Vascular Dysfunction and Insulin Resistance in Aging

: Insulin was discovered in 1922 by Banting and Best. Since that time, extensive research on the mechanisms of insulin activity and action has continued. Currently, it is known that the role of insulin is much greater than simply regulating carbohydrate metabolism. Insulin in physiological concentration is also necessary to maintain normal vascular function. : Insulin resistance is defined as a pathological condition characterized by reduced sensitivity of skeletal muscles, liver, and adipose tissue, to insulin and its downstream metabolic effects under normal serum glucose concentrations. There are also selective forms of insulin resistance with unique features, including vascular insulin resistance. Insulin resistance, both classical and vascular, contributes to vascular impairment resulting in increased risk of cardiovascular disease. Furthermore, in the elderly population, additional factors including redistribution of fat concentrations, low-grade inflammation, and decreased self-repair capacity [or cell senescence] amplify the vascular abnormalities related to insulin resistance.

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Programming of growth, insulin resistance and vascular dysfunction in offspring of late gestation diabetic rats

Clinical Science ◽

10.1042/cs20080550 ◽

2009 ◽

Vol 117 (3) ◽

pp. 129-138 ◽

Cited By ~ 32

Author(s):

Emily M. Segar ◽

Andrew W. Norris ◽

Jian-Rong Yao ◽

Shanming Hu ◽

Stacia L. Koppenhafer ◽

...

Keyword(s):

Insulin Resistance ◽

Vascular Function ◽

Vascular Dysfunction ◽

Diabetic Rats ◽

Late Gestation ◽

Group Differences ◽

Pregnant Rats ◽

Increased Risk ◽

Specific Insulin ◽

Diabetic Mothers

ODM (offspring of diabetic mothers) have an increased risk of developing metabolic and cardiovascular dysfunction; however, few studies have focused on the susceptibility to disease in offspring of mothers developing diabetes during pregnancy. We developed an animal model of late gestation diabetic pregnancy and characterized metabolic and vascular function in the offspring. Diabetes was induced by streptozotocin (50 mg/kg of body weight, intraperitoneally) in pregnant rats on gestational day 13 and was partially controlled by twice-daily injections of insulin. At 2 months of age, ODM had slightly better glucose tolerance than controls (P<0.05); however, by 6 months of age this trend had reversed. A euglycaemic–hyperinsulinamic clamp revealed insulin resistance in male ODM (P<0.05). In 6–8-month-old female ODM, aortas had significantly enhanced contractility in response to KCl, ET-1 (endothelin-1) and NA (noradrenaline). No differences in responses to ET-1 and NA were apparent with co-administration of L-NNA (NG-nitro-L-arginine). Relaxation in response to ACh (acetylcholine), but not SNP (sodium nitroprusside), was significantly impaired in female ODM. In contrast, males had no between-group differences in response to vasoconstrictors, whereas relaxation to SNP and ACh was greater in ODM compared with control animals. Thus the development of diabetes during pregnancy programmes gender-specific insulin resistance and vascular dysfunction in adult offspring.

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Uremic Sarcopenia and Its Possible Nutritional Approach

Nutrients ◽

10.3390/nu13010147 ◽

2021 ◽

Vol 13 (1) ◽

pp. 147

Author(s):

Annalisa Noce ◽

Giulia Marrone ◽

Eleonora Ottaviani ◽

Cristina Guerriero ◽

Francesca Di Daniele ◽

...

Keyword(s):

Physical Activity ◽

Pathological Condition ◽

Nutritional Therapy ◽

Nutritional Supplement ◽

Low Grade ◽

Inflammatory Status ◽

Protein Energy ◽

Fiber Diet ◽

Increased Risk ◽

Intradialytic Parenteral Nutrition

Uremic sarcopenia is a frequent condition present in chronic kidney disease (CKD) patients and is characterized by reduced muscle mass, muscle strength and physical performance. Uremic sarcopenia is related to an increased risk of hospitalization and all-causes mortality. This pathological condition is caused not only by advanced age but also by others factors typical of CKD patients such as metabolic acidosis, hemodialysis therapy, low-grade inflammatory status and inadequate protein-energy intake. Currently, treatments available to ameliorate uremic sarcopenia include nutritional therapy (oral nutritional supplement, inter/intradialytic parenteral nutrition, enteral nutrition, high protein and fiber diet and percutaneous endoscopic gastrectomy) and a personalized program of physical activity. The aim of this review is to analyze the possible benefits induced by nutritional therapy alone or in combination with a personalized program of physical activity, on onset and/or progression of uremic sarcopenia.

