Is Type 2 Diabetes Mellitus a Vascular Condition?
2003; Lippincott Williams & Wilkins; Volume: 23; Issue: 10 Linguagem: Inglês
10.1161/01.atv.0000094360.38911.71
ISSN1524-4636
AutoresFrank B. Hu, Meir J. Stampfer,
Tópico(s)Adipokines, Inflammation, and Metabolic Diseases
ResumoHomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 23, No. 10Is Type 2 Diabetes Mellitus a Vascular Condition? Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBIs Type 2 Diabetes Mellitus a Vascular Condition? Frank B. Hu and Meir J. Stampfer Frank B. HuFrank B. Hu From the Departments of Nutrition and Epidemiology, Harvard School of Public Health, Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass. and Meir J. StampferMeir J. Stampfer From the Departments of Nutrition and Epidemiology, Harvard School of Public Health, Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass. Originally published1 Oct 2003https://doi.org/10.1161/01.ATV.0000094360.38911.71Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:1715–1716Cardiovascular disease (CVD) is the most common complication of type 2 diabetes. However, CVD risk factors are elevated long before the development of diabetes,1 and the development of CVD can also precede the clinical diagnosis of type 2 diabetes.2 The close relationship between diabetes and CVD has led to the "common-soil" hypothesis,3 postulating that type 2 diabetes and CVD share common genetic and environmental antecedents, ie, "they spring from a common soil." The hypothesis implies that atherosclerosis might not be simply a consequence of diabetes but that diabetes and CVD are a single entity sharing an underlying pathophysiology.See page 1845Multiple lines of evidence support the common-soil hypothesis. In epidemiologic studies, the same set of diet and lifestyle factors (a diet higher in glycemic load and trans fat and lower in fiber and polyunsaturated fat, smoking, overweight and obesity, lack of regular exercise, and abstinence from alcohol) explains more than 80% of cases of coronary heart disease4 and 90% of cases of type 2 diabetes.5 Low birth weight, a marker of intrauterine nutritional deficiency, has been associated with increased risk of both diabetes and CVD in later life.6 In addition, pharmacological and lifestyle strategies to prevent type 2 diabetes have resulted in significant reductions in the occurrence of the metabolic syndrome and cardiovascular risk factors in subjects with impaired glucose tolerance,7 although it remains to be seen whether this will translate into a reduction in clinical CVD events. Furthermore, hypertension and dyslipidemia are significant predictors of type 2 diabetes, and statins and angiotensin-converting enzyme (ACE) inhibitors, which are effective in CHD prevention, have been associated with a reduced risk of incident type 2 diabetes in secondary analyses.8–10In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Hunt et al11 provide further direct evidence for the link between diabetes and atherosclerosis. Their careful study found that, after adjustment for age and sex, both common and internal carotid artery intima-media thickness (IMT) were significantly higher among 66 prediabetic individuals than among 1 127 nondiabetic individuals who remained free of diabetes. Also, elevated IMT was a significant predictor of incident type 2 diabetes during follow-up in age- and sex-adjusted analyses. These associations became nonsignificant after further adjustment for elements of the metabolic syndrome, such as blood lipids, blood pressure, 2-hour glucose, and central obesity, suggesting that the metabolic syndrome constitutes the common antecedent linking diabetes and progression of atherosclerosis. This important study provides the first evidence that subclinical atherosclerosis predicts future risk of type 2 diabetes.At the cellular level, the mechanisms linking metabolic syndrome, type 2 diabetes, and atherosclerosis have not been clearly defined. However, emerging data suggest that diabetes and CVD are both vascular conditions that share an underlying pathophysiology, ie, endothelial dysfunction. The theory postulates that, whereas clinical CVD is a result of endothelial dysfunction in large- and medium-sized arteries, type 2 diabetes is induced by dysfunction in the capillary and arteriolar endothelium, with a vast surface area in intimate contact with metabolically active, insulin-sensitive tissues such as skeletal muscle.12 It is thought that chronic endothelial activation and impaired nitric oxide–mediated vasodilatation directly cause inadequate insulin delivery to these tissues, resulting in peripheral insulin resistance and reduced glucose uptake.Historically, the vascular endothelium was thought to be a static monolayer of cells in the body, acting as a semipermeable barrier between the bloodstream and tissue.13 It is now understood that the endothelium is an active and