From a clinical and epidemiologic point of view, diabetes is an undisputable, major risk factor for cardiovascular complications. The magnitude of the diabetes mortality link – is of the same order as that of a coronary event (a doubling in the risk of death), and for this reason, current guidelines regard diabetes as equivalent to coronary heart disease. There is no question that diabetes engenders a proatherogenic milieu, affects myocardial, brain and renal structure and triggers a series of metabolic and neuroendocrine effects, ultimately leading to hypertension and major organ failure. Renoretinal complications, that is, the effect of microvascular damage, are associated in a causal manner with hyperglycemia. However, the strength of the association between glycosylated hemoglobin and cardiovascular risk is quantitatively small, and it is still unclear whether amelioration of metabolic control can translate into better cardiovascular outcomes. In the United Kingdom Prospective Diabetes Study (UKPDS), better glycemic control did not lower the risk for cardiovascular events . In the recent Action to Control Cardiovascular Risk in Diabetes (ACCORD)  and Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE)  trials, near-normal plasma glucose control for up to 5 years did not reduce cardiovascular event rates. Yet, in line with the notion that optimal glucose control may have favorable microcirculatory effects, the incidence rate of microalbuminuria and diabetic nephropathy was reduced in patients in the active arm of the ADVANCE study. The coherent lack of cardiovascular protection by near-normal glycemia in ACCORD and ADVANCE underscores the relevance of nonglycemic risk factors that often accompany diabetes, such as endothelial dysfunction, hypertension, hyperlipidemia and thrombosis. Results of ACCORD and ADVANCE make the need of focusing on the prevention of diabetes even more compelling, a formidable task demanding more detailed knowledge than we have now on how this disease is engendered.
Can endothelial dysfunction cause diabetes?
Although the underpinning of metabolic syndrome does not stand careful scientific scrutiny , the hypothesis by Reaven  that implicates insulin resistance in atherogenesis is still compatible with current scientific knowledge. In Reaven's view, insulin resistance is the primary abnormality that gives rise to dyslipidemia, hypertension, glucose intolerance and type-2 diabetes. This hypothesis takes a cell physiology alteration (insulin resistance) as a starting point for a complex series of hemodynamic and metabolic sequelae, ultimately leading to cardiovascular damage. In this perspective, the vascular endothelium is seen as a target of disease, that is, as the territory where atherosclerosis initiates and evolves. However, disturbed endothelial regulation per se may have metabolic consequences (see below) and be directly implicated in the very origin of insulin resistance and diabetes . In other words, diabetes may be envisaged as a consequence of endothelial dysfunction and as an amplifier of the atherogenesis process (Fig. 1). In cross-sectional studies, endothelial dysfunction is strongly related to insulin resistance , but this association has been mainly interpreted according to the conventional view that endothelium is the target of atherosclerosis rather than a factor inciting insulin resistance. At arteriolar and capillary level, a dysfunctional endothelium may have a primary role in the very generation of insulin resistance and by this way contribute to atherosclerosis in medium and large vessels. It is not rare for cardiovascular complications to antedate the appearance of diabetes. Type-2 diabetes and atherosclerosis have common mechanisms, and insulin resistance may represent a shared antecedent of these diseases. Notably, both hypertension and insulin resistance are characterized by disturbed endothelial vasodilatation. Compromised endothelial vasodilatation and endothelial activation are commonly seen in patients with classical cardiovascular risk factors , and these alterations are currently considered as the effect of exposure to proatherogenic factors. Yet, for insulin resistance and resulting metabolic alterations, the reverse interpretation cannot be excluded a priori. Endothelial dysfunction is strongly associated both to acute  and chronic inflammation , that is, to a condition that is currently considered as a potentially important risk factor for type-2 diabetes . However, the hypothesis that inflammation is a step in the chain of events whereby endothelial dysfunction leads to insulin resistance and diabetes is not supported by available studies (see below). Furthermore, the endothelial dysfunction–diabetes link is also independent of individual insulin resistance profile indicating that mechanism(s) behind the endothelium-driven pathway to diabetes do not fit into the established interpretative schema of this disease.
