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1.
Alcohol ; 2020 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-33232792

RESUMO

INTRODUCTION: Excess energy intake by spectators at a sporting event (i.e., a tailgate) might cause acute negative health effects. However, limited data exist regarding the effects of overeating and alcohol consumption on lipid metabolism and the potential to gain intrahepatic triacylglycerols (IHTG). We tested the hypothesis that overconsumption of food and alcohol would significantly increase both hepatic de novo lipogenesis (DNL) and IHTG. METHODS: Eighteen males (mean±SD, age: 31.4±7.3 y, BMI: 32.1±5.9 kg/m2) were fed alcoholic drinks to elevate blood alcohol for 5hr, while highly-palatable food was presented. Blood samples were collected and DNL in TG-rich lipoproteins (TRL) was measured by GC/MS, IHTG was measured via MRS (n=15), and substrate oxidation via indirect calorimetry. RESULTS: Subjects consumed 5,087±149 kcal (191±25% excess of total daily energy needs including 171±24g alcohol), which increased plasma insulin, glucose, TG, and decreased NEFA (ANOVA P≤0.003 for all). Both DNL and TRL-TG increased (P<0.001) while IHTG did not change in the group as a whole (P=0.229). Individual subject data revealed remarkably differing responses for IHTG (9 increased, 5 decreased, 1 did not change). Despite maintaining equal breath alcohol levels, subjects with IHTG elevations exhibited higher DNL, consumed 90% less alcohol (P=0.048), tended to consume more carbohydrates, and exhibited lower whole-body fat oxidation (not significant) compared to those whose IHTG was reduced. DISCUSSION: This study demonstrate that acute excess energy intake may have differing effects on an individual's DNL and IHTG, and dietary carbohydrate may impact DNL more than alcohol. CLINICALTRIALS. GOV IDENTIFIER: NCT02141880.

2.
Artigo em Inglês | MEDLINE | ID: mdl-32982972

RESUMO

During exercise, there is coordination between various hormonal systems to ensure glucoregulation. This study examined if hypoglycemia occurs during moderate-intensity exercise in non-obese and obese individuals with and without type 2 diabetes (T2D). Eighteen non-obese, 18 obese, and 10 obese with T2D completed 2 study days that included a meal at 1,800 h followed by rest (NOEX) or exercise (PMEX; 45 min/55% of VO2 max 2 h post meal). Glucose, insulin, and glucagon concentrations were measured throughout this 5.5 h period. Subjects with T2D had elevated glucose responses to the meal on both study days, compared to non-obese and obese subjects (P < 0.05). During evening exercise (PMEX), subjects with T2D had a greater drop in glucose concentration (-98.4 ± 13.3 mg/dL) compared to obese (-44.8 ± 7.1 mg/dL) and non-obese (-39.3 ± 6.1 mg/dL; P < 0.01) subjects. Glucose levels decreased more so in females than males in both conditions (P < 0.01). Nadir glucose levels <70 mg/dL were observed in 33 subjects during NOEX and 39 subjects during PMEX. Obese males had a larger exercise-induced insulin drop than obese females (P = 0.01). During PMEX, peak glucagon concentrations were elevated compared to NOEX (P < 0.001). Male participants with T2D had an increased glucagon response during NOEX and PMEX compared to females (P < 0.01). In conclusion, in individuals with varying glucose tolerance, there is a dramatic drop in glucose levels during moderate-intensity exercise, despite appropriate insulin concentrations prior to exercise, and glucagon levels rising during exercise. Moderate-intensity exercise can result in low glucose concentrations (<60 mg/dL), and yet many of these individuals will be asymptomatic.

