scholarly journals Apolipoprotein E4 mediates insulin resistance-associated cerebrovascular dysfunction and the post-prandial response

2017 ◽  
Vol 39 (5) ◽  
pp. 770-781 ◽  
Author(s):  
Lance A Johnson ◽  
Eileen Ruth Torres ◽  
Sydney Weber Boutros ◽  
Esha Patel ◽  
Tunde Akinyeke ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cerebral Blood Volume ◽  
Cerebral Metabolism ◽  
Metabolic Dysfunction ◽  
Cerebrovascular Function ◽  
Age Related ◽  
Increased Risk ◽  
Cerebrovascular Dysfunction ◽  
Potential Link ◽  
Age Related Cognitive Decline

Metabolic dysfunction, commonly a result of diets high in saturated fats and sugar, is associated with impaired cognitive function and an increased risk of age-related cognitive decline (ACD) and Alzheimer’s disease (AD). Compared to the E3 isoform of apolipoprotein (apoE), the E4 isoform is a major genetic risk factor for ACD, AD, and for developing cognitive impairments following various environmental challenges, including dietary challenges such as a high-fat diet (HFD). Both insulin resistance (IR) and E4 are associated with metabolic and vascular impairments. Deficits in cerebral metabolism and cerebrovascular function have been proposed as initiating events leading to these impairments. In the current study, we employed a model of human apoE targeted replacement mice and HFD-induced obesity to study the potential link between E4 and IR, at rest and following a postprandial challenge. HFD-induced IR was associated with impaired cognition, reduced cerebral blood volume and decreased glucose uptake. These effects were more profound in E4 than E3 mice. Furthermore, the cognitive, metabolic and cerebrovascular responses to an exogenous glucose load showed an apoE isoform-dependent response, with E4, but not E3 mice, acutely benefiting from a spike in blood glucose.

scholarly journals Association of hormonal dysregulation with metabolic syndrome in older women: data from the InCHIANTI study

2007 ◽  
Vol 292 (1) ◽  
pp. E353-E358 ◽  
Author(s):  
Marcello Maggio ◽  
Fulvio Lauretani ◽  
Gian Paolo Ceda ◽  
Stefania Bandinelli ◽  
Shehzad Basaria ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Older Women ◽  
Inflammatory Markers ◽  
Hormone Replacement ◽  
Sex Hormone Binding Globulin ◽  
Bilateral Oophorectomy ◽  
Age Related ◽  
Increased Risk ◽  
Igf I

Metabolic syndrome (MetS) is a strong risk factor for type 2 diabetes and cardiovascular disease. Conditions associated with hyperandrogenism are often associated with glucose intolerance and other features of MetS in young women. As the prevalence of MetS increases with age and is probably multifactorial, it is reasonable to hypothesize that age-related changes in androgens and other hormones might contribute to the development of MetS in older persons. However, this hypothesis has never been tested in older women. We hypothesized that high levels of testosterone, dehydroepiandrosterone sulfate (DHEA-S), and cortisol and low levels of sex hormone-binding globulin (SHBG) and IGF-I would be associated with MetS in a representative cohort of older Italian women independently of confounders (including inflammatory markers). After exclusion of participants on hormone replacement therapy and those with a history of bilateral oophorectomy, 512 women (≥65 yr) had complete data on testosterone, cortisol, DHEA-S, SHBG, fasting insulin, total and free IGF-I, IL-6, and C-reactive protein (CRP). MetS was defined according to ATP-III criteria. Insulin resistance was calculated according to HOMA. MetS was found in 145 women (28.3%). Participants with vs. those without MetS had higher age-adjusted levels of bioavailable testosterone ( P < 0.001), IL-6 ( P < 0.001), CRP ( P < 0.001), and HOMA ( P < 0.001) and lower levels of SHBG ( P < 0.001). After adjustment for potential confounders, participants with decreased SHBG had an increased risk of MetS ( P < 0.0001) vs. those with low SHBG. In a further model including all hormones and confounders, log SHBG was the only independent factor associated with MetS (OR: 0.44, 95% CI 0.21–0.91, P = 0.027). In older women, SHBG is negatively associated with MetS independently of confounders, including inflammatory markers and insulin resistance. Further studies are needed to support the notion that raising SHBG is a potential therapeutic target for prevention and treatment of MetS.

