Generalized impairment of vasodilator reactivity during hyperinsulinemia in patients with obesity-related metabolic syndrome

Defective insulin-dependent vasodilation might contribute importantly to metabolic and vascular abnormalities of the metabolic syndrome (MetS). However, despite extensive investigation, the precise mechanisms involved in insulin's vasoactive effects have not been fully elucidated. Therefore, this study sought to better characterize insulin's physiological actions on vascular reactivity and their potential derangement in the MetS. Forearm blood flow responses to graded doses of acetylcholine, sodium nitroprusside, and verapamil were assessed by strain-gauge plethysmography in patients with obesity-related MetS ( n = 20) and in matched controls ( n = 18) before and after intra-arterial infusion of insulin (0.2 mU·kg−1·min−1). Possible involvement of increased oxidative stress in the impaired insulin-stimulated vasodilator responsiveness of patients with MetS ( n = 12) was also investigated using vitamin C (25 mg/min). In control subjects, significant potentiation of the vasodilator responses to acetylcholine, nitroprusside, and verapamil was observed after insulin infusion (all P < 0.05). However, no significant change in vasodilator reactivity to either of these drugs was observed following hyperinsulinemia in patients with MetS (all P > 0.05). Interestingly, administration of vitamin C to patients with MetS during hyperinsulinemia significantly enhanced the vasodilator responsiveness to acetylcholine, nitroprusside, and verapamil (all P < 0.05 vs. hyperinsulinemia alone). In conclusion, insulin exerts a generalized facilitatory action on vasodilator reactivity, and this effect is impaired in patients with MetS likely because of increased oxidative stress. Given the importance of vasodilator reactivity in affecting glucose disposal and vascular homeostasis, this defect may then contribute to the development of metabolic and vascular complications in insulin-resistant states.

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Rho-kinase inhibition improves vasodilator responsiveness during hyperinsulinemia in the metabolic syndrome

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00206.2012 ◽

2012 ◽

Vol 303 (6) ◽

pp. E806-E811 ◽

Cited By ~ 12

Author(s):

Francesca Schinzari ◽

Manfredi Tesauro ◽

Valentina Rovella ◽

Nicola Di Daniele ◽

Paolo Gentileschi ◽

...

Keyword(s):

Oxidative Stress ◽

Metabolic Syndrome ◽

Vitamin C ◽

Insulin Infusion ◽

Rho Kinase ◽

Facilitatory Effect ◽

The Metabolic Syndrome ◽

Before And After ◽

Forearm Circulation ◽

Rock Inhibition

In patients with the metabolic syndrome (MetS), the facilitatory effect of insulin on forearm vasodilator responsiveness to different stimuli is impaired. Whether the RhoA/Rho kinase (ROCK) pathway is involved in this abnormality is unknown. We tested the hypotheses that, in MetS patients, ROCK inhibition with fasudil restores insulin-stimulated vasodilator reactivity and that oxidative stress plays a role in this mechanism. Endothelium-dependent and -independent forearm blood flow responses to acetylcholine (ACh) and sodium nitroprusside (SNP), respectively, were assessed in MetS patients ( n = 8) and healthy controls ( n = 5) before and after the addition of fasudil (200 μg/min) to an intra-arterial infusion of insulin (0.1 mU/kg/min). In MetS patients ( n = 5), fasudil was also infused without hyperinsulinemia. The possible involvement of oxidative stress in the effect of fasudil during hyperinsulinemia was investigated in MetS patients ( n = 5) by infusing vitamin C (25 mg/min). In MetS patients, compared with saline, fasudil enhanced endothelium-dependent and -independent vasodilator responses during insulin infusion ( P < 0.001 and P = 0.008, respectively), but not in the absence of hyperinsulinemia ( P = 0.25 and P = 0.13, respectively). By contrast, fasudil did not affect vasoreactivity to ACh and SNP during hyperinsulinemia in controls ( P = 0.11 and P = 0.56, respectively). In MetS patients, fasudil added to insulin and vitamin C did not further enhance vasodilation to ACh and SNP ( P = 0.15 and P = 0.43, respectively). In the forearm circulation of patients with the MetS, ROCK inhibition by fasudil improves endothelium-dependent and -independent vasodilator responsiveness during hyperinsulinemia; increased oxidative stress seems to be involved in the pathophysiology of this phenomenon.