3.
Am J Physiol Renal Physiol ; 318(5): F1220-F1228, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32281419

RESUMO

Consumption of a Western diet (WD) induces central aortic stiffening that contributes to the transmittance of pulsatile blood flow to end organs, including the kidney. Our recent work supports that endothelial epithelial Na+ channel (EnNaC) expression and activation enhances aortic endothelial cell stiffening through reductions in endothelial nitric oxide (NO) synthase (eNOS) and bioavailable NO that result in inflammatory and oxidant responses and perivascular fibrosis. However, the role that EnNaC activation has on endothelial responses in the renal circulation remains unknown. We hypothesized that cell-specific deletion of the α-subunit of EnNaC would prevent WD-induced central aortic stiffness and protect the kidney from endothelial dysfunction and vascular stiffening. Twenty-eight-week-old female αEnNaC knockout and wild-type mice were fed either mouse chow or WD containing excess fat (46%), sucrose, and fructose (17.5% each). WD feeding increased fat mass, indexes of vascular stiffening in the aorta and renal artery (in vivo pulse wave velocity and ultrasound), and renal endothelial cell stiffening (ex vivo atomic force microscopy). WD further impaired aortic endothelium-dependent relaxation and renal artery compliance (pressure myography) without changes in blood pressure. WD-induced renal arterial stiffening occurred in parallel to attenuated eNOS activation, increased oxidative stress, and aortic and renal perivascular fibrosis. αEnNaC deletion prevented these abnormalities and support a novel mechanism by which WD contributes to renal arterial stiffening that is endothelium and Na+ channel dependent. These results demonstrate that cell-specific EnNaC is important in propagating pulsatility into the renal circulation, generating oxidant stress, reduced bioavailable NO, and renal vessel wall fibrosis and stiffening.


Assuntos
Aorta/metabolismo , Dieta Ocidental/efeitos adversos , Canais Epiteliais de Sódio/metabolismo , Artéria Renal/fisiopatologia , Doenças Vasculares/metabolismo , Rigidez Vascular , Animais , Aorta/patologia , Aorta/fisiopatologia , Elasticidade , Canais Epiteliais de Sódio/deficiência , Canais Epiteliais de Sódio/genética , Feminino , Fibrose , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo , Artéria Renal/patologia , Transdução de Sinais , Doenças Vasculares/genética , Doenças Vasculares/patologia , Doenças Vasculares/fisiopatologia , Remodelação Vascular
4.
Metabolism ; 109: 154223, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32275972

RESUMO

OBJECTIVE: Obesity is associated with myocardial fibrosis and impaired diastolic relaxation, abnormalities that are especially prevalent in women. Normal coronary vascular endothelial function is integral in mediating diastolic relaxation, and recent work suggests increased activation of the endothelial cell (EC) mineralocorticoid receptor (ECMR) is associated with impaired diastolic relaxation. As the endothelial Na+ channel (EnNaC) is a downstream target of the ECMR, we sought to determine whether EC-specific deletion of the critical alpha subunit, αEnNaC, would prevent diet induced-impairment of diastolic relaxation in female mice. METHODS AND MATERIALS: Female αEnNaC KO mice and littermate controls were fed a Western diet (WD) high in fat (46%), fructose corn syrup (17.5%) and sucrose (17.5%) for 12-16 weeks. Measurements were conducted for in vivo cardiac function, in vitro cardiomyocyte stiffness and EnNaC activity in primary cultured ECs. Additional biochemical studies examined indicators of oxidative stress, including aspects of antioxidant Nrf2 signaling, in cardiac tissue. RESULTS: Deletion of αEnNaC in female mice fed a WD significantly attenuated WD mediated impairment in diastolic relaxation. Improved cardiac relaxation was accompanied by decreased EnNaC-mediated Na+ currents in ECs and reduced myocardial oxidative stress. Further, deletion of αEnNaC prevented WD-mediated increases in isolated cardiomyocyte stiffness. CONCLUSION: Collectively, these findings support the notion that WD feeding in female mice promotes activation of EnNaC in the vasculature leading to increased cardiomyocyte stiffness and diastolic dysfunction.


Assuntos
Diástole/efeitos dos fármacos , Dieta Ocidental/efeitos adversos , Células Endoteliais/química , Coração/fisiopatologia , Canais de Sódio/metabolismo , Rigidez Vascular/efeitos dos fármacos , Animais , Células Cultivadas , Células Endoteliais/metabolismo , Feminino , Camundongos , Camundongos Knockout , Miócitos Cardíacos/patologia , Estresse Oxidativo , Canais de Sódio/deficiência
5.
Metabolism ; 99: 57-66, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31302199

