the world s greatest killer. 1 According to the World Health Organization models, by 2025 the number of persons with diabetes will expand by 35 percent worldwide. 1 What will be our role as health care professionals as we endeavor to deal with the combined impact of cardiovascular disease and diabetes? No matter what our specialty we will be touched, if not through our patients, through our families and friends. We must begin with a thorough knowledge and understanding of the adversaries, diabetes and cardiovascular disease. Although less well understood than our evolving understanding of the pathogenesis of atherosclerosis itself, novel risk factors for the accelerated development of atherosclerosis in the presence of diabetes have been identified. 2 This paper will focus on those mechanisms of diabetes that may predispose a hastening of the atherosclerotic process. Diabetes Mellitus and Cardiovascular Disease Risk As it relates to cardiovascular risk, notable differences exist between the two types of diabetes, with type II diabetic individuals developing CVD at a younger age, having a higher rate of multi-vessel disease and poorer outcomes post myocardial infarction than their type I counterparts. 2 The Multiple Risk Factor Intervention Trial(MR.FIT) found diabetic men with one, two or three CVD risk factors experienced higher disease mortality than nondiabetic individuals with the same number of risk factors. Diabetes played an additive role when combined with one or more risk factors. 3 The United Kingdom Prospective Study (UKPDS) following newly detected diabetic individuals, found increased risk of CVD was significantly associated with risk factors of increased LDL, decreased HDL increased HGB A1c, elevated systolic blood pressure and smoking when measured at baseline. 4 Despite the undeniable association of established CVD risk factors and diabetes, these risk factors account for only 50 per cent of the excess CVD in the diabetic. 2,5 Hyperglycemia, hyperinsulinemia and insulin resistance, dyslipidemia, increased plasma oxidative stress, enhanced fibrinolysis and abnormal vasodilator function are some of the proposed mechanisms and novel risk factors for the accelerated development of atherosclerosis and diabetes. 2 Mechanisms of Vascular Dysfunction in Diabetes Numerous mechanisms contribute to the pathogenesis of diabetic vascular diseases, many of which are complex, incompletely understood and continue to be intensely investigated. The hallmark of diabetic vascular disease is thickening of the basement membranes, which develop in relation to the duration of diabetes and degree of glycemic control. 6 The contribution of hyperglycemia, hyperinsulemia and dyslipidemia to diabetic vascular complications will be briefly reviewed. Hyperglycemia. Although still controversial, hyperglycemia has emerged as a leading candidate responsible for the excess of diabetes risk. 5 A number of studies following type 1 and type 2 diabetic individuals, adjusting for other risks, have substantiated a dose response

2 relationship between hyperglycemia and CVD risk. In the San Antonio Heart Study, diabetic subjects in the top of the quartile of fasting plasma glucose (FPG) had a CVD mortality 4.7 times the risk of subjects in quartiles 1 and 2 combined. 7 Ten years of follow-up of type 1 diabetics in the Wisconsin Epidemiological Study, showed that for every 1 percent increase in glycated hemoglobin, the risk ratio for CVD nearly doubled. 8 A continuous graded relationship between blood glucose and risk of CVD is demonstrated in the preliminary data from the 2853 patients in the Framingham Offspring Study. 9 It is unclear if there is a critical value that exists above which CVD raises. Although better glycemic control is broadly beneficial, these are observational studies only, and to date, there is little evidence that treating to tighter glycemic levels reduces CVD risk. A number of mechanisms have been proposed for the contribution of hyperglycemia in CVD. Suggested mechanisms include: glycation of collagen and other vessel-wall proteins and lipoproteins; accelerated generation of reactive oxygen species; increased oxidative stress on glycated end products, LDL cholesterol, and vascular endothelial cells; alteration in haemorrheological characteristics or changes in vascular reactivity. 