The endothelial dysfunction–diabetes connection: epidemiologic and mechanistic insights
Arterial pressure often antedates and predicts the development of type-2 diabetes. In a study in the Netherlands in the early 1990s, hypertension predicted diabetes, but this phenomenon was entirely attributed to antihypertensive treatment rather than to hypertension per se . In subsequent analyses in the Atherosclerosis Risk in Community (ARIC) study  and the Women's health study , hypertension explained the incidence of new cases of diabetes independent of antihypertensive drug therapy and other risk factors. In the Monica-Kora study , there was a 90 and 40% excess risk for incident diabetes in men and women with established hypertension in comparison with coeval normotensive cohorts. The strong link between arterial pressure per se and the incidence of diabetes can be due to the fact that insulin resistance is a characteristic of essential hypertension . However, the coexistent relationship between endothelial dysfunction and hypertension  suggests that disturbed endothelial function is involved in the pathogenesis of both conditions, hypertension and diabetes. In a nested case–contro; study within the Nurses' Health Study  and in the Monika-Kora study , E-selectin coherently signaled an increased risk for incident diabetes independent of other risk factors. Notably, in the Nurses' Health Study, the predictive power of this biomarker was unaffected by adjustment for C-reactive protein (CRP), insulinemia and glycosylated hemoglobin. More recently, the independent link between disturbed endothelial function and incident diabetes was confirmed in two studies in nonobese postmenopausal women  and essential hypertensive patients  testing the forearm vasodilatory response to ischemia and acetylcholine, respectively. In line with biomarker-based observations in the Nurse Health Study, the effect of endothelial dysfunction in essential hypertensive patients  was independent of CRP and baseline insulin sensitivity. Confirmation of the link in question by these functional studies is important because disturbed vasomotion is central to the diabetogenic effect of endothelial dysfunction. Impaired endothelium-dependent vasodilatation may indeed limit insulin-dependent capillary recruitment  and redistribution of flow and insulin access to metabolically active, insulin-sensitive areas in the skeletal muscle . Furthermore, altered endothelial permeability may affect insulin concentration in the interstitium, which is a fundamental step determining insulin action . Experimental studies in humans demonstrated that, well within the physiological range, endothelial function is a relevant element linking arterial pressure and insulin sensitivity . In keeping with data suggesting a relevant role of nitric oxide-dependent vasodilatation in the regulation of insulin sensitivity in healthy people, transgenic mice with knockout mutations in the endothelial nitric oxide synthase gene, along with endothelial dysfunction, display a clear-cut insulin-resistant state .
Albuminuria as a predictor of diabetes
In individuals without obvious renal disease, albuminuria is currently seen as an expression of endothelial dysfunction at the level of renal microcirculation. Studies based on this biomarker revealed an additional facet of the endothelial dysfunction-diabetes link . In the current issue of the journal, Halimi et al.  in the Data from an Epidemiological Study on the Insulin Resistance syndrome (DESIR) study offer a new, well calibrated analysis of this association accounting for sex, lifestyle and other risk factors. In men (but not in women), urinary albumin was related with incident diabetes in a dose-dependent manner. Remarkably, a pronounced increase in the risk of diabetes was evident in the ‘normal range’ of albuminuria because individuals with a urine albumin concentration between 9 and 12 mg/l had an 81% excess probability of developing the disease as compared with the reference category (< 9 mg/l). Furthermore, the relationship held true after adjustments for BMI, sporting activity, diet, smoking, waist circumference, insulin and insulin sensitivity, lipids, family history of diabetes and CRP. Changes in body weight, glucose and insulin sensitivity over time did not modify the strength of this association. Thus DESIR, a study based on a measure of endothelial dysfunction at renal level, fully confirms the predictive value of albuminuria for diabetes and supports the contention that such a relationship most likely underlies a causal link. Even though the possibility of residual confounding in epidemiologic studies should never be overlooked (see below), these data as well as previous studies based on biomarkers of endothelial activation  or on the vasodilatory response to acetylcholine  coherently show that the endothelial function–diabetes link is largely independent of inflammation (as assessed by CRP) as well as baseline and evolving insulin sensitivity. Halimi et al.  cautiously speculate that adiponectin deficiency, an endothelial protective factor with insulin-sensitizing property, may explain why a high albumin excretion rate is so strongly associated with incident diabetes. Albuminuria is a hallmark in the adiponectin gene knockout mice, and this alteration is inversely associated with plasma adiponectin  in obese African–Americans, a population characterized by a high risk for diabetes.