RESUMO

OBJECTIVE: Mineralocorticoid receptor activation of the epithelial sodium channel in endothelial cells (ECs) (EnNaC) is accompanied by aldosterone induced endothelial stiffening and impaired nitric oxide (NO)-mediated arterial relaxation. Recent data support enhanced activity of the alpha subunit of EnNaC (αEnNaC) mediates this aldosterone induced endothelial stiffening and associated endothelial NO synthase (eNOS) activation. There is mounting evidence that diet induced obesity diminishes expression and activation of AMP-activated protein kinase α (AMPKα), sirtuin 1 (Sirt1), which would be expected to lead to impaired downstream eNOS activation. Thereby, we posited that enhanced EnNaC activation contributes to diet induced obesity related increases in stiffness of the endothelium and diminished NO mediated vascular relaxation by increasing oxidative stress and related inhibition of AMPKα, Sirt1, and associated eNOS inactivation. MATERIALS/METHODS: Sixteen to twenty week-old αEnNaC knockout (αEnNaC-/-) and wild type littermate (EnNaC+/+) female mice were fed a mouse chow or an obesogenic western diet (WD) containing excess fat (46%) and fructose (17.5%) for 16 weeks. Sodium currents of ECs, endothelial stiffness and NO mediated aortic relaxation were examined along with indices of aortic oxidative stress, vascular remodeling and fibrosis. RESULTS: Enhanced EnNaC activation-mediated WD-induced increases in sodium currents in isolated lung ECs, increased endothelial stiffness and impaired aortic endothelium-dependent relaxation to acetylcholine (10-9-10-4 mol/L). These abnormalities occurred in conjunction with WD-mediated aortic tissue oxidative stress, inflammation, and decreased activation of AMPKα, Sirt1, and downstream eNOS were substantially mitigated in αEnNaC-/- mice. Importantly, αEnNaC-/- prevented WD induced increases in endothelial stiffness and related impairment of endothelium-dependent relaxation as well as aortic fibrosis and remodeling. However, EnNaC signaling was not involved in diet-induced abnormal expression of adipokines and CYP11b2 in abdominal aortic perivascular adipose tissue. CONCLUSION: These data suggest that endothelial specific EnNaC activation mediates WD-induced endothelial stiffness, impaired eNOS activation, aortic fibrosis and remodeling through increased aortic oxidative stress and increased inflammation related to a reduction of AMPKα and Sirt 1 mediated eNOS phosphorylation/activation and NO production.


Assuntos
Dieta/efeitos adversos , Células Endoteliais/metabolismo , Canais Epiteliais de Sódio/metabolismo , Epitélio/metabolismo , Obesidade/metabolismo , Obesidade/patologia , Animais , Dieta Ocidental , Canais Epiteliais de Sódio/genética , Epitélio/patologia , Camundongos , Camundongos Knockout , Músculo Liso Vascular , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Sirtuína 1/metabolismo , Rigidez Vascular/efeitos dos fármacos , Vasodilatação
6.
Curr Hypertens Rep ; 20(10): 88, 2018 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-30109433

RESUMO

PURPOSE OF THE REVIEW: In the present review, we will discuss the evidence and the mechanisms underlying the complex interplay between obesity, mineralocorticoid receptor activation, and cardiovascular dysfunction with special emphasis on the pathogenesis of cardiovascular disease (CVD) in obese and insulin-resistant females. RECENT FINDINGS: Since the initial isolation of aldosterone in 1953 and the cloning of the mineralocorticoid receptor (MR) decades later, our understanding has expanded tremendously regarding their involvement in the pathogenesis of CVD. Recent results from both pre-clinical and clinical studies support a close correlation between increase adiposity and enhanced aldosterone production (MR activation). Importantly, insulin resistance and obese females are more prone to the deleterious cardiovascular effects of MR activation, and enhanced MR activation in females has emerged as an important causative event in the genesis of a more severe CVD in diabetic women. Different clinical trials have been completed examining the effect of MR blockade in subjects with CVD. Despite its important beneficial mortality impact, side effects are frequent and a newer MR antagonist, finerenone, with less risk of hyperkalemia is currently being tested in large clinical trials.


Assuntos
Doenças Cardiovasculares/fisiopatologia , Resistência à Insulina/fisiologia , Obesidade/fisiopatologia , Receptores de Mineralocorticoides/fisiologia , Animais , Doenças Cardiovasculares/tratamento farmacológico , Feminino , Humanos , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Naftiridinas/uso terapêutico
7.
Am J Physiol Regul Integr Comp Physiol ; 313(2): R67-R77, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28539355

