European Heart Journal Advance Access originally published online on February 26, 2008
European Heart Journal 2008 29(7):952-953; doi:10.1093/eurheartj/ehn037
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Risk of type 2 diabetes mellitus in those with hypertension
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Essential hypertension is common and is an important risk factor for coronary heart disease, stroke, atherosclerosis, and peripheral vascular disease. Free radicals, nitric oxide (NO), eicosanoids, pro- and anti-inflammatory cytokines, long-chain polyunsaturated fatty acids (LCPUFAs), folic acid, tetrahydrobiopterin (BH4), and vitamin C play a significant role in the pathobiology of hypertension. Vascular endothelium produces vasodilators: prostacyclin (PGI2), NO, and endothelium-derived hyperpolarizing factor, and other vasoactive factors such as endothelins and prostaglandin E1 (PGE1).1 Under physiological conditions a balance is maintained between endothelial vasoconstrictors and vasodilators such that normal blood pressure is maintained. When this balance is altered more in favour of vasoconstrictors and/or when the concentrations of vasodilators are reduced, hypertension develops. One mechanism by which endothelium-dependent vasodilatation is impaired is due to an increase in the oxidative stress that inactivates NO and PGI2.
Polymorphonuclear leucocytes of patients with uncontrolled essential hypertension produce significantly large amounts of O2–., hydrogen peroxide (H2O2), and lipid peroxides,2 indicating that an increase in oxidative stress occurs in hypertension. In addition, a decrease in the levels of superoxide dismutase (SOD), catalase, glutathione peroxidase, and vitamin E in the RBC membranes of uncontrolled hypertensives was noted. These biochemical abnormalities revert to normal after the control of hypertension.1,2 O2–. is a potent vasoconstrictor,3 implying that an increase in free radical generation could be responsible for the heightened peripheral vascular resistance in hypertension. Furthermore, SOD deficiency is seen in hypertension4 and SOD activity decreases with advancing age.5 Thus, decreased NO bioavailability and increased O2–. generation with increasing age due to enhanced NAD(P)H oxidase activity could be responsible for oxidative stress seen in hypertension.
An increase in pulse pressure was associated with elevated C-reactive protein (CRP) among healthy US adults.6 Elevated plasma IL-6 levels in women with hypertension and insulin resistance in men was noted.7 A graded positive relationship between blood pressure and levels of ICAM-1 (intercellular adhesion molecule-1) as well as IL-6 was noted in healthy men,8 suggesting that low-grade systemic inflammation occurs in hypertension.
Plasma levels of CRP, TNF-
, and IL-6 are elevated in subjects with type 2 diabetes.9 Subjects with elevated CRP levels were two times more likely to develop diabetes.10 Dietary glycemic load is significantly and positively associated with plasma CRP,11 suggesting that hyperglycemia induces inflammation. Neutralization or inhibitors of CRP abrogated the increase in infarct size and cardiac dysfunction,12 indicating that efforts designed to decrease inflammation produces cardioprotection, and might, possibly, decrease the risk of diabetes.
Acute raise in plasma glucose levels in normal and impaired glucose tolerance (IGT) subjects increased plasma IL-6, TNF-, and IL-18 levels, and these increases were much larger and lasted longer in IGT subjects compared with control.13 TNF- secretion was suppressed in younger subjects in response to glucose challenge, but not in the older subjects.14 Furthermore, hyperglycemia induced the production of acute phase reactants from the adipose tissue.15 These data suggest that an increased incidence of type 2 diabetes in the elderly could be due to alterations in the homeostatic mechanisms that control TNF-, IL-6, and CRP levels, and that low-grade systemic inflammation occurs in type 2 diabetes. Since low-grade systemic inflammation occurs both in hypertension and type 2 diabetes mellitus, it is not surprising that Conen et al.16 observed blood pressure progression as a strong and independent predictor of occurrence of type 2 diabetes in hypertensives. It would have been more helpful had Conen et al. studied which of the inflammatory markers are more specific to predict the development of type 2 diabetes in hypertensives. In view of the overlap biochemical abnormalities in obesity, type 2 diabetes, hypertension, and insulin resistance such as cytokines, adipokines, reactive oxygen species, anti-oxidants, and NO, it is necessary to identify specific biochemical abnormalities that are true to each of these conditions, though common biochemical abnormalities suggest a more generalized pathophysiological process in them.17 It is likely that proteomics and gene expression profile studies could give more clues as to such specific biochemical abnormalities in these conditions.
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[Abstract/Free Full Text] - Conen D, Ridker PM, Mora S, Buring JE, Glynn RJ. Blood pressure and risk of developing type 2 diabetes mellitus: The Women's Health Study. Eur Heart J (2007) 28:2937–2943.
[Abstract/Free Full Text] - Das UN. Is metabolic syndrome X a disorder of the brain with the initiation of low-grade systemic inflammatory events during the perinatal period? J Nutr Biochem (2007) 18:701–713.[CrossRef][Medline]
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