Vascular function in Type 2 diabetes mellitus and pre-diabetes: the case for intrinsic endotheliopathy

Tooke, JE; Goh, K.L.

doi:10.1046/j.1464-5491.1999.00099.x

Cited by 54 publications

(46 citation statements)

References 57 publications

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“…Our data suggest that an endothelial disruption caused by dexamethasone treatment inactivates the NO synthase that has an important role in this newly described animal model of insulin resistance and metabolic syndrome. Insulin resistance, before the development of type 2 diabetes and/or hypertension, may cause endothelial dysfunction with a key role in the pathogenesis of vascular complications (8,33). Metformin is able to increase peripheral insulin sensitivity and insulin-mediated glucose uptake in the cells, increasing insulininduced translation of GLUT4 from an intracellular pool to the plasma membrane and increasing the functional activity of the glucose carrier without altering the de novo synthesis of the glucose carrier both in vivo (15) and in vitro (15).…”

Section: Discussionmentioning

confidence: 99%

Low-dose dexamethasone in the rat: a model to study insulin resistance

Severino

Brizzi

Solinas

et al. 2002

American Journal of Physiology-Endocrinology and Metabolism

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The main aim of this study was to set up a new animal model to study insulin resistance. Wistar rats (6 or 7 per group) received the following for 4 wk in experiment 1: 1) vehicle, 2) 2 g/day subcutaneous dexamethasone, 3) metformin (400 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 os), and 4) dexamethasone plus metformin. In experiment 2 the rats received the following: 1) vehicle, 2) dexamethasone, 3) dexamethasone plus arginine (2%; as substrate of the nitric oxide synthase for nitric oxide production) in tap water, and 4) dexamethasone plus isosorbide dinitrate (70 mg/kg; as direct nitric oxide donor) in tap water. Insulin sensitivity was significantly reduced by dexamethasone already at week 1, before the increase in blood pressure (day 15) and without significant changes in body weight compared with vehicle. Dexamethasone-treated rats had significantly higher triglycerides, hematocrit, and insulin, whereas serum total nitrates/ nitrites were lower compared with vehicle. The concomitant treatment with metformin minimized all the described effects of dexamethasone. In experiment 2, only isosorbide dinitrate was able to prevent the observed dexamethasoneinduced metabolic, hemodynamic, and insulin sensitivity changes. Chronic low-dose subcutaneous dexamethasone (2 g/ day) is a useful model to study the relationships between insulin resistance and blood pressure in the rat, and dexamethasone might decrease insulin sensitivity and increase blood pressure through an endothelium-mediated mechanism.glucocorticoids; metabolic syndrome; metformin; hypertension THERE IS CONSIDERABLE evidence that abnormalities of glucose, insulin, and lipoprotein metabolism occur more frequently in untreated hypertensive patients than in normotensive subjects. It could be argued that the relationship between high blood pressure and metabolic disorder is incidental, but, on the other hand, there is evidence that changes in glucose, insulin, and lipoprotein metabolism play a role in the etiopathology and/or clinical course of hypertension. In human hypertension, subtle changes in adrenal steroid metabolism have been suggested (28,29,36), indicating that glucocorticoids, besides the well-known Cushing syndrome, might have an important role in the development of high blood pressure. Moreover, glucocorticoids have been shown to reduce cellular glucose uptake affecting the glucose transport system per se (7), with no direct effects on the insulin receptor (26). Thus glucocorticoids alter glucose metabolism, and in turn they have a role in the development of peripheral insulin resistance. Insulin resistance may be an impetus for the development of hypertension, impaired carbohydrate tolerance, and lipid alteration, but the underlying mechanisms are still unclear. Similar metabolic abnormalities occur in rodent models of hypertension. For example, endothelial dysfunction precedes hypertension in an experimental model of fructose-induced insulin resistance (9, 24), but fructoseinduced insulin resistance is not easily comparable to humans. At the best of our knowledge,...

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Section: Discussionmentioning

confidence: 99%

Low-dose dexamethasone in the rat: a model to study insulin resistance

Severino

Brizzi

Solinas

et al. 2002

American Journal of Physiology-Endocrinology and Metabolism

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“…The effect was reduced by benfotiamine; the corresponding changes were 7.35 Ϯ 0.41 (baseline), 8.62 Ϯ 0.66 (2 h) (P Ͻ 0.05 vs. baseline; P Ͻ 0.05 vs. HAGE), 6.37 Ϯ 0.46 (4 h), and 6.12 Ϯ 0.31 nmol/ml (6 h) . All fasting parameters (FMD, reactive hyperemia, E-selectin, ICAM-1, VCAM-1, CRP, fibrinogen, CML, MG, and TBARS) were comparable between study days.…”

Section: Change In Reactive Hyperemia Following Hage (E) and Hageϩbt mentioning

confidence: 93%

Benfotiamine Prevents Macro- and Microvascular Endothelial Dysfunction and Oxidative Stress Following a Meal Rich in Advanced Glycation End Products in Individuals With Type 2 Diabetes