RESUMO

Consumption of a high-fat, high-fructose diet [Western diet (WD)] promotes vascular stiffness, a critical factor in the development of cardiovascular disease (CVD). Obese and diabetic women exhibit greater arterial stiffness than men, which contributes to the increased incidence of CVD in these women. Furthermore, high-fructose diets result in elevated plasma concentrations of uric acid via xanthine oxidase (XO) activation, and uric acid elevation is also associated with increased vascular stiffness. However, the mechanisms by which increased xanthine oxidase activity and uric acid contribute to vascular stiffness in obese females remain to be fully uncovered. Accordingly, we examined the impact of XO inhibition on endothelial function and vascular stiffness in female C57BL/6J mice fed a WD or regular chow for 16 wk. WD feeding resulted in increased arterial stiffness, measured by atomic force microscopy in aortic explants (16.19 ± 1.72 vs. 5.21 ± 0.54 kPa, P < 0.05), as well as abnormal aortic endothelium-dependent and -independent vasorelaxation. XO inhibition with allopurinol (widely utilized in the clinical setting) substantially improved vascular relaxation and attenuated stiffness (16.9 ± 0.50 vs. 3.44 ± 0.50 kPa, P < 0.05) while simultaneously lowering serum uric acid levels (0.55 ± 0.98 vs. 0.21 ± 0.04 mg/dL, P < 0.05). In addition, allopurinol improved WD-induced markers of fibrosis and oxidative stress in aortic tissue, as analyzed by immunohistochemistry and transmission electronic microscopy. Collectively, these results demonstrate that XO inhibition protects against WD-induced vascular oxidative stress, fibrosis, impaired vasorelaxation, and aortic stiffness in females. Furthermore, excessive oxidative stress resulting from XO activation appears to play a key role in mediating vascular dysfunction induced by chronic exposure to WD consumption in females.


Assuntos
Alopurinol/administração & dosagem , Aorta/fisiologia , Dieta Ocidental , Ácido Úrico/sangue , Rigidez Vascular/fisiologia , Vasodilatação/fisiologia , Xantina Oxidase/metabolismo , Animais , Aorta/efeitos dos fármacos , Inibidores Enzimáticos/administração & dosagem , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Rigidez Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Sistema Vasomotor/efeitos dos fármacos , Sistema Vasomotor/fisiologia , Xantina Oxidase/antagonistas & inibidores
8.
Endocrinology ; 157(4): 1590-600, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26872089

RESUMO

Consumption of a diet high in fat and refined carbohydrates (Western diet [WD]) is associated with obesity and insulin resistance, both major risk factors for cardiovascular disease (CVD). In women, obesity and insulin resistance abrogate the protection against CVD likely afforded by estrogen signaling through estrogen receptor (ER)α. Indeed, WD in females results in increased vascular stiffness, which is independently associated with CVD. We tested the hypothesis that loss of ERα signaling in the endothelium exacerbates WD-induced vascular stiffening in female mice. We used a novel model of endothelial cell (EC)-specific ERα knockout (EC-ERαKO), obtained after sequential crossing of the ERα double floxed mice and VE-Cadherin Cre-recombinase mice. Ten-week-old females, EC-ERαKO and aged-matched genopairs were fed either a regular chow diet (control diet) or WD for 8 weeks. Vascular stiffness was measured in vivo by pulse wave velocity and ex vivo in aortic explants by atomic force microscopy. In addition, vascular reactivity was assessed in isolated aortic rings. Initial characterization of the model fed a control diet did not reveal changes in whole-body insulin sensitivity, aortic vasoreactivity, or vascular stiffness in the EC-ERαKO mice. Interestingly, ablation of ERα in ECs reduced WD-induced vascular stiffness and improved endothelial-dependent dilation. In the setting of a WD, endothelial ERα signaling contributes to vascular stiffening in females. The precise mechanisms underlying the detrimental effects of endothelial ERα in the setting of a WD remain to be elucidated.


Assuntos
Dieta Ocidental , Células Endoteliais/metabolismo , Receptor alfa de Estrogênio/metabolismo , Rigidez Vascular/fisiologia , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Aorta Torácica/metabolismo , Aorta Torácica/fisiologia , Caderinas/genética , Caderinas/metabolismo , Receptor alfa de Estrogênio/genética , Feminino , Artéria Femoral/fisiologia , Immunoblotting , Camundongos Knockout , Camundongos Transgênicos , Microscopia de Força Atômica , Análise de Onda de Pulso , Fator de Crescimento Transformador beta/metabolismo , Rigidez Vascular/genética , Vasodilatação
9.
Am J Physiol Heart Circ Physiol ; 310(2): H300-9, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26566729