Where do we go from here?
Preventing or retarding diabetes and its devastating sequelae is a major clinical and public health issue. Therefore, the identification of mediators of endothelial dysfunction that play a causal role in the pathogenesis of diabetes is of primary relevance. Endothelial dysfunction is a phenotype influenced by the full series of Framingham risk factors  and a variety of nontraditional risk factors such as mild anemia , vitamin D deficiency , air pollution , depression  and socio-economic status. Thus, confounding in studies testing the effect of endothelial dysfunction on the incidence rate of diabetes is a real possibility. Even extensive multivariate analyses such as those performed in the study by Halimi et al.  and in other recent studies may be insufficient to protect from such a problem. Mendelian randomization  may represent an interesting option to further explore the nature of this association. This approach holds that, because the assortment of genes at conception is a random process, the genetic component of variation in a given risk factor is unlikely to be affected by confounding and reverse causation, whereas these may still have an obvious influence on the variation depending on environmental influences. In other words, if the association between a modifiable risk factor (endothelial function in our case) and disease is causal, genetic variants associated with this risk factor (gene polymorphisms) should be related to the occurrence of disease (diabetes) to the extent predicted by the magnitude of its association with the risk factor (biomarkers, hemodynamic tests of endothelial function). Associations of polymorphisms in the endothelial nitric oxide synthase gene with diabetes have already been reported [34,35], but publication bias and other methodological problems still leave the question open. Large-scale genetic association studies using tagging polymorphisms represent a valid possibility for testing the hypothesis better . However, these studies demand sample sizes well beyond those performed so far.
Mendelian randomization apart, circumstantial evidence gathered in clinical studies seems to support a causal role of endothelial dysfunction in diabetes. Drugs exerting beneficial effects on endothelial function also reduce insulin resistance and the risk of diabetes. Insulin sensitization by metformin not only corrects hyperglycemia in diabetic patients but also prevents the very occurrence of diabetes . Intriguingly, this drug also lowers circulating E-selectin levels and increases endothelium-dependent vasodilatation in type-2 diabetic patients . Two major classes of drugs such as statins and angiotensin-converting enzyme (ACE) inhibitors that ameliorate endothelial dysfunction  also reduce the risk of incident diabetes by about 30% [39,40]. However, whether improving endothelial dysfunction by statins or ACE inhibitors or other medications may actually prevent type-2 diabetes remains to be confirmed in specifically designed clinical trials. Well planned intervention studies contemplating validated measures of endothelial function will solve this fascinating scientific dilemma and will hopefully serve to improve public health policies aimed at controlling the much concerning diabetes epidemic.
1 Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet
2 Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, et al
. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358:2545–2559.
3 Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, et al
. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358:2560–2572.
4 Kahn R, Buse J, Ferrannini E, Stern M. The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2005; 28:2289–2304.
5 Reaven GM. Role of insulin resistance in human disease (syndrome X): an expanded definition. Annu Rev Med 1993; 44:121–131.
6 Pinkney JH, Stehouwer CD, Coppack SW, Yudkin JS. Endothelial dysfunction: cause of the insulin resistance syndrome. Diabetes 1997; 46(Suppl 2):S9–S13.
