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1.
Elife ; 102021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33720009

RESUMO

Measures of lung function are heritable, and thus, we sought to utilise genetics to propose drug-repurposing candidates that could improve respiratory outcomes. Lung function measures were found to be genetically correlated with seven druggable biochemical traits, with further evidence of a causal relationship between increased fasting glucose and diminished lung function. Moreover, we developed polygenic scores for lung function specifically within pathways with known drug targets and investigated their relationship with pulmonary phenotypes and gene expression in independent cohorts to prioritise individuals who may benefit from particular drug-repurposing opportunities. A transcriptome-wide association study (TWAS) of lung function was then performed which identified several drug-gene interactions with predicted lung function increasing modes of action. Drugs that regulate blood glucose were uncovered through both polygenic scoring and TWAS methodologies. In summary, we provided genetic justification for a number of novel drug-repurposing opportunities that could improve lung function.


Assuntos
Reposicionamento de Medicamentos/métodos , Hiperglicemia/genética , Pneumopatias/tratamento farmacológico , Pneumopatias/genética , Glicemia/metabolismo , Causalidade , Bases de Dados Genéticas , Estudo de Associação Genômica Ampla/métodos , Humanos , Hiperglicemia/metabolismo , Hiperglicemia/fisiopatologia , Pulmão/efeitos dos fármacos , Pulmão/fisiologia , Pulmão/fisiopatologia , Pneumopatias/metabolismo , Pneumopatias/fisiopatologia , Herança Multifatorial , Fenótipo , Polimorfismo de Nucleotídeo Único , Testes de Função Respiratória/métodos , Transcriptoma
2.
Am J Med Sci ; 361(3): 297-302, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33500122

RESUMO

Critically ill patients frequently have hyperglycemia. This event may reflect severe stress with an imbalance between anabolic hormones and catabolic hormones. Alternatively, it may reflect alterations in either insulin levels or insulin function. Insulin is a pleiotropic hormone with multiple important metabolic effects. In patients with sepsis, insulin levels are increased but insulin sensitivity is decreased. However, there is variability in insulin sensitivity, and this creates variability in glucose levels and insulin requirements and increases the frequency of hypo- and hyperglycemia. The factors that influence insulin sensitivity are complex and include inhibition of tyrosine kinase activity of the beta subunit, increased proteolytic activity resulting in loss of receptors from the plasma membrane, and possibly the transfer of insulin receptors into the nucleus where they bind to gene promoters. Better understanding of the role of insulin in critically ill patients requires prospective studies measuring insulin levels in various patient groups and the development of a simple measure of insulin sensitivity.


Assuntos
Hiperglicemia/fisiopatologia , Resistência à Insulina/fisiologia , Insulina/metabolismo , Sepse/metabolismo , Humanos , Sepse/fisiopatologia
3.
Diabetes Res Clin Pract ; 171: 108561, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33310127

RESUMO

AIMS: To investigate the prognostic value of admission blood glucose (BG) in predicting COVID-19 outcomes, including poor composite outcomes (mortality/severity), mortality, and severity. METHODS: Eligible studies evaluating the association between admission fasting BG (FBG) and random BG (RBG) levels with COVID-19 outcomes were included and assessed for risk of bias with the Quality in Prognosis Studies tool. Random-effects dose-response meta-analysis was conducted to investigate potential linear or non-linear exposure-response gradient. RESULTS: The search yielded 35 studies involving a total of 14,502 patients. We discovered independent association between admission FBG and poor COVID-19 prognosis. Furthermore, we demonstrated non-linear relationship between admission FBG and severity (Pnon-linearity < 0.001), where each 1 mmol/L increase augmented the risk of severity by 33% (risk ratio 1.33 [95% CI: 1.26-1.40]). Albeit exhibiting similar trends, study scarcity limited the evidence strength on the independent prognostic value of admission RBG. GRADE assessment yielded high-quality evidence for the association between admission FBG and COVID-19 severity, and moderate-quality evidence for its association with mortality and poor outcomes. CONCLUSION: High admission FBG level independently predicted poor COVID-19 prognosis. Further research to confirm the prognostic value of admission RBG and to ascertain the estimated dose-response risk between admission FBG and COVID-19 severity are required.