RESUMO

Previous studies have reported exaggerated increases in arterial blood pressure during exercise in type 2 diabetes (T2D) patients. However, little is known regarding the underlying neural mechanism(s) involved. We hypothesized that T2D patients would exhibit an augmented muscle metaboreflex activation and this contributes to greater pressor and sympathetic responses during exercise. Mean arterial pressure (MAP), heart rate (HR), and muscle sympathetic nerve activity (MSNA) were measured in 16 patients with T2D (8 normotensive and 8 hypertensive) and 10 healthy controls. Graded isolation of the muscle metaboreflex was achieved by postexercise ischemia (PEI) following static handgrip performed at 30% and 40% maximal voluntary contraction (MVC). A cold pressor test (CPT) was also performed as a generalized sympathoexcitatory stimulus. Increases in MAP and MSNA during 30 and 40% MVC handgrip were augmented in T2D patients compared with controls (P < 0.05), and these differences were maintained during PEI (MAP: 30% MVC PEI: T2D, Δ16 ± 2 mmHg vs. controls, Δ8 ± 1 mmHg; 40% MVC PEI: T2D, Δ26 ± 3 mmHg vs. controls, Δ16 ± 2 mmHg, both P < 0.05). MAP and MSNA responses to handgrip and PEI were not different between normotensive and hypertensive T2D patients (P > 0.05). Interestingly, MSNA responses were also greater in T2D patients compared with controls during the CPT (P < 0.05). Collectively, these findings indicate that muscle metaboreflex activation is augmented in T2D patients and this contributes, in part, to augmented pressor and sympathetic responses to exercise in this patient group. Greater CPT responses suggest that a heightened central sympathetic reactivity may be involved.


Assuntos
Pressão Sanguínea , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Adulto , Pressão Arterial , Temperatura Baixa , Exercício Físico , Feminino , Força da Mão , Frequência Cardíaca , Humanos , Isquemia , Contração Isométrica , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/inervação , Pressão
11.
Horm Mol Biol Clin Investig ; 22(1): 19-26, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25941914

RESUMO

Obesity is a leading risk factor for the development of type 2 diabetes mellitus (DM2) and cardiovascular disease (CVD), however the underlying mechanisms still remain to be fully uncovered. It is now well accepted that dysfunctional adipose tissue in conditions of obesity is a critical source of inflammation that impacts the cardiovascular system and contributes to CVD. Although traditionally visceral adipose tissue has been linked to increased CVD risk, there is mounting interest in the role that fat accumulation around the vasculature plays in the pathogenesis of vascular dysfunction. Perivascular adipose tissue (PVAT) is in intimate contact with large, medium and small diameter arterial beds in several tissues, and has been shown to control vascular function as well as remodeling. PVAT does not merely mirror visceral adipose tissue changes seen in obesity, but has unique features that impact vascular biology. In lean individuals PVAT exerts vasodilatory and anti-inflammatory functions, however obesity results in PVAT inflammation, characterized by imbalance between pro- and anti-inflammatory cells as wells as adipokines. PVAT inflammation promotes insulin resistance in the vasculature, thus resulting in impaired insulin-mediated vasodilatory responses and vascular remodeling. In this review we address current knowledge about the mechanisms that link PVAT inflammation to insulin resistance and vascular dysfunction. Indeed, PVAT emerges as a novel type of adipose tissue that participates in the pathogenesis of CVD, independently to a large extent to visceral adipose tissue.


Assuntos
Tecido Adiposo/metabolismo , Artérias/patologia , Doenças Cardiovasculares/metabolismo , Resistência à Insulina , Veias/patologia , Tecido Adiposo/patologia , Artérias/metabolismo , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/patologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Veias/metabolismo
12.
Diabetes ; 64(6): 1988-2001, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25605806

RESUMO

Novel therapies are needed for treating the increasing prevalence of hepatic steatosis in Western populations. In this regard, dipeptidyl peptidase-4 (DPP-4) inhibitors have recently been reported to attenuate the development of hepatic steatosis, but the potential mechanisms remain poorly defined. In the current study, 4-week-old C57Bl/6 mice were fed a high-fat/high-fructose Western diet (WD) or a WD containing the DPP-4 inhibitor, MK0626, for 16 weeks. The DPP-4 inhibitor prevented WD-induced hepatic steatosis and reduced hepatic insulin resistance by enhancing insulin suppression of hepatic glucose output. WD-induced accumulation of hepatic triacylglycerol (TAG) and diacylglycerol (DAG) content was significantly attenuated with DPP-4 inhibitor treatment. In addition, MK0626 significantly reduced mitochondrial incomplete palmitate oxidation and increased indices of pyruvate dehydrogenase activity, TCA cycle flux, and hepatic TAG secretion. Furthermore, DPP-4 inhibition rescued WD-induced decreases in hepatic PGC-1α and CPT-1 mRNA expression and hepatic Sirt1 protein content. Moreover, plasma uric acid levels in mice fed the WD were decreased after MK0626 treatment. These studies suggest that DPP-4 inhibition ameliorates hepatic steatosis and insulin resistance by suppressing hepatic TAG and DAG accumulation through enhanced mitochondrial carbohydrate utilization and hepatic TAG secretion/export with a concomitant reduction of uric acid production.