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The Metabolic Syndrome: Requiescat in Pace

Clinical Chemistry ◽

10.1373/clinchem.2005.048611 ◽

2005 ◽

Vol 51 (6) ◽

pp. 931-938 ◽

Cited By ~ 259

Author(s):

Gerald M Reaven

Keyword(s):

Insulin Resistance ◽

Metabolic Syndrome ◽

Diagnostic Category ◽

Lifestyle Changes ◽

Glucose Disposal ◽

Healthy Population ◽

Insulin Resistant ◽

The Metabolic Syndrome ◽

Increased Risk ◽

Apparently Healthy

Abstract Values for insulin-mediated glucose disposal vary continuously throughout a population of apparently healthy individuals, with at least a sixfold variation between the most insulin sensitive and most insulin resistant of these individuals. The more insulin resistant a person, the more insulin must be secreted to prevent decompensation of glucose tolerance. Insulin resistance is not a disease, but a description of a physiologic state, and approximately one third of an apparently healthy population is sufficiently insulin resistant to be at increased risk to develop a cluster of abnormalities and related clinical syndromes. The primary value of the concept of insulin resistance is that it provides a conceptual framework with which to place a substantial number of apparently unrelated biological events into a pathophysiological construct. In contrast, the metabolic syndrome was introduced as a diagnostic category to identify individuals that satisfy three of five relatively arbitrarily chosen criteria to initiate lifestyle changes with the goal of decreasing risk of cardiovascular disease. Consequently, the value of the notion of the metabolic syndrome must be considered not in pathophysiologic terms, but as a pragmatic approach to obtain a better clinical outcome. In this review, an effort is made to critically evaluate the concept of the metabolic syndrome, the criteria chosen to identify individuals with the syndrome, and the clinical utility of making, or not making, a diagnosis of the metabolic syndrome.

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Telomere Length and Oxidative Stress and Its Relation with Metabolic Syndrome Components in the Aging

Biology ◽

10.3390/biology10040253 ◽

2021 ◽

Vol 10 (4) ◽

pp. 253

Author(s):

Graciela Gavia-García ◽

Juana Rosado-Pérez ◽

Taide Laurita Arista-Ugalde ◽

Itzen Aguiñiga-Sánchez ◽

Edelmiro Santiago-Osorio ◽

...

Keyword(s):

Oxidative Stress ◽

Metabolic Syndrome ◽

Telomere Length ◽

Scientific Evidence ◽

Telomeric Dna ◽

Biochemical Alterations ◽

The Metabolic Syndrome ◽

Age Related ◽

And Function

A great amount of scientific evidence supports that Oxidative Stress (OxS) can contribute to telomeric attrition and also plays an important role in the development of certain age-related diseases, among them the metabolic syndrome (MetS), which is characterised by clinical and biochemical alterations such as obesity, dyslipidaemia, arterial hypertension, hyperglycaemia, and insulin resistance, all of which are considered as risk factors for type 2 diabetes mellitus (T2DM) and cardiovascular diseases, which are associated in turn with an increase of OxS. In this sense, we review scientific evidence that supports the association between OxS with telomere length (TL) dynamics and the relationship with MetS components in aging. It was analysed whether each MetS component affects the telomere length separately or if they all affect it together. Likewise, this review provides a summary of the structure and function of telomeres and telomerase, the mechanisms of telomeric DNA repair, how telomere length may influence the fate of cells or be linked to inflammation and the development of age-related diseases, and finally, how the lifestyles can affect telomere length.

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Weight loss is associated with improved endothelial dysfunction via NOX2-generated oxidative stress down-regulation in patients with the metabolic syndrome

Internal and Emergency Medicine ◽

10.1007/s11739-011-0591-x ◽

2011 ◽

Vol 7 (3) ◽

pp. 219-227 ◽

Cited By ~ 31

Author(s):

Francesco Angelico ◽

Lorenzo Loffredo ◽

Pasquale Pignatelli ◽

Teresa Augelletti ◽

Roberto Carnevale ◽

...