et al. 2006

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OBJECTIVE -Diabetes is characterized by marked postprandial endothelial dysfunction induced by hyperglycemia, hypertriglyceridemia, advanced glycation end products (AGEs), and dicarbonyls (e.g., methylglyoxal [MG]). In vitro hyperglycemia-induced MG formation and endothelial dysfunction could be blocked by benfotiamine, but in vivo effects of benfotiamine on postprandial endothelial dysfunction and MG synthesis have not been investigated in humans until now.RESEARCH DESIGN AND METHODS -Thirteen people with type 2 diabetes were given a heat-processed test meal with a high AGE content (HAGE; 15.100 AGE kU, 580 kcal, 54 g protein, 17 g lipids, and 48 g carbohydrates) before and after a 3-day therapy with benfotiamine (1,050 mg/day). Macrovascular flow-mediated dilatation (FMD) and microvascular reactive hyperemia, along with serum markers of endothelial disfunction (E-selectin, vascular cell adhesion molecule-1, and intracellular adhesion molecule-1), oxidative stress, AGE, and MG were measured during both test meal days after an overnight fast and then at 2, 4, and 6 h postprandially.RESULTS -The HAGE induced a maximum reactive hyperemia decrease of Ϫ60.0% after 2 h and a maximum FMD impairment of Ϫ35.1% after 4 h, without affecting endotheliumindependent vasodilatation. The effects of HAGE on both FMD and reactive hyperemia were completely prevented by benfotiamine. Serum markers of endothelial dysfunction and oxidative stress, as well as AGE, increased after HAGE. These effects were significantly reduced by benfotiamine.CONCLUSIONS -Our study confirms micro-and macrovascular endothelial dysfunction accompanied by increased oxidative stress following a real-life, heat-processed, AGE-rich meal in individuals with type 2 diabetes and suggests benfotiamine as a potential treatment. Diabetes Care 29:2064 -2071, 2006E ndothelial dysfunction is an early marker of atherosclerosis and accompanies states showing a high cardiovascular risk, such as smoking (1), dyslipidemia (2), arterial hypertension (3), obesity (4), coronary artery disease (5), congestive heart failure (6), and type 1 (7) and type 2 (8) diabetes. Postprandial endothelial dysfunction has been proposed as the link between postprandial dysmetabolism and atherosclerosis (9) and occurs not only in patients with cardiovascular disease (10) or diabetes (11) but even in healthy subjects (12). Distinctive and cumulative (11) effects of hyperglycemia (13) and hypertriglyceridemia (14) on postprandial endothelial dysfunction have been shown. Since the postprandial state covers most of our daytime, interventions aimed at reducing postprandial endothelial dysfunction might play a decisive role in prevention of atherosclerosis. Several therapeutic approaches have been suggested for the treatment of postprandial endothelial dysfunction, including insulin, folic acid, tetrahydrobiopterin, vitamins C and E, and statins (11). These approaches aim at reducing postprandial oxidative stress (vitamins C and E, statins, and partly folic acid), postprandial hyperglycemia (insul...

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“…In type 2 diabetes, in contrast, the impairment is evident at diagnosis, which has fuelled the hypothesis that microvascular functional abnormalities may precede the development of hyperglycaemia. In support of this hypothesis, reduced vasodilatory capacity has been demonstrated in subjects with impaired glucose tolerance in the forearm vasculature [5], and in the forearm skin microcirculation and brachial arteries of subjects with fasting hyperglycaemia [6]. In one study of 24 subjects with fasting hyperglycaemia, maximum microvascular vasodilatory capacity (MMVC) was also shown to be inversely correlated with fasting insulin levels [7].…”

Section: Introductionmentioning

confidence: 98%

“…The concept that endothelial dysfunction may precede glucose intolerance in predisposed individuals is supported by the observations that endothelial dysfunction occurs in association with other elements of the insulin resistance syndrome [9]such as hypertension [10]and dyslipidaemia [11]or its precursor state of low birth weight for gestational age [12, 13]. Such observations have led some authors to propose a causal role for endothelial dysfunction in the generation of the metabolic features of insulin resistance [6, 9], and thence the development of disease states.…”

Section: Introductionmentioning

confidence: 99%

Vascular Function in Women with Previous Gestational Diabetes mellitus

et al. 2002

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It is hypothesised that vascular dysfunction, which characterises type 2 diabetes, may predate development of hyperglycaemia. 17 women with previous gestational diabetes mellitus, and thus at risk of developing type 2 diabetes, were matched with normal controls for body mass index, menstrual phase, smoking, age, blood pressure, and lipid profiles. All had normal glucose tolerance. Tests of microvascular and macrovascular function, including endothelium-dependent and -independent vasodilatation, were performed. Laser Doppler fluximetry of maximum skin microvascular hyperaemia in response to local heating of the dorsum of the foot to 42°C for 30 min was impaired in subjects compared to controls [subjects = 1.15 (0.73–1.73) V median (range) versus controls = 1.50 (0.95–2.29) V, p = 0.008]. There were no differences in laser Doppler perfusion imaging of responses to forearm skin iontophoresis of acetylcholine [subjects = 1.59 (0.32–2.55) V median (range) versus controls = 1.79 (0.72–2.06) V; p = 0.81] and sodium nitroprusside [subjects = 1.39 (0.8–3.14) V versus controls = 1.41 (0.34–2.19) V; p = 0.68], ultrasound estimation of brachial artery flow-mediated dilatation [subjects = 1.65 (–0.5–9.07)% versus controls = 2.77 (0.63–6.6)%; p = 0.42] and glyceryl trinitrate-induced dilatation [subjects = 15.20 (6.64–20.91)% versus controls = 15.92 (3.94–22.09)%; p = 0.48]. Microvascular maximum hyperaemia was impaired in the index group, suggesting the presence of a defect in vascular function. This defect was not explained by those aspects of endothelial function measured by the other techniques.

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Vascular function in Type 2 diabetes mellitus and pre-diabetes: the case for intrinsic endotheliopathy

Cited by 54 publications

References 57 publications

Low-dose dexamethasone in the rat: a model to study insulin resistance

Low-dose dexamethasone in the rat: a model to study insulin resistance

Benfotiamine Prevents Macro- and Microvascular Endothelial Dysfunction and Oxidative Stress Following a Meal Rich in Advanced Glycation End Products in Individuals With Type 2 Diabetes

Vascular Function in Women with Previous Gestational Diabetes mellitus

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