Assuntos
Dieta Ocidental/efeitos adversos , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Resistência à Insulina/fisiologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Mitocôndrias/metabolismo , Animais , Western Blotting , Composição Corporal/efeitos dos fármacos , Ceramidas/sangue , Camundongos , Camundongos Endogâmicos C57BL , Palmitatos/sangue , Ácido Pirúvico/sangue , Triazóis/uso terapêutico , Triglicerídeos/sangue
13.
Endocrinology ; 155(6): 2266-76, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24712875

RESUMO

Therapies to prevent renal injury in obese hypertensive individuals are being actively sought due to the obesity epidemic arising from the Western diet (WD), which is high in fructose and fat. Recently, activation of the immune system and hyperuricemia, observed with high fructose intake, have been linked to the pathophysiology of hypertension and renal injury. Because dipeptidyl peptidase 4 (DPP4) is a driver of maladaptive T-cell/macrophage responses, renal-protective benefits of DPP4 inhibition in the WD-fed mice were examined. Mice fed a WD for 16 weeks were given the DPP4 inhibitor MK0626 in their diet beginning at 4 weeks of age. WD-fed mice were obese, hypertensive, and insulin-resistant and manifested proteinuria and increased plasma DPP4 activity and uric acid levels. WD-fed mice also had elevated kidney DPP4 activity and monocyte chemoattractant protein-1 and IL-12 levels and suppressed IL-10 levels in the kidney, suggesting macrophage-driven inflammation, glomerular and tubulointerstitial injury. WD-induced increases in DPP4 activation in the plasma and kidney and proteinuria in WD mice were abrogated by MK0626, although blood pressure and systemic insulin sensitivity were not improved. Contemporaneously, MK0626 reduced serum uric acid levels, renal oxidative stress, and IL-12 levels and increased IL-10 levels, suggesting that suppression of DPP4 activity leads to suppression of renal immune/inflammatory injury responses to a WD. Taken together, these results demonstrate that DPP4 inhibition prevents high-fructose/high-fat diet-induced glomerular and tubular injury independent of blood pressure/insulin sensitivity and offers a potentially novel therapy for diabetic and obesity-related kidney disease.


Assuntos
Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Nefropatias/etiologia , Nefropatias/prevenção & controle , Obesidade/complicações , Obesidade/tratamento farmacológico , Triazóis/uso terapêutico , Animais , Peso Corporal/efeitos dos fármacos , Inibidores da Dipeptidil Peptidase IV/farmacologia , Resistência à Insulina , Rim/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL
14.
Endocrinol Metab Clin North Am ; 43(1): 103-22, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24582094

RESUMO

Patients with hypertension and type 2 diabetes are at increased risk of cardiovascular and chronic renal disease. Factors involved in the pathogenesis of both hypertension and type 2 diabetes include inappropriate activation of the renin-angiotensin-aldosterone system, oxidative stress, inflammation, impaired insulin-mediated vasodilatation, augmented sympathetic nervous system activation, altered innate and adaptive immunity, and abnormal sodium processing by the kidney. The renin-angiotensin-aldosterone system blockade is a key therapeutic strategy in the treatment of hypertension in type 2 diabetes. Emerging therapies for resistant hypertension as often exists in patients with diabetes, include renal denervation and carotid body denervation.