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PCOS without hyperandrogenism is associated with higher plasma Trimethylamine N-oxide levels

BMC Endocrine Disorders ◽

10.1186/s12902-019-0486-9 ◽

2020 ◽

Vol 20 (1) ◽

Cited By ~ 2

Author(s):

Jiayu Huang ◽

Lin Liu ◽

Chunyan Chen ◽

Ying Gao

Keyword(s):

Insulin Resistance ◽

Polycystic Ovary ◽

Predictive Biomarker ◽

Normal Weight ◽

Inflammatory Factors ◽

Low Grade ◽

Model Assessment ◽

Increased Risk ◽

Homeostatic Model Assessment ◽

Low Grade Inflammation

Abstract Background Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder, and its pathogenesis is still under debate. Trimethylamine-N-oxide (TMAO) is a small, organic compound generated by the gut microbiome with a hypothesized relation to insulin resistance (IR) and low-grade inflammation in PCOS. By comparing plasma TMAO levels in non-PCOS participants and PCOS patients without hyperandrogenism (HA), we aimed to determine whether plasma TMAO levels correlate with PCOS without HA and to analyze their relationship with low-grade inflammation and IR. Methods A total of 27 PCOS patients without HA and 23 non-PCOS participants were enrolled in this study and subdivided into “nonobese” and “obese” arms for each group. Levels of plasma TMAO were quantified, and basic clinical characteristics and plasma biomarkers of inflammation were assessed. Results First, plasma TMAO levels, insulin levels and homeostatic model assessment of insulin resistance (HOMA-IR) values were higher in PCOS patients without HA, especially in the obese subgroup. Second, the levels of the inflammatory factors interleukin (IL)-17A, IL-18 and interferon gamma (IFN-γ) were significantly increased in obese PCOS patients without HA. Third, plasma TMAO levels were associated with body mass index (BMI) in the normal-weight groups, and the obese groups had higher fasting plasma insulin (FINS) and HOMA-IR values. Finally, logistic regression showed that the plasma levels of TMAO and luteinizing hormone/follicle-stimulating hormone (LH/FSH) were independent predictors of PCOS and indicated an increased risk of PCOS. Conclusions Elevated plasma TMAO levels may be associated with the pathogenesis of PCOS without HA and correlated with increased systemic inflammation. Further studies are needed to determine the suitability of TMAO as a predictive biomarker and to identify possible therapies for PCOS.

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Defoliation constrains xylem and phloem functionality

Tree Physiology ◽

10.1093/treephys/tpz029 ◽

2019 ◽

Vol 39 (7) ◽

pp. 1099-1108 ◽

Cited By ~ 5

Author(s):

Rachel M Hillabrand ◽

Uwe G Hacke ◽

Victor J Lieffers

Keyword(s):

Vascular Function ◽

Tree Mortality ◽

Vascular Tissue ◽

Vascular Dysfunction ◽

Sieve Tube ◽

Carbon Limitation ◽

Transport Efficiency ◽

Increased Risk ◽

Phloem Fibers ◽

The Stability

AbstractInsect defoliation contributes to tree mortality under drought conditions. Defoliation-induced alterations to the vascular transport structure may increase tree vulnerability to drought; however, this has been rarely studied. To evaluate the response of tree vascular function following defoliation, 2-year-old balsam poplar were manually defoliated, and both physiological and anatomical measurements were made after allowing for re-foliation. Hydraulic conductivity measurements showed that defoliated trees had both increased vulnerability to embolism and decreased water transport efficiency, likely due to misshapen xylem vessels. Anatomical measurements revealed novel insights into defoliation-induced alterations to the phloem. Phloem sieve tube diameter was reduced in the stems of defoliated trees, suggesting reduced transport capability. In addition, phloem fibers were absent, or reduced in number, in stems, shoot tips and petioles of new leaves, potentially reducing the stability of the vascular tissue. Results from this study suggest that the defoliation leads to trees with increased risk for vascular dysfunction and drought-induced mortality through alterations in the vascular structure, and highlights a route through which carbon limitation can influence hydraulic dysfunction.