dynamic tissue essential to maintaining homeostasis of cell adhesion and migration, thrombosis, and fibrinolysis.13,14 When the vascular endothelium encounters pro-inflammatory stimuli, endothelial cells are activated by increasing production and expression of soluble adhesion molecules such as ICAM-1, VCAM-1, and E- and P-selectin.15 Plasma levels of these molecules are significantly elevated in both type 1 and type 2 diabetic patients compared with matched controls, and elevated levels appear to be strongly related to plasma lipids, metabolic control, and markers of oxidative stress.16 Patients with elevated triglycerides and low HDL had significantly increased levels of ICAM-1, VCAM-1, and E-selectin.17 Two prospective studies have shown that elevated levels of ICAM-1 and E-selectin significantly predict future risk of CVD.18,19 Recently, elevated E-selectin was found to be a strong independent predictor of type 2 diabetes in the Nurses' Health Study.20 In addition, Meigs et al21 found that microalbuminuria, a marker of diffuse endothelial dysfunction, was associated with type 2 diabetes and with CVD. These results support the idea that endothelial dysfunction is a common precursor of both diabetes and CVD.Another line of evidence supporting the vascular etiology of type 2 diabetes comes from recent evidence that chronic inflammation may be involved in the pathogenesis of insulin resistance and type 2 diabetes. The concept of atherosclerosis as an inflammatory disease is now well established.22 Recent data have demonstrated that elevated levels of C-reactive protein (CRP), a sensitive marker of chronic inflammation, are associated with obesity, insulin resistance, and glucose intolerance.23–25 In several prospective studies, elevated CRP levels significantly predict risk of type 2 diabetes.26–29 In addition, pro-inflammatory adipocyte cytokines, such as tumor necrosis factor alpha-α (TNF-α) and IL-6, are significantly elevated in type 2 diabetes.29 Elevated production of TNF-α and IL-6 elicit the production of acute phase reactants such as CRP and fibrinogen by the liver. TNF-α, IL-6, and CRP in turn stimulate endothelial production of adhesion molecules such as ICAM, VCAM, and E-selectin. These pro-inflammatory cytokines and molecules directly affect vascular walls, not only promoting atherosclerosis, but also leading to impaired vascular reactivity, reduced insulin delivery, and increased peripheral insulin resistance.30 Thus, vascular endothelial dysfunction can be considered a unifying factor for the diabetogenic effects of excess adiposity, low-grade inflammation, and the metabolic syndrome, as well as the common soil for diabetes and CVD.The concept of diabetes as a vascular condition not only gives rise to a new paradigm for understanding the etiology of diabetes and CVD, but it also has implications for the prevention and treatment of the two conditions. First, elevated levels of inflammatory and endothelial markers may help identify populations at high risk for both type 2 diabetes and CVD. So far, CRP appears to be the most consistent and robust predictor of both conditions. Second, if endothelial dysfunction is the root cause of both diabetes and CVD, strategies to improve endothelial dysfunction and reduce chronic inflammation should be able to help prevent and treat both conditions. Therapies with statins and ACE inhibitors, which have been shown to reduce CRP and endothelial markers, have also been associated with a reduced risk of incident type 2 diabetes.8–10 On the other hand, insulin-sensitizing agents such as metformin and thiazolidinediones, which also improve endothelial function, may prove to play a role in the prevention of both diabetes and CVD. Nonetheless, modification of diet and lifestyle factors, which are fundamental causes of type 2 diabetes and CVD, should remain the first line of defense against heightened chronic inflammation and generalized endothelial dysfunction.FootnotesCorrespondence to Dr Frank Hu, Department of Nutrition, Harvard School of Public Health, 665 Huntington Ave, Boston, MA 02115. E-mail [email protected] References 1 Haffner SM, Stern MP, Hazuda HP, Mitchell BD, Patterson JK. Cardiovascular risk factors in confirmed prediabetic individuals: does the clock for coronary heart disease start ticking before the onset of clinical diabetes?. JAMA. 1990; 263: 2893–2898.CrossrefMedlineGoogle Scholar2 Hu FB, Stampfer MJ, Haffner SM, Solomon CG, Willett WC, Manson JE. Elevated risk of cardiovascular disease prior to clinical diagnosis of type 2 diabetes. Diabetes Care. 2002; 25: 1129–1134.CrossrefMedlineGoogle Scholar3 Stern MP. Diabetes and cardiovascular disease: the "common soil" hypothesis. Diabetes. 