Assuntos
Comorbidade , Diabetes Mellitus Tipo 2 , Hipertensão , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/terapia , Humanos , Hipertensão/epidemiologia , Hipertensão/metabolismo , Hipertensão/terapia
15.
Ann N Y Acad Sci ; 1311: 138-50, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24650277

RESUMO

Two-thirds of adults in the United States are overweight or obese, and another 26 million have type 2 diabetes. Decreased insulin sensitivity in cardiovascular tissue is an underlying abnormality in these individuals. Insulin metabolic signaling increases endothelial cell nitric oxide (NO) production. Impaired vascular insulin sensitivity is an early defect leading to impaired vascular relaxation. In overweight and obese persons, as well as in those with hypertension, systemic and vascular insulin resistance often occur in conjunction with activation of the cardiovascular tissue renin-angiotensin-aldosterone system (RAAS). Activated angiotensin II type 1 receptor and mineralocorticoid receptor signaling promote the development of vascular insulin resistance and impaired endothelial NO-mediated relaxation. Research in this area has implicated excessive serine phosphorylation and proteasomal degradation of the docking protein insulin receptor substrate and enhanced signaling through hybrid insulin/insulin-like growth factor receptor as important mechanisms underlying RAAS impediment of downstream vascular insulin metabolic signaling. This review will present recent evidence supporting the notion that RAAS signaling represents a potential pathway for the development of vascular insulin resistance and impaired endothelial-mediated vasodilation.


Assuntos
Sistema Cardiovascular/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Endotélio Vascular/metabolismo , Resistência à Insulina/fisiologia , Insulina/metabolismo , Sobrepeso/metabolismo , Sistema Cardiovascular/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Endotélio Vascular/fisiopatologia , Obesidade/metabolismo , Obesidade/fisiopatologia , Sobrepeso/fisiopatologia , Estados Unidos
16.
Cardiorenal Med ; 3(2): 154-164, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23922555

RESUMO

Angiotensin receptor (type 1) blockers (ARBs) can reduce both hypertension and insulin resistance induced by local and systemic activation of the renin-angiotensin-aldosterone system. The effectiveness of azilsartan medoxomil (AZIL-M), a novel imidazole-based ARB, to facilitate metabolic improvements in conditions of angiotensin II (Ang II)-associated insulin resistance is currently unknown. The aim of this study was to determine the impact of chronic AZIL-M treatment on glucose transport activity and key insulin signaling elements in red skeletal muscle of Ang II-treated rats. Male Sprague-Dawley rats were treated for 8 weeks with or without Ang II (200 ng/kg/min) combined with either vehicle or AZIL-M (1 mg/kg/day). Ang II induced significant (p < 0.05) increases in blood pressure, which were completely prevented by AZIL-M. Furthermore, Ang II reduced insulin-mediated glucose transport activity in incubated soleus muscle, and AZIL-M co-treatment increased this parameter. Moreover, AZIL-M treatment of Ang II-infused animals increased the absolute phosphorylation of insulin signaling molecules, including Akt [both Ser473 (81%) and Thr308 (23%)] and AS160 Thr642 (42%), in red gastrocnemius muscle frozen in situ. Absolute AMPKα (Thr172) phosphorylation increased (98%) by AZIL-M treatment, and relative Thr389 phosphorylation of p70 S6K1, a negative regulator of insulin signaling, decreased (51%) with AZIL-M treatment. These results indicate that ARB AZIL-M improves the in vitro insulin action on glucose transport in red soleus muscle and the functionality of the Akt/AS160 axis in red gastrocnemius muscle in situ in Ang II-induced insulin-resistant rats, with the latter modification possibly associated with enhanced AMPKα and suppressed p70 S6K1 activation.

18.
Horm Mol Biol Clin Investig ; 15(2): 49-57, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25436732

RESUMO

Obesity is a leading contributor to morbidity and mortality worldwide. Chronic overnutrition and lack of physical activity result in excess deposition of adipose tissue and insulin resistance, which plays a key role in the pathophysiology of type 2 diabetes mellitus (DM2) and associated cardiovascular disease (CVD). Dysfunctional adipose tissue in obese individuals is characterized by chronic low-grade inflammation that spreads to several tissues as well as systemically and is able to impact the cardiovascular system, resulting in both functional and anatomical abnormalities. Inflammation is characterized by abnormalities in both innate and adaptive immunity including adipose tissue infiltration by CD4+ T lymphocytes, pro-inflammatory (M1) macrophages, and increased production of adipokines. The renin-angiotensin-aldosterone system (RAAS) is inappropriately activated in adipose tissue and contributes to originating and perpetuating inflammation and excessive oxidative stress by increasing production of reactive oxygen species (ROS). In turn, ROS and pro-inflammatory adipokines cause resistance to the metabolic actions of insulin in several tissues including cardiovascular and adipose tissue. Insulin resistance in cardiovascular tissues is characterized by impaired vascular reactivity and abnormal cardiac contractility as well as hypertrophy, fibrosis, and remodeling, which ultimately result in CVD. In this context, weight loss through caloric restriction, regular physical activity, and surgery as well as pharmacologic RAAS blockade all play a key role in reducing obesity-related cardiovascular morbidity and mortality.