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

2018 ◽  
Vol 96 (1) ◽  
pp. 97-102 ◽  
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.

scholarly journals Medin aggregation causes cerebrovascular dysfunction in aging wild-type mice

2020 ◽  
Vol 117 (38) ◽  
pp. 23925-23931
Author(s):  
Karoline Degenhardt ◽  
Jessica Wagner ◽  
Angelos Skodras ◽  
Michael Candlish ◽  
Anna Julia Koppelmann ◽  
...  
Keyword(s):  
Healthy Aging ◽  
Vascular Dysfunction ◽  
Upper Body ◽  
Dependent Manner ◽  
Wild Type ◽  
Brain Vasculature ◽  
Cerebrovascular Function ◽  
Age Related ◽  
Novel Approach ◽  
Cerebrovascular Dysfunction

Medin is the most common amyloid known in humans, as it can be found in blood vessels of the upper body in virtually everybody over 50 years of age. However, it remains unknown whether deposition of Medin plays a causal role in age-related vascular dysfunction. We now report that aggregates of Medin also develop in the aorta and brain vasculature of wild-type mice in an age-dependent manner. Strikingly, genetic deficiency of the Medin precursor protein, MFG-E8, eliminates not only vascular aggregates but also prevents age-associated decline of cerebrovascular function in mice. Given the prevalence of Medin aggregates in the general population and its role in vascular dysfunction with aging, targeting Medin may become a novel approach to sustain healthy aging.

scholarly journals Complex mechanisms linking neurocognitive dysfunction to insulin resistance and other metabolic dysfunction

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 353 ◽  
Author(s):  
Luke E. Stoeckel ◽  
Zoe Arvanitakis ◽  
Sam Gandy ◽  
Dana Small ◽  
C. Ronald Kahn ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Kidney Diseases ◽  
Scientific Evidence ◽  
Metabolic Dysfunction ◽  
Neurocognitive Dysfunction ◽  
Epidemiologic Evidence ◽  
Increased Risk ◽  
Patients With Diabetes ◽  
Advance Research ◽  
State Of The Science

Scientific evidence has established several links between metabolic and neurocognitive dysfunction, and epidemiologic evidence has revealed an increased risk of Alzheimer’s disease and vascular dementia in patients with diabetes. In July 2015, the National Institute of Diabetes, Digestive, and Kidney Diseases gathered experts from multiple clinical and scientific disciplines, in a workshop entitled “The Intersection of Metabolic and Neurocognitive Dysfunction”, to clarify the state-of-the-science on the mechanisms linking metabolic dysfunction, and insulin resistance and diabetes in particular, to neurocognitive impairment and dementia. This perspective is intended to serve as a summary of the opinions expressed at this meeting, which focused on identifying gaps and opportunities to advance research in this emerging area with important public health relevance.

scholarly journals Insulin resistance and sarcopenia: mechanistic links between common co-morbidities

2016 ◽  
Vol 229 (2) ◽  
pp. R67-R81 ◽  
Author(s):  
Mark E Cleasby ◽  
Pauline M Jamieson ◽  
Philip J Atherton
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Mammalian Target Of Rapamycin ◽  
Later Life ◽  
The Elderly ◽  
Clinical Syndrome ◽  
Physiological Processes ◽  
Age Related ◽  
Increased Risk ◽  
Amp Activated Protein Kinase

Insulin resistance (IR) in skeletal muscle is a key defect mediating the link between obesity and type 2 diabetes, a disease that typically affects people in later life. Sarcopenia (age-related loss of muscle mass and quality) is a risk factor for a number of frailty-related conditions that occur in the elderly. In addition, a syndrome of ‘sarcopenic obesity’ (SO) is now increasingly recognised, which is common in older people and is applied to individuals that simultaneously show obesity, IR and sarcopenia. Such individuals are at an increased risk of adverse health events compared with those who are obese or sarcopenic alone. However, there are no licenced treatments for sarcopenia or SO, the syndrome is poorly defined clinically and the mechanisms that might explain a common aetiology are not yet well characterised. In this review, we detail the nature and extent of the clinical syndrome, highlight some of the key physiological processes that are dysregulated and discuss some candidate molecular pathways that could be implicated in both metabolic and anabolic defects in skeletal muscle, with an eye towards future therapeutic options. In particular, the potential roles of Akt/mammalian target of rapamycin signalling, AMP-activated protein kinase, myostatin, urocortins and vitamin D are discussed.