7 Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron AD. Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J Clin Invest 1996; 97:2601–2610.
8 Brunner H, Cockcroft JR, Deanfield J, Donald A, Ferrannini E, Halcox J, et al
. Endothelial function and dysfunction. Part II: association with cardiovascular risk factors and diseases. A statement by the Working Group on Endothelins and Endothelial Factors of the European Society of Hypertension. J Hypertens 2005; 23:233–246.
9 Hingorani AD, Cross J, Kharbanda RK, Mullen MJ, Bhagat K, Taylor M, et al
. Acute systemic inflammation impairs endothelium-dependent dilatation in humans. Circulation 2000; 102:994–999.
10 Vita JA, Keaney JF Jr, Larson MG, Keyes MJ, Massaro JM, Lipinska I, et al
. Brachial artery vasodilator function and systemic inflammation in the Framingham Offspring Study. Circulation 2004; 110:3604–3609.
11 Hu FB, Meigs JB, Li TY, Rifai N, Manson JE. Inflammatory markers and risk of developing type 2 diabetes in women. Diabetes 2004; 53:693–700.
12 Stolk RP, van Splunder I, Schouten JS, Witteman JC, Hofman A, Grobbee DE. High blood pressure and the incidence of noninsulin dependent diabetes mellitus: findings in a 11.5 year follow-up study in The Netherlands. Eur J Epidemiol 1993; 9:134–139.
13 Gress TW, Nieto FJ, Shahar E, Wofford MR, Brancati FL. Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus. Atherosclerosis Risk in Communities Study. N Engl J Med 2000; 342:905–912.
14 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.
15 Meisinger C, Doring A, Heier M. Blood pressure and risk of type 2 diabetes mellitus in men and women from the general population: the Monitoring Trends and Determinants on Cardiovascular Diseases/Cooperative Health Research in the Region of Augsburg Cohort Study. J Hypertens 2008; 26:1809–1815.
16 Ferrannini E, Buzzigoli G, Bonadonna R, Giorico MA, Oleggini M, Graziadei L, et al
. Insulin resistance in essential hypertension. N Engl J Med 1987; 317:350–357.
17 Meigs JB, Hu FB, Rifai N, Manson JE. Biomarkers of endothelial dysfunction and risk of type 2 diabetes mellitus. JAMA 2004; 291:1978–1986.
18 Thorand B, Baumert J, Chambless L, Meisinger C, Kolb H, Doring A, et al
. Elevated markers of endothelial dysfunction predict type 2 diabetes mellitus in middle-aged men and women from the general population. Arterioscler Thromb Vasc Biol 2006; 26:398–405.
19 Rossi R, Cioni E, Nuzzo A, Origliani G, Modena MG. Endothelial-dependent vasodilation and incidence of type 2 diabetes in a population of healthy postmenopausal women. Diabetes Care 2005; 28:702–707.
20 Perticone F, Maio R, Sciacqua A, Andreozzi F, Iemma G, Perticone M, et al
. Endothelial dysfunction and C-reactive protein are risk factors for diabetes in essential hypertension. Diabetes 2008; 57:167–171.
21 Serne EH, IJzerman RG, Gans RO, Nijveldt R, De Vries G, Evertz R, et al
. Direct evidence for insulin-induced capillary recruitment in skin of healthy subjects during physiological hyperinsulinemia. Diabetes 2002; 51:1515–1522.
22 Bonadonna RC, Saccomani MP, Del PS, Bonora E, DeFronzo RA, Cobelli C. Role of tissue-specific blood flow and tissue recruitment in insulin-mediated glucose uptake of human skeletal muscle. Circulation 1998; 98:234–241.
23 Miles PD, Levisetti M, Reichart D, Khoursheed M, Moossa AR, Olefsky JM. Kinetics of insulin action in vivo. Identification of rate-limiting steps. Diabetes 1995; 44:947–953.