1995; 44: 369–374.CrossrefMedlineGoogle Scholar4 Stampfer MJ, Hu FB, Manson JE, Rimm EB, Willett WC. Primary prevention of coronary heart disease in women through diet and lifestyle. N Engl J Med. 2000; 343: 16–22.CrossrefMedlineGoogle Scholar5 Hu FB, Manson JE, Stampfer MJ, Colditz G, Liu S, Solomon CG, Willett WC. Diet, lifestyle, and the risk of type 2 diabetes mellitus in women. N Engl J Med. 2001; 345: 790–797.CrossrefMedlineGoogle Scholar6 Rich-Edwards JW, Stampfer MJ, Manson JE, Rosner B, Hankinson SE, Colditz GA, Willett WC, Hennekens CH. Birth weight and risk of cardiovascular disease in a cohort of women followed up since 1976. BMJ. 1997; 315: 396–400.CrossrefMedlineGoogle Scholar7 The Diabetes Prevention Program Research Group. The effects of intensive lifestyle intervention (ILS) and metformin (MET) on the incidence of metabolic syndrome among participants in the Diabetes Prevention Program (DPP). Diabetes. 2003; 52: A58. Abstract.Google Scholar8 Freeman DJ, Norrie J, Sattar N, Neely RD, Cobbe SM, Ford I, Isles C, Lorimer AR, Macfarlane PW, McKillop JH, Packard CJ, Shepherd J, Gaw A. Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation. 2001; 103: 357–362.CrossrefMedlineGoogle Scholar9 Yusuf S, Gerstein H, Hoogwerf B, Pogue J, Bosch J, Wolffenbuttel BH, Zinman B. Ramipril and the development of diabetes. JAMA. 2001; 286: 1882–1885.CrossrefMedlineGoogle Scholar10 Vermes E, Ducharme A, Bourassa MG, Lessard M, White M, Tardif JC. Enalapril reduces the incidence of diabetes in patients with chronic heart failure: insight from the Studies Of Left Ventricular Dysfunction (SOLVD). Circulation. 2003; 107: 1291–1296.LinkGoogle Scholar11 Hunt KJ, Williams K, Rivera D, O'Leary DH, Haffner SM, Stern MP, Gonzales Villalpando C. Elevated carotid artery intima-media thickness levels in individuals who subsequently develop type 2 diabetes. Arterioscler Thromb Vasc Biol. 2003; 23: 1845–1850.LinkGoogle Scholar12 Pinkney JH, Stehouwer CD, Coppack SW, Yudkin JS. Endothelial dysfunction: cause of the insulin resistance syndrome. Diabetes. 1997; 46 (Suppl 2): S9–S13.CrossrefMedlineGoogle Scholar13 Cooke JP. The endothelium: a new target for therapy. Vasc Med. 2000; 5: 49–53.CrossrefMedlineGoogle Scholar14 Vane JR, Born GVR, Welzel D. The Endothelial Cell in Health and Disease. Stuttgart, Germany: Schattauer; 1995.Google Scholar15 Ceriello A, Falleti E, Bortolotti N, Motz E, Cavarape A, Russo A, Gonano F, Bartoli E. Increased circulating intercellular adhesion molecule-1 levels in type II diabetic patients: the possible role of metabolic control and oxidative stress. Metabolism. 1996; 45: 498–501.CrossrefMedlineGoogle Scholar16 Cominacini L, Pasini AF, Garbin U, Davoli A, De Santis A, Campagnola M, Rigoni A, Zenti MG, Moghetti P, Lo Cascio V. Elevated levels of soluble E-selectin in patients with IDDM and NIDDM: relation to metabolic control. Diabetologia. 1995; 38: 1122–1124.CrossrefMedlineGoogle Scholar17 Hackman A, Abe Y, Insull WJ, Pownall H, Smith L, Dunn K, Gotto AMJ, Ballantyne CM. Levels of soluble cell adhesion molecules in patients with dyslipidemia. Circulation. 1996; 93: 1334–1338.CrossrefMedlineGoogle Scholar18 Ridker PM, Hennekens CH, Roitman-Johnson B, Stampfer MJ, Allen J. Plasma concentration of soluble intercellular adhesion molecule 1 and risks of future myocardial infarction in apparently healthy men. Lancet. 1998; 351: 88–92.CrossrefMedlineGoogle Scholar19 Hwang S-J, Ballantyne CM, Sharrett AR, Smith LC, Davis CE, Gotto AMJ, Boerwinkle E. Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases: the Atherosclerosis Risk in Communities (ARIC) Study. Circulation. 1997; 96: 4219–4225.CrossrefMedlineGoogle Scholar20 Meigs JB, Hu FB, Manson JE. Endothelial dysfunction predicts development of type 2 diabetes. Diabetes. 2003; 52: A58. Abstract.Google Scholar21 Meigs JB, D'Agostino RB Sr, Nathan DM, Rifai N, Wilson PW. Longitudinal association of glycemia and microalbuminuria: the Framingham Offspring Study. Diabetes Care. 2002; 25: 977–983.CrossrefMedlineGoogle Scholar22 Ridker PM. Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation. 2003; 107: 363–369.LinkGoogle Scholar23 Visser M, Bouter LM, McQuillan GM, Wener MH, Harris TB. Elevated C-reactive protein levels in overweight and obese adults. JAMA. 1999; 282: 2131–2135.CrossrefMedlineGoogle Scholar24 Festa A, D'Agostino R Jr, Howard G, Mykkanen L, Tracy RP, Haffner SM. Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation. 2000; 102: 42–47.CrossrefMedlineGoogle Scholar25 Pradhan AD, Cook NR, Buring JE, Manson JE, Ridker PM. C-reactive protein is independently associated with fasting insulin in nondiabetic women. Arterioscler Thromb Vasc Biol. 2003; 23: 650–655.LinkGoogle Scholar26 Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA. 2001; 286: 327–334.CrossrefMedlineGoogle Scholar27 Barzilay JI, Abraham L, Heckbert SR, Cushman M, Kuller LH, Resnick HE, Tracy RP. The relation of markers of inflammation to the development of glucose disorders in the elderly: the Cardiovascular Health Study. 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