Rosuvastatin improves cerebrovascular function in Zucker obese rats by inhibiting NAD(P)H oxidase-dependent superoxide production

2006 ◽  
Vol 290 (3) ◽  
pp. H1264-H1270 ◽  
Author(s):  
Benedek Erdös ◽  
James A. Snipes ◽  
Christina D. Tulbert ◽  
Prasad Katakam ◽  
Allison W. Miller ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cerebral Arteries ◽  
Superoxide Production ◽  
Lipid Lowering ◽  
Insulin Resistant ◽  
Cranial Window ◽  
Cerebrovascular Function ◽  
Cerebrovascular Dysfunction ◽  
Obese Rats ◽  
Lipid Lowering Effect

Insulin-resistance induces cerebrovascular dysfunction and increases the risk for stroke. We investigated whether rosuvastatin (RSV), a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, can reverse reduced cerebrovascular responsiveness in insulin-resistant rats. Dilator responses of the basilar artery (BA) were examined after 1-day or 4-wk RSV (2 mg·kg−1·day−1) treatment in anesthetized 12-wk-old insulin-resistant Zucker obese (ZO) and lean (ZL) rats by using a cranial window preparation. Vehicle-treated ZO rats had significantly higher fasting insulin, total cholesterol (TC), and triglyceride (TG) levels compared with ZL rats. In addition, in the ZO rats, dilator responses of the BA to acetylcholine, iloprost, cromakalim, and potassium chloride were significantly reduced when compared with ZL rats. One-day RSV treatment improved dilator responses of the ZO BAs without altering lipid levels. Four-week RSV treatment lowered both TC and TG by 30% and also improved dilator responses of the ZO BAs, although without additional effects compared with the 1-day RSV treatment. NAD(P)H oxidase-dependent superoxide production was significantly higher in the cerebral arteries of vehicle-treated ZO rats compared with ZL rats, but both 1-day and 4-wk RSV treatments normalized elevated superoxide levels in the ZO arteries. These findings demonstrate that RSV improves cerebrovascular function in insulin-resistance independently from its lipid-lowering effect by the inhibition of NAD(P)H oxidase.

scholarly journals Hyperandrogenemia Induced by Letrozole Treatment of Pubertal Female Mice Results in Hyperinsulinemia Prior to Weight Gain and Insulin Resistance

Endocrinology ◽  
2017 ◽  
Vol 158 (9) ◽  
pp. 2988-3003 ◽  
Author(s):  
Danalea V Skarra ◽  
Angelina Hernández-Carretero ◽  
Alissa J Rivera ◽  
Arya R Anvar ◽  
Varykina G Thackray
Keyword(s):  
Insulin Resistance ◽  
Weight Gain ◽  
Polycystic Ovary ◽  
Metabolic Phenotype ◽  
Metabolic Dysfunction ◽  
Polycystic Ovaries ◽  
Female Mice ◽  
Increased Risk ◽  
Letrozole Treatment ◽  
Glucose Stimulated Insulin Secretion