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Galantamine alleviates oxidative stress alongside anti-inflammatory and cardio-metabolic effects in subjects with the metabolic syndrome in a randomized trial

10.1101/2019.12.30.19016105 ◽

2020 ◽

Author(s):

Carine Teles Sangaleti ◽

Keyla Yukari Katayama ◽

Kátia De Angelis ◽

Tércio Lemos de Moraes ◽

Amanda Aparecida Araújo ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Metabolic Syndrome ◽

Autonomic Regulation ◽

Metabolic Effects ◽

Antioxidant Enzyme Activities ◽

Low Grade ◽

The Metabolic Syndrome ◽

Inflammatory State ◽

Anti Inflammatory

AbstractBackgroundThe metabolic syndrome (MetS) is an obesity-driven disorder with pandemic proportions and limited treatment options. Oxidative stress, low-grade inflammation and altered autonomic regulation, are important components of MetS pathophysiology. We recently reported that galantamine, an acetylcholinesterase inhibitor and an FDA-approved drug (for Alzheimer’s disease) alleviates the inflammatory state in MetS subjects. Here we examined the effects of galantamine on oxidative stress in parallel with inflammatory and cardio-metabolic parameters in subjects with MetS.MethodsThe effects of galantamine treatment, 8 mg daily for 4 weeks, followed by 16 mg daily for 8 weeks or placebo were studied in randomly assigned subjects with MetS (n=22 per group) of both genders. Oxidative stress, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase activities, lipid and protein peroxidation, and nitrite levels were analyzed before and at the end of the treatment. In addition, plasma cytokine and adipokine levels, insulin resistance (HOMA-IR) and other relevant cardio-metabolic indices were analyzed. Autonomic regulation was also examined by heart rate variability (HRV) before treatment, and at every 4 weeks of treatment.ResultsGalantamine treatment significantly increased antioxidant enzyme activities, including SOD (+1.65 USOD/mg protein, [95% CI 0.39 to 2.92], P=0.004) and CAT (+0.93 nmol/mg, [95% CI 0.34 to 1.51], P=0.011), decreased lipid peroxidation (thiobarbituric acid reactive substances, -5.45 pmol/mg, [95% CI -10.97 to 0.067], P=0.053) and systemic nitrite levels (-0.05 nit/mg protein, [95% CI -0.21 to 0.10], P=0.038) compared with placebo. In addition, galantamine significantly alleviated the inflammatory state and insulin resistance, and decreased the low frequency/high frequency ratio of HRV, following 8 and 12 weeks of drug treatment.ConclusionLow-dose galantamine alleviates oxidative stress, alongside beneficial anti-inflammatory, and metabolic effects, and modulates autonomic regulation in subjects with MetS. These findings are of considerable interest for further studies with galantamine to ameliorate MetS pathophysiology.

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Salt-Sensitivity of Blood Pressure and Insulin Resistance

Frontiers in Physiology ◽

10.3389/fphys.2021.793924 ◽

2021 ◽

Vol 12 ◽

Author(s):

Lale A. Ertuglu ◽

Fernando Elijovich ◽

Cheryl L. Laffer ◽

Annet Kirabo

Keyword(s):

Insulin Resistance ◽

Blood Pressure ◽

Insulin Sensitivity ◽

Immune Activation ◽

Vascular Function ◽

Vascular Dysfunction ◽

Salt Sensitivity ◽

Common Denominator ◽

Peroxisome Proliferator ◽

Cardiovascular Morbidity And Mortality

Salt sensitivity of blood pressure (SSBP) is an independent risk factor for cardiovascular morbidity and mortality that is seen in both hypertensive and normotensive populations. Insulin resistance (IR) strongly correlates with SSBP and affects nearly 50% of salt sensitive people. While the precise mechanism by which IR and SSBP relate remains elusive, several common pathways are involved in the genesis of both processes, including vascular dysfunction and immune activation. Vascular dysfunction associated with insulin resistance is characterized by loss of nitric oxide (NO)-mediated vasodilation and heightened endothelin-1 induced vasoconstriction, as well as capillary rarefaction. It manifests with increased blood pressure (BP) in salt sensitive murine models. Another common denominator in the pathogenesis of insulin resistance, hypertension, and salt sensitivity (SS) is immune activation involving pro-inflammatory cytokines like tumor necrosis factor (TNF)-α, IL-1β, and IL-6. In the last decade, a new understanding of interstitial sodium storage in tissues such as skin and muscle has revolutionized traditional concepts of body sodium handling and pathogenesis of SS. We have shown that interstitial Na+ can trigger a T cell mediated inflammatory response through formation of isolevuglandin protein adducts in antigen presenting cells (APCs), and that this response is implicated in salt sensitive hypertension. The peroxisome proliferator-activated receptor γ (PPARγ) is a transcription factor that modulates both insulin sensitivity and BP. PPARγ agonists increase insulin sensitivity and ameliorate salt sensitivity, whereas deficiency of PPARγ results in severe insulin resistance and hypertension. These findings suggest that PPARγ plays a role in the common pathogenesis of insulin sensitivity and salt sensitivity, perhaps via effects on the immune system and vascular function. The goal of this review is to discuss those mechanisms that may play a role in both SSBP and in insulin resistance.