2 Extracellular glucose can glycate proteins without enzyme action and generate oxidative by-products. Glycated proteins (Advanced Glycation End-products) accumulate in the extracellular matrix and bind to specific AGE-receptors that are expressed on the cell surface. AGE receptors are being extensively investigated for their contribution to the accelerated vascular complications of diabetes. Cells contain several receptors of AGEs that mediate their biological effects. Exposure to AGE modified proteins can elicit the production of inflammatory cytokines from vascular cells, cause impaired endothelial dependent vasodilator function and increase the expression of various leukocyte adhesion molecules implicated in atherosclerosis. 5 Insulin. Although it has been suggested that hyperinsulinemia may be the link between hyperglycemia and CVD, the specific role of insulin in the etiology of atherosclerosis is poorly understood. It is thought that insulin resistance and compensatory hyperinsulinemia may contribute to atherogenic risk through several different mechanisms. Insulin resistance commonly precedes hyperglycemia, and insulin resistance has been shown to have a positive correlation with CVD. Diabetes is frequently associated with the risk factors of obesity, dyslipidemia, and hypertension. Most individuals with this group of disorders also have insulin resistance. This group of disorders has been named syndrome X, the insulin resistance syndrome, and CVD metabolic syndrome. Insulin resistance syndrome includes glucose intolerance, and elevated levels of fasting insulin and triglycerides. 10 In normal conditions, insulin has a protective vasodilatory action that may be mediated by nitric oxide. Nitric oxide has documented anti-atherogenic functions via the suppression of adhesion molecule expression and inhibition of smooth-muscle-cell migration and growth. In insulin resistance states, the ability of insulin to induce vasodilation is low, suggesting an impairment or inactivation of nitric oxide. Increased

3 insulin action is also thought to contribute to atherogenesis through smooth-muscle cell hypertrophy and hyperplasia and increased extracellular proteins. A hypothesis generated to explain data from the Framingham Offspring Study, suggested that the atherogenic effects of hyperglycemia or hyperinsulinemia might be mediated through factors predisposing to acute thrombosis. 10 Markers of decreased fibrinolytic potential include elevated levels of plasminogen activator inhibitor 1 (PAI-1) antigen or tissue-type plasminogen activator (tpa) antigen. These markers are associated with increased risk for CVD among non-diabetic individuals. The Framingham Offspring Study, found strong positive associations between levels of fasting insulin and levels of markers indicating impaired fibrinolyisis in both men and women. 10 Elevated levels of PAI-1 appear to increase the formation of acellular, thin-walled plaques susceptible to rupture. Increases of fibrinolytic markers have been shown to correlate with elevated markers of inflammation and endothelial dysfunction. 10 Is fibrinolysis the cause or the effect of hyperinsulinemia is a question that remains unanswered. Final comments from the Framingham Offspring Study suggest that modification of the fibrinolytic state by improving insulin sensitivity, particularly in people with impaired or diabetic glucose tolerance, may offer a new approach to reducing CVD risk. Dyslipidemia and Associated Metabolic Abnormalities. Dysplipidemia is the most thoroughly studied and established mechanism for the increased risk of atherogenesis identified in type II diabetes. 5 Studies investigating dyslipidemia and diabetes have been done primarily with individuals with type II diabetes because of the increased incidence of dyslipidemia in this population. 11 In type l patients with good glycemic control, lipids may appear to be better than the average for subjects without diabetes, however lipoproteins may be abnormal in composition and as a result more atherogenic. 12 Numerous studies have also shown that dyslipidemias are more prevalent in diabetic women, and probably a very important contributor to the increased CVD risk in this group. The most common dyslipidemias observed in type II diabetes are high triglycerides and reduced high-density lipoprotein (HDL) cholesterol. Low-density lipoprotein concentration is not usually higher than in individuals without diabetes, but the LDL particles themselves tend to be small and dense. Small dense LDL particles are believed to be more atherogenic because they are more easily glycated and susceptible to oxidation. 11 Interventional studies have shown that the benefit of lowering LDL is similar in the diabetic and non-diabetic population. 11 Central to the pathogenesis of dyslipidemia in diabetes is the increased presentation of free fatty acids to the liver, which provide the substrate for triglyceride-rich lipoproteins - very low density (VLDL) production in the liver. 5 Abdominal obesity, a common finding in type II diabetic men, provides a further source of free fatty acids which in turn fuel production of VLDL. Contributing to the adverse effect of increased VLDL production is the decreased catabolism of triglyceride-rich lipoproteins. Liprotein lipase, an enzyme