24 Serne EH, Stehouwer CD, ter Maaten JC, ter Wee PM, Rauwerda JA, Donker AJ, et al
. Microvascular function relates to insulin sensitivity and blood pressure in normal subjects. Circulation 1999; 99:896–902.
25 Duplain H, Burcelin R, Sartori C, Cook S, Egli M, Lepori M, et al
. Insulin resistance, hyperlipidemia, and hypertension in mice lacking endothelial nitric oxide synthase. Circulation 2001; 104:342–345.
26 Brantsma AH, Bakker SJ, Hillege HL, de Zeeuw D, de Jong PE, Gansevoort RT. Urinary albumin excretion and its relation with C-reactive protein and the metabolic syndrome in the prediction of type 2 diabetes. Diabetes Care 2005; 28:2525–2530.
27 Halimi JM, Bonnet F, Céline L, Balkau B, Tichet J, Marre M. Urinary albumin excretion is a risk factor for diabetes mellitus in men, independently of initial metabolic profile and development of insulin resistance. The D. E. S. I. R Study. J Hypertens 2008; 26:2198–2206.
28 Sharma K, Ramachandrarao S, Qiu G, Usui HK, Zhu Y, Dunn SR, et al
. Adiponectin regulates albuminuria and podocyte function in mice. J Clin Invest 2008; 118:1645–1656.
29 Natali A, Toschi E, Baldeweg S, Casolaro A, Baldi S, Sironi AM, et al
. Haematocrit, type 2 diabetes, and endothelium-dependent vasodilatation of resistance vessels. Eur Heart J 2005; 26:464–471.
30 London GM, Guerin AP, Verbeke FH, Pannier B, Boutouyrie P, Marchais SJ, et al
. Mineral metabolism and arterial functions in end-stage renal disease: potential role of 25-hydroxyvitamin D deficiency. J Am Soc Nephrol 2007; 18:613–620.
31 Mills NL, Tornqvist H, Robinson SD, Gonzalez M, Darnley K, Macnee W, et al
. Diesel exhaust inhalation causes vascular dysfunction and impaired endogenous fibrinolysis. Circulation 2005; 112:3930–3936.
32 Broadley AJ, Korszun A, Jones CJ, Frenneaux MP. Arterial endothelial function is impaired in treated depression. Heart 2002; 88:521–523.
33 Davey Smith G, Ebrahim S, Lewis S, Hansell AL, Palmer LJ, Burton PR. Genetic epidemiology and public health: hope, hype, and future prospects. Lancet 2005; 366:1484–1498.
34 Ohtoshi K, Yamasaki Y, Gorogawa S, Hayaishi-Okano R, Node K, Matsuhisa M, et al
. Association of (−)786T-C mutation of endothelial nitric oxide synthase gene with insulin resistance. Diabetologia 2002; 45:1594–1601.
35 Monti LD, Barlassina C, Citterio L, Galluccio E, Berzuini C, Setola E, et al
. Endothelial nitric oxide synthase polymorphisms are associated with type 2 diabetes and the insulin resistance syndrome. Diabetes 2003; 52:1270–1275.
36 Casas JP, Cavalleri GL, Bautista LE, Smeeth L, Humphries SE, Hingorani AD. Endothelial nitric oxide synthase gene polymorphisms and cardiovascular disease: a HuGE review. Am J Epidemiol 2006; 164:921–935.
37 Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al
. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346:393–403.
38 Mather KJ, Verma S, Anderson TJ. Improved endothelial function with metformin in type 2 diabetes mellitus. J Am Coll Cardiol 2001; 37:1344–1350.
39 Freeman DJ, Norrie J, Sattar N, Neely RD, Cobbe SM, Ford I, et al
. 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.
40 Yusuf S, Gerstein H, Hoogwerf B, Pogue J, Bosch J, Wolffenbuttel BH, et al
. Ramipril and the development of diabetes. JAMA 2001; 286:1882–1885.