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Inflammation and Insulin Resistance as Risk Factors and Potential Therapeutic Targets for Alzheimer’s Disease

Frontiers in Neuroscience ◽

10.3389/fnins.2021.653651 ◽

2021 ◽

Vol 15 ◽

Author(s):

Angeles Vinuesa ◽

Carlos Pomilio ◽

Amal Gregosa ◽

Melisa Bentivegna ◽

Jessica Presa ◽

...

Keyword(s):

Risk Factors ◽

Alzheimer’S Disease ◽

Insulin Resistance ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Brain Aging ◽

Therapeutic Targets ◽

Low Grade ◽

Increased Risk ◽

The Impact

Overnutrition and modern diets containing high proportions of saturated fat are among the major factors contributing to a low-grade state of inflammation, hyperglycemia and dyslipidemia. In the last decades, the global rise of type 2 diabetes and obesity prevalence has elicited a great interest in understanding how changes in metabolic function lead to an increased risk for premature brain aging and the development of neurodegenerative disorders such as Alzheimer’s disease (AD). Cognitive impairment and decreased neurogenic capacity could be a consequence of metabolic disturbances. In these scenarios, the interplay between inflammation and insulin resistance could represent a potential therapeutic target to prevent or ameliorate neurodegeneration and cognitive impairment. The present review aims to provide an update on the impact of metabolic stress pathways on AD with a focus on inflammation and insulin resistance as risk factors and therapeutic targets.

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Adipocyte Specific HO-1 Gene Therapy Is Effective in Antioxidant Treatment of Insulin Resistance and Vascular Function in an Obese Mice Model

Antioxidants ◽

10.3390/antiox9010040 ◽

2020 ◽

Vol 9 (1) ◽

pp. 40 ◽

Cited By ~ 11

Author(s):

Shailendra P. Singh ◽

Menachem Greenberg ◽

Yosef Glick ◽

Lars Bellner ◽

Gaia Favero ◽

...

Keyword(s):

Insulin Resistance ◽

Gene Therapy ◽

Adipose Tissue ◽

Vascular Function ◽

Therapeutic Approach ◽

Vascular Dysfunction ◽

Cellular Respiration ◽

Heme Oxygenase 1 ◽

Obese Mice ◽

Mice Model

Obesity is a risk factor for vascular dysfunction and insulin resistance. The study aim was to demonstrate that adipocyte-specific HO-1 (heme oxygenase-1) gene therapy is a therapeutic approach for preventing the development of obesity-induced metabolic disease in an obese-mice model. Specific expression of HO-1 in adipose tissue was achieved by using a lentiviral vector expressing HO-1 under the control of the adiponectin vector (Lnv-adipo-HO-1). Mice fed a high-fat diet (HFD) developed adipocyte hypertrophy, fibrosis, decreased mitochondrial respiration, increased levels of inflammatory adipokines, insulin resistance, vascular dysfunction, and impaired heart mitochondrial signaling. These detrimental effects were prevented by the selective expression of HO-1 in adipocytes. Lnv-adipo-HO-1-transfected mice on a HFD display increased cellular respiration, increased oxygen consumption, increased mitochondrial function, and decreased adipocyte size. Moreover, RNA arrays confirmed that targeting adipocytes with HO-1 overrides the genetic susceptibility of adiposopathy and correlated with restoration of the expression of anti-inflammatory, thermogenic, and mitochondrial genes. Our data demonstrate that HO-1 gene therapy improved adipose tissue function and had positive impact on distal organs, suggesting that specific targeting of HO-1 gene therapy is an attractive therapeutic approach for improving insulin sensitivity, metabolic activity, and vascular function in obesity.