Keyword(s):

Oxidative Stress ◽

Metabolic Syndrome ◽

Weight Loss ◽

Endothelial Dysfunction ◽

Down Regulation ◽

The Metabolic Syndrome

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Effect of High Dose Vitamin C Supplementation on Muscle Soreness, Damage, Function, and Oxidative Stress to Eccentric Exercise

International Journal of Sport Nutrition and Exercise Metabolism ◽

10.1123/ijsnem.16.3.270 ◽

2006 ◽

Vol 16 (3) ◽

pp. 270-280 ◽

Cited By ~ 65

Author(s):

S.C. Bryer ◽

A.H. Goldfarb

Keyword(s):

Oxidative Stress ◽

Vitamin C ◽

Eccentric Exercise ◽

Muscle Function ◽

Muscle Soreness ◽

Damage Function ◽

High Dose ◽

Before And After ◽

Vitamin C Supplementation ◽

Glutathione Oxidation

This study investigated if vitamin C supplementation before and after eccentric exercise could reduce muscle soreness (MS), oxidative stress, and muscle function. Eighteen healthy men randomly assigned to either a placebo (P) or vitamin C (VC) (3 g/d) treatment group took pills for 2 wk prior and 4 d after performing 70 eccentric elbow extensions with their non-dominant arm. MS increased in both groups with significantly reduced MS for the first 24 h with VC. Range of motion was reduced equally in both groups after the exercise (P ≥ 0.05). Muscle force declined equally and was unaffected by treatment. VC attenuated the creatine kinase (CK) increase at 48 h after exercise with similar CK after this time. Gluta-thione ratio (oxidized glutathione/total glutathione) was significantly increased at 4 and 24 h with P but VC prevented this change. These data suggest that vitamin C pretreatment can reduce MS, delay CK increase, and prevent blood glutathione oxidation with little influence on muscle function loss.

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Abstract 3672: Loss of Perivascular Adipocyte Paracrine Function Leads to Increased Vascular Tone and Glucose Intolerance in Hypertension

Circulation ◽

10.1161/circ.118.suppl_18.s_463-b ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Kaivan Khavandi ◽

Adam Greenstein ◽

Sarah Withers ◽

Kazuhiko Sonoyama ◽

Sarah Lewis ◽

...

Keyword(s):

Oxidative Stress ◽

Metabolic Syndrome ◽

Adipose Tissue ◽

Vascular Tone ◽

Tnf Alpha ◽

Perivascular Adipose Tissue ◽

The Metabolic Syndrome ◽

Adipocyte Cell ◽

Therapeutic Opportunity

In order to investigate the contribution of perivascular adipose tissue (PVAT) to arterial function, a total of 55 small arteries harvested from 35 skin biopsies of patients with Metabolic Syndrome and matched controls were mounted as ring preparations in a wire myograph. Contractility to cumulative doses of Norepinephrine in the presence or absence of PVAT showed an anticontractile effect in arteries from healthy volunteers (p=0.009), which was lost in patients with Metabolic Syndrome. Bioassay studies confirmed that PVAT releases a hydrophilic anticontractile factor in health, which is absent in obesity. Using a soluble fragment of the human Type 1 receptor, we identified that the anticontractile factor was adiponectin, which is the sole mediator of vasodilation, acting by increasing endothelial bioavailability of nitric oxide. Significant endothelial dysfunction was observed in patients with Metabolic Syndrome (p<0.001). Quantitative image analysis of adipose tissue revealed significantly increased adipocyte cell size in patients with Metabolic Syndrome, compared with healthy controls (p<0.006). There was immunohistochemical evidence of inflammation with upregulation of TNF-alpha receptor 1 in these patients (p<0.001). Application of exogenous TNF-alpha abolished the anticontractile effect of PVAT by reducing adiponectin bioavailability. Oxidative stress also induced by cytokines TNF-alpha and IL-6 but not IL-1, reduced adiponectin production from PVAT and increased basal tone. When the obese microenvironment was replicated in vitro by inflicting hypoxia on PVAT, adiponectin activity was lost but then rescued by incubation with cytokine antagonists. Further application of the adiponectin receptor fragment abolished PVAT relaxation. We conclude that in healthy arteries, PVAT releases adiponectin which reduces vascular tone. In obesity, this is lost by a cascade of adipocyte hypertrophy, hypoxia, inflammation and oxidative stress. The resulting vasoconstriction contributes to hypertension, hypertriglyceridaemia and insulin resistance. Direct targeting of adiponectin release from PVAT therefore provides a novel therapeutic opportunity in the Metabolic Syndrome.