Abstract Women with polycystic ovary syndrome (PCOS) diagnosed with hyperandrogenism and ovulatory dysfunction have an increased risk of developing metabolic disorders, including type 2 diabetes and cardiovascular disease. We previously developed a model that uses letrozole to elevate endogenous testosterone levels in female mice. This model has hallmarks of PCOS, including hyperandrogenism, anovulation, and polycystic ovaries, as well as increased abdominal adiposity and glucose intolerance. In the current study, we further characterized the metabolic dysfunction that occurs after letrozole treatment to determine whether this model represents a PCOS-like metabolic phenotype. We focused on whether letrozole treatment results in altered pancreatic or liver function as well as insulin resistance. We also investigated whether hyperinsulinemia occurs secondary to weight gain and insulin resistance in this model or if it can occur independently. Our study demonstrated that letrozole-treated mice developed hyperinsulinemia after 1 week of treatment and without evidence of insulin resistance. After 2 weeks of letrozole treatment, mice became significantly heavier than placebo mice, demonstrating that weight gain was not required to develop hyperinsulinemia. After 5 weeks of letrozole treatment, mice exhibited blunted glucose-stimulated insulin secretion, insulin resistance, and impaired insulin-induced phosphorylation of AKT in skeletal muscle. Moreover, letrozole-treated mice exhibited dyslipidemia after 5 weeks of treatment but no evidence of hepatic disease. Our study demonstrated that the letrozole-induced PCOS mouse model exhibits multiple features of the metabolic dysregulation observed in obese, hyperandrogenic women with PCOS. This model will be useful for mechanistic studies investigating how hyperandrogenemia affects metabolism in females.

scholarly journals “White Paper” meeting summary and catalyst for future inquiry: Complex mechanisms linking neurocognitive dysfunction to insulin resistance and other metabolic dysfunction

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 353 ◽  
Author(s):  
Luke E. Stoeckel ◽  
Zoe Arvanitakis ◽  
Sam Gandy ◽  
Dana Small ◽  
C. Ronald Kahn ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Kidney Diseases ◽  
Scientific Evidence ◽  
White Paper ◽  
Metabolic Dysfunction ◽  
Neurocognitive Dysfunction ◽  
Epidemiologic Evidence ◽  
Increased Risk ◽  
Patients With Diabetes ◽  
Advance Research

Scientific evidence has established several links between metabolic and neurocognitive dysfunction, and epidemiologic evidence has revealed an increased risk of Alzheimer’s disease and vascular dementia in patients with diabetes. In July 2015, the National Institute of Diabetes, Digestive, and Kidney Diseases gathered experts from multiple clinical and scientific disciplines, in a workshop entitled “The Intersection of Metabolic and Neurocognitive Dysfunction”, to clarify the state-of-the-science on the mechanisms linking metabolic dysfunction, and insulin resistance and diabetes in particular, to neurocognitive impairment and dementia. This perspective is intended to serve as a summary of the opinions expressed at this meeting, which focused on identifying gaps and opportunities to advance research in this emerging area with important public health relevance.

scholarly journals Dysfunction of Mouse Cerebral Arteries during Early Aging

2015 ◽  
Vol 35 (9) ◽  
pp. 1445-1453 ◽  
Author(s):  
Matilde Balbi ◽  
Mitrajit Ghosh ◽  
Thomas A Longden ◽  
Max Jativa Vega ◽  
Benno Gesierich ◽  
...  
Keyword(s):  
Cerebral Arteries ◽  
Brain Slices ◽  
Neurovascular Coupling ◽  
Global Changes ◽  
Cerebral Vessel ◽  
Pial Vessels ◽  
Age Related ◽  
Increased Risk ◽  
Cerebrovascular Dysfunction

Aging leads to a gradual decline in the fidelity of cerebral blood flow (CBF) responses to neuronal activation, resulting in an increased risk for stroke and dementia. However, it is currently unknown when age-related cerebrovascular dysfunction starts or which vascular components and functions are first affected. The aim of this study was to examine the function of microcirculation throughout aging in mice. Microcirculation was challenged by inhalation of 5% and 10% CO2 or by forepaw stimulation in 6-week, 8-month, and 12-month-old FVB/N mice. The resulting dilation of pial vessels and increase in CBF was measured by intravital fluorescence microscopy and laser Doppler fluxmetry, respectively. Neurovascular coupling and astrocytic endfoot Ca2+ were measured in acute brain slices from 18-month-old mice. We did not reveal any changes in CBF after CO2 reactivity up to an age of 12 months. However, direct visualization of pial vessels by in vivo microscopy showed a significant, age-dependent loss of CO2 reactivity starting at 8 months of age. At the same age neurovascular coupling was also significantly affected. These results suggest that aging does not affect cerebral vessel function simultaneously, but starts in pial microvessels months before global changes in CBF are detectable.

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