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Nutraceuticals as a potential adjunct therapy toward improving vascular health in CKD

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00152.2019 ◽

2019 ◽

Vol 317 (5) ◽

pp. R719-R732 ◽

Cited By ~ 1

Author(s):

Nicholas T. Kruse

Keyword(s):

Oxidative Stress ◽

Vascular Function ◽

Vascular Dysfunction ◽

Vascular Health ◽

Fully Integrated ◽

Beneficial Effects ◽

Increased Risk ◽

Health Related ◽

No Bioavailability ◽

Mitochondria Targeting

Chronic kidney disease (CKD) is a major public health epidemic and increases risk for developing cardiovascular disease (CVD). Vascular dysfunction is a major independent risk factor toward increased risk for CVD in CKD. Several mechanisms have been postulated to result in vascular dysfunction in CKD, including oxidative stress-mediated inflammation by redox imbalance and reduced nitric oxide (NO) bioavailability and synthesis. Therefore, strategies that decrease oxidative stress and/or increase NO bioactivity may have major clinical implications toward improving vascular health and reducing the burden of CVD in CKD. Nutraceutical therapy in the form of polyphenols, dietary nitrates, or selective mitochondria-targeting therapies has recently been shown to improve vascular function by reducing oxidative stress and/or increasing NO bioavailability and synthesis. This review, therefore, highlights these three emerging nutraceuticals recently implicated in pathophysiological improvement of vascular function in CKD. This review also describes those pathophysiological mechanisms thought to be responsible for the beneficial effects on the vasculature and possible experimental considerations that may exist within human CKD populations. It is clear throughout this review that human-based mechanistic preclinical and health-related clinical studies are lacking regarding whether nutraceuticals do indeed improve vascular function in patients with CKD. As such, a comprehensive, detailed, and fully integrated understanding of nutraceuticals and vasculature function is necessary in patients with CKD. Many opportunities exist for original mechanistic and therapeutic discoveries and investigations on select nutraceuticals and their impact on vascular outcomes in patients with CKD, and these will remain exciting avenues of research in the future.

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Role of Exercise in Vascular Function and Inflammatory Profile in Age-Related Obesity

Journal of Immunology Research ◽

10.1155/2018/7134235 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 3

Author(s):

Anna Pedrinolla ◽

Massimo Venturelli ◽

Emine Kirmizi ◽

Federica Moschetta ◽

Monica Zardini ◽

...

Keyword(s):

Vascular Function ◽

Vascular Dysfunction ◽

Exercise Program ◽

Normal Weight ◽

Low Grade ◽

Supervised Exercise ◽

Age Related ◽

Long Term Effect ◽

Negative Effect ◽

Inflammatory Profile

In western countries, aging is often accompanied by obesity and age-related obesity is characterized by vascular dysfunction and a low-grade inflammatory profile. Exercise is a nonpharmacological strategy able to decrease the development and incidence of risk factors for several health-threatening diseases. Nonetheless, its long-term effect on vascular function and inflammation in age-related obesity is still unclear. The aim of this study was to investigate the effect of regular, supervised exercise on inflammatory profile and vascular function in age-related obesity. We also hypothesized that vascular function and inflammatory profile would have been correlated in overweight and obese individuals. Thirty normal weight (NW; 70 ± 5 years, 23.9 ± 2.6 BMI) and forty overweight and obese elderly (OW&OB; 69 ± 5 years, 30.1 ± 2.3 BMI) regularly taking part in a structured, supervised exercise program were enrolled in the study and evaluated for vascular function (flow-mediated dilation; FMD) and inflammatory profile (plasma CRP, IL-1β, IL-1ra, IL-6, IL-8, IL-10, TNF-α, and MCP-1). Although no differences between groups were found concerning performance and the weekly amount of physical activity, the OW&OB group compared with the NW group demonstrated higher systolic and diastolic blood pressure (+10%, p=0.001; +9%, p=0.005, respectively); lower FMD% (−36%, p<0.001) and FMD/shear rate (−40%, p=0.001); and higher levels of CRP (+33%, p=0.005), IL-6 (+36%, p=0.048), MCP-1 (+17%, p=0.004), and TNF-α (+16%, p=0.031). No correlations between vascular function and inflammation were found in OW&OB or NW. Although exercising regularly, overweight and obese elderly exhibited poorer vascular function and higher proinflammatory markers compared with the leaner group. These results support the idea that exercise alone cannot counteract the negative effect of adiposity on vascular function and inflammatory profile in elderly individuals and these two processes are not necessarily related.

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