4 that plays a central role in clearing postprandial lipemia (consisting largely of triglyceride-rich particles), is decreased in uncontrolled type ll diabetes. 5 Contiguously, states of higher VLDL are associated with low HDL levels because of the intimate relationship between lipoprotein lipase activity (reduced in DM), cholesterol ester transfer protein activity, and efficient HDL. The protective role of HDL in shielding LDL from oxidation also appears to be diminished in diabetes, suggesting differences in the qualitative as well as quantitative aspects of HDL in diabetes. 5 Conclusion Knowledge of diabetes and the mechanisms that predispose its sufferers to accelerated atherosclerosis has advanced. AGE receptors and metabolic syndrome have become part of our new language. We need to prepare ourselves to deal with the accelerating challenge of both diabetes and cardiovascular disease. Cardiac rehabilitation or other secondary prevention programs provide expert and quantifiable gains with respect to the identification and modification of risk factors which lead to the development and progression of atherosclerosis and its all too often intimate companion, diabetes (Stone, Cyr, Friesen, Kennedy-Symmonds, Stene, 1999). 13 References 1. Gaziano, J. M. (2001). Global burden of cardiovascular disease. In Braunwald E, Zipes D.P., & Libby P. (Eds.), Heart disease a textbook of cardiovascular medicine (pp. 1-17). Philadelphia: W.B. Saunders. 2. Nathan, M. N. & Singer, D. E. (1997). The epidemiology of cardiovascular disease in type 2 diabetes mellitus: How sweet it is... or is it? Lancet, 350 (suppl 1), 4-9. 3. Stamler, J., Vaccaro, O., Neaton, J., Wentworth d. for the Multiple Risk Factor Intervention Trial Research group. (1993). Diabetes, other risk factors, and 12 year cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care, 16, 434-444. 4. Turner, R. C. (1998). The U.K. Prospective Diabetes Study: A review. Diabetes Care, 21 (Suppl 3), C35-C38. 5. Nesto, R. W. & Libby, P. (2001). Diabetes Mellitus and the Cardiovascular System. In Braunwald E, Zipes D.P., & Libby P. (Eds.), Heart Disease A textbook of cardiovascular medicine (6 ed., pp. 2133-2150). Philadelphia: S.B. Saunders. 6. Feener, E. P., & King, G. L. (1997). Vascular dysfunction in diabetes mellitus. Lancet, 350 (Suppl), 9-13. 7. Wei, M., Haffner, S. M., & Gaskill, S. P. (1998). Effects of diabetes and level of ischemia on allcause and cardiovascular mortality. The San Antonio Heart Study. Diabetes Care, 21, 1167-1172. 8. Klein, R., Klein, B. E., & Moss, S. E. (1995). The Wisconsin epidemiological study of diabetic retinopathy. Diabetes, 44, 796-801. 9. Kannel W.B., & McGee, D. L. (1979). Diabetes and cardiovascular disease. The Framingham study. Journal of the American Medical Association, 2411, 2035-2038.

5 10. Meigs, J. B., Mittleman, M. A., Nathan, D. M., Tofler, G. H., Singer, D. E., Murphy-Sheey, P. M., Lipinska, I., & Wilson, P. W. F. (2000). Hyperinsulinemia, hyperglycemia, and impaired hemostasis: The Framingham offspring study. Journal of the American Medical Association, 283, 221-228. 11. Powers, A. C. (2001). Diabetes Mellitus. In Braunwald E, Fauci Anthony, Kasper D, Hauser S, Longo D, & Jameson JL (Eds.), Harrison's principles of internal medicine (15 ed., pp. 2109-2137). New York: McGraw-Hill Companies. 12. Adults with diabetes and patients with concomitant dyslipidemia and hypertension (1999). In A.Gotto, & H. Pownall (Eds.), Manuel of lipid disorders: Reducing the risk for coronary heart disease (2 ed., pp. 371-380). Media: Williams & Wilkins. 13. Stone, J. A., Cyr, C., Friesen, M., Kennedy-Symmonds, H., & Stene, R. (1999). Canadian Guidelines for Cardiac Rehabilitation and Cardiovascular Disease Prevention. In J.A.Stone, C. Cyr, M. Friesen, H. Kennedy-Symmonds, & R. Stene (Eds.), (1 ed., pp. 1-25). Winnipeg. Acknowledgements Editing suggestions were kindly provided by Dr. Alun Edwards, MB, F.R.C.P. Clinical Associate Professor Department of Medicine, University of Calgary Medical Leader, Regional Diabetes Education Centre, Calgary Health Region, Calgary Alberta and Dr. Karen L Then, MN, Phd, NPC, Associate Professor, Faculty of Nursing, University of Calgary, Calgary Alberta.