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Abstract P033: Relationship Between Adiponectin Level and Metabolic Syndrome after Weight Loss in Patients with Abdominal Obesity

Circulation ◽

10.1161/circ.127.suppl_12.ap033 ◽

2013 ◽

Vol 127 (suppl_12) ◽

Author(s):

Aelita Berezina ◽

Olga Belyaeva ◽

Olga Berkovich ◽

Elena Baranova ◽

Tatyina Karonova

Keyword(s):

Metabolic Syndrome ◽

Weight Loss ◽

Abdominal Obesity ◽

Metabolic Disorders ◽

Intervention Program ◽

Adiponectin Level ◽

The Metabolic Syndrome ◽

Outpatient Intervention ◽

Before And After ◽

The Relationship

Objective: to investigate the relationship between adiponectin level and metabolic syndrome (MS) after weight loss in patients with abdominal obesity (AO). Method: A 3-year randomized lifestyle intervention trial performed in 153 patients with AO, age 43,2±0,8 yrs, BMI 32,1±1,9 kg/m 2 . 74 patients keep hypocaloric diet (gr.1), 79 patients keep diet and performed aerobic exercise (gr.2). Adiponectin concentration, body mass (BM), waist circumference (WC), body fat (BF), BMI, the levels of BP, glucose, insulin, HOMA-IR, TC, HDL-C, LDL-C, TG, CRP were measured before and after a 3-years outpatient intervention program. Results. 100% patients with AO had some metabolic disorders and 38% had MS before the treatment. The adiponectin levels and others parameters didn’t differ between the groups before intervention (p>0,05). In 3 years 53 (71,6%) and 58 (73,4%) patients from 1 and 2 groups reduced weight. The rate of improving BM, BMI, BF, WC, HDL-C, TG and insulin was grater in patients gr.2 (p<0,05). The favorable dynamics of MS (MS didn’t appeared at the end of study or didn’t registered in patients who had it before) didn’t differ between the groups 1 and 2 (81,1% and 91,4%, p>0,05). The increasing of adiponectin level occurred more often in patients gr.2, than gr.1 (93,1% and 58,5%, p=0,001, respectively). Adiponectin level increased only in patients gr.2 (18,0±1,1mcg/ml and 23,8±1,3 mcg/ml, p= [[Unable to Display Character: р]]=0,0001), didn’t changed in gr.1 (p>0,05). It was established that in patients with combination of weight loss and increasing of adiponectin level favorable dynamics of MS occurred more often than in patients who lost weight without increasing of adiponectin level (91,7% and 69,2%, p=0,0001). In patients with favorable dynamics of MS increasing of adiponectin level had met more often, than in patients with unfavorable dynamics of MS (MS continued or appeared) (88,6% and 11,4%, p=0,0001). Increasing of adiponectin level associated with positive dynamics of the MS - OR=9,1 (4,0-20,6). Conclusion. Combination of weight loss and increasing of adiponectin level associated with favorable dynamics of the metabolic syndrome.

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Female offspring born to obese and insulin-resistant dams are not at increased risk for obesity and metabolic dysfunction during early development

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2017-0371 ◽

2018 ◽

Vol 96 (1) ◽

pp. 97-102 ◽

Cited By ~ 1

Author(s):

Hanin Aburasayn ◽

Rami Al Batran ◽

Keshav Gopal ◽

Malak Almutairi ◽

Amina Eshreif ◽

...

Keyword(s):

Insulin Resistance ◽

Metabolic Syndrome ◽

Female Offspring ◽

Metabolic Dysfunction ◽

Insulin Resistant ◽

The Metabolic Syndrome ◽

Rate Versus ◽

Increased Risk ◽

Study Completion ◽

Reduced Rate

The percentage of women who are obese at the time of conception or during pregnancy is increasing, with animal and human studies demonstrating that offspring born to obese dams or mothers are at increased risk for obesity and the metabolic syndrome. Our goal was to confirm in an experimental model of metabolic syndrome in the dam, whether the offspring would be at increased risk of obesity. Conversely, we observed that male offspring born to dams with metabolic syndrome had no alterations in their body mass profiles, whereas female offspring born to dams with metabolic syndrome were heavier at weaning, but exhibited no perturbations in energy metabolism. Moreover, they gained weight at a reduced rate versus female offspring born to healthy dams, and thus weighed less at study completion. Hence, our findings suggest that factors other than increased adiposity and insulin resistance during pregnancy are responsible for the increased risk of obesity in children born to obese mothers.

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