Assuntos
Tecido Adiposo/imunologia , Doenças Cardiovasculares/complicações , Inflamação/complicações , Resistência à Insulina , Obesidade/complicações , Sistema Renina-Angiotensina , Tecido Adiposo/metabolismo , Animais , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/metabolismo , Humanos , Imunidade Inata , Inflamação/imunologia , Inflamação/metabolismo , Obesidade/imunologia , Obesidade/metabolismo , Estresse Oxidativo
19.
Cardiorenal Med ; 2(3): 200-210, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22969776

RESUMO

BACKGROUND/AIMS: There are important sex-related differences in the prevalence of obesity, type 2 diabetes mellitus and cardiovascular disease. Indeed, premenopausal women have a lower prevalence of these conditions relative to age-matched men. Estrogen participates in the modulation of insulin sensitivity, energy balance, and body composition. In this paper, we investigated the impact of estrogen signaling through estrogen receptor α (ERα) on systemic insulin sensitivity and insulin signaling in skeletal muscle. METHODS: In 14- and 30-week-old female ERα knockout (ERαKO) mice and age-matched controls, we assessed insulin sensitivity by a euglycemic-hyperinsulinemic clamp and intraperitoneal glucose tolerance testing. Blood pressure was evaluated by tail cuff and telemetry. We studied ex vivo insulin-stimulated glucose uptake in skeletal muscle tissue, as well as insulin metabolic signaling molecule phosphorylation by immunoblotting and oxidative stress by immunostaining for 3-nitrotyrosine. RESULTS: Body weight was higher in ERαKO mice at 14 and 30 weeks of age. At 30 weeks, intraperitoneal glucose tolerance testing and clamp results demonstrated impaired systemic insulin sensitivity in ERαKO mice. Insulin-stimulated glucose uptake in soleus was lower in ERαKO mice at both ages. The insulin receptor substrate 1/phosphatidylinositol 3-kinase association and the activation of protein kinase B were decreased in ERαKO mice, whereas immunostaining for 3-nitrotyrosine was increased. CONCLUSIONS: Our data demonstrate a critical age-dependent role for estrogen signaling through ERα on whole-body insulin sensitivity and insulin metabolic signaling in skeletal muscle tissue. These findings have potential translational implications for the prevention and management of type 2 diabetes mellitus and cardiovascular disease in women, who are at increased risk for these conditions.

20.
Curr Diabetes Rev ; 8(2): 76-83, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22229253

RESUMO

The incidence of type 2 diabetes mellitus (DM2) has increased dramatically over the last several decades, largely driven by equally worrisome growing rates of obesity. Chronic diabetic complications are leading causes of morbidity and mortality worldwide. Key players in the pathophysiology of DM2 are insulin resistance and ß cell dysfunction, which in turn is a result of both ß cell functional abnormality as well as reduced ß cell mass. The mechanisms implicated are multifactorial and include genetic and environmental factors related to obesity. Glucose homeostasis is critically dependent on a finely regulated balance between insulin sensitivity and output in the pancreas, and insulin resistance demands a corresponding rise in insulin output in order to maintain normal glycemia. However, this compensation is lost in individuals predisposed to DM2, resulting in overt hyperglycemia. Furthermore, insulin resistance related to excess adiposity is linked to several abnormalities which impact ß cell function and viability. These include glucotoxicity, lipotoxicity, increased oxidative stress, and inflammation. In addition, insulin signaling in the ß cell is essential to its own functionality and viability, and obesity-related abnormalities in insulin signaling are known to induce failure of insulin secretion and hyperglycemia. Insulin resistance in the ß cell arises from defects in phosphorylation/activation of insulin receptor substrates (IRS) proteins, which result in impairment in glucose sensing, glucose stimulated insulin secretion, and also in increased loss of ß cells. This review intends to provide an update on the main characteristics and mechanisms that link obesity and insulin resistance to ß cell dysfunction in the pathogenesis of DM2.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Ingestão de Energia , Resistência à Insulina , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Obesidade/metabolismo , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Humanos , Insulina/uso terapêutico , Masculino , Estado Nutricional , Obesidade/complicações , Obesidade/fisiopatologia , Estados Unidos
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