Assuntos
Glicemia/análise , Diabetes Mellitus/mortalidade , Hiperglicemia/fisiopatologia , /isolamento & purificação , /complicações , /virologia , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/metabolismo , Diabetes Mellitus/virologia , Humanos , Prognóstico , Fatores de Risco , Taxa de Sobrevida
4.
Nutrients ; 12(12)2020 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-33371247

RESUMO

Glucose is the primary energy source for the brain, and exposure to both high and low levels of glucose has been associated with numerous adverse central nervous system (CNS) outcomes. While a large body of work has highlighted the impact of hyperglycemia on peripheral and central measures of oxidative stress, cognitive deficits, and vascular complications in Type 1 and Type 2 diabetes, there is growing evidence that glycemic variability significantly drives increased oxidative stress, leading to neuroinflammation and cognitive dysfunction. In this review, the latest data on the impact of glycemic variability on brain function and neuroinflammation will be presented. Because high levels of oxidative stress have been linked to dysfunction of the blood-brain barrier (BBB), special emphasis will be placed on studies investigating the impact of glycemic variability on endothelial and vascular inflammation. The latest clinical and preclinical/in vitro data will be reviewed, and clinical/therapeutic implications will be discussed.


Assuntos
Glicemia/metabolismo , Fenômenos Fisiológicos Cardiovasculares/efeitos dos fármacos , Sistema Nervoso Central/fisiopatologia , Hiperglicemia/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Barreira Hematoencefálica/fisiopatologia , Encéfalo/metabolismo , Humanos , Inflamação
5.
J Pharmacol Sci ; 144(4): 197-203, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33070838

RESUMO

The role of cytoskeleton dynamics in the oxidative stress toward human vasculature has been unclear. The current study examined whether the cytoskeleton-disrupting agent cytochalasin B reduces oxidative stress caused by high glucose in the human arterial smooth muscle. All experiments in the human omental arteries without endothelium or the cultured human coronary artery smooth muscle cells were performed in d-glucose (5.5 mmol/L). The exposure toward d-glucose (20 mmol/L) for 60 min reduced the relaxation or hyperpolarization to an ATP sensitive K+ channel (KATP) opener levcromakalim (10-8 to 3 × 10-6 mol/L and 3 × 10-6 mol/L, respectively). Cytochalasin B and a superoxide inhibitor Tiron, restored them similarly. Cytochalasin B reduced the NADPH oxidase activity, leading to a decrease in superoxide levels of the arteries treated with high d-glucose. Also, cytochalasin B impaired the F-actin constitution and the membrane translocation of an NADPH oxidase subunit p47phox in artery smooth muscle cells treated with high d-glucose. A clinical concentration of cytochalasin B prevented human vascular smooth muscle malfunction via the oxidative stress caused by high glucose. Regulation of the cytoskeleton may be essential to keep the normal vascular function in patients with hyperglycemia.


Assuntos
Citocalasina B/farmacologia , Citoesqueleto/metabolismo , Glucose/efeitos adversos , Hiperglicemia/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Adulto , Idoso , Células Cultivadas , Cromakalim/farmacologia , Feminino , Humanos , Hiperglicemia/fisiopatologia , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Relaxamento Muscular/efeitos dos fármacos , NADPH Oxidases/metabolismo , Superóxidos/metabolismo
6.
PLoS One ; 15(10): e0239720, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33017436

RESUMO

BACKGROUND: Women with hyperglycaemia first detected in pregnancy (HFDP), including those with gestational diabetes mellitus (GDM), should undergo a glucose evaluation 4-12 weeks after delivery. Globally, suboptimal postpartum return rates limit the opportunity to intervene in women with sustained hyperglycaemia and pragmatic solutions should be sought to bridge this gap. OBJECTIVE: To assess the utility of postpartum in-hospital glucose evaluation to predict the outcome of the oral glucose tolerance test (OGTT) performed 4-12 weeks after delivery. METHODS: The study was performed prospectively at Tygerberg Hospital, Cape Town, South Africa. Women with HFDP, classified as GDM based on the modified National Institute for Health and Care Excellence criteria, who delivered between November 2018 and June 2019 were included in the study. Fasting plasma glucose (FPG) was performed 24-72 hours after delivery (t1) in the postnatal ward, provided glucose lowering medication was discontinued at delivery. An OGTT 4-12 weeks postpartum (t2) was scheduled for the total cohort. We compared glucose values and glucose categories at t1 and t2 and evaluated antenatal characteristics of women who returned, compared to the group that was lost to follow-up. RESULTS: In-hospital post-delivery glucose assessment (t1) was performed in 115 women. Glucose levels were significantly lower at t1 compared to antenatal diagnostic values (t0) and assessment at t2. Of the fourteen women with hyperglycaemia at t2, none had abnormal fasting glucose concentrations at t1. Women with HFDP who fulfilled criteria for overt diabetes at t0, all (24/115) had normal fasting glucose levels at t1 except for IFG in one (1/24). The antenatal characteristics of women with HFDP who returned at t2, were similar to the women who did not return. CONCLUSION: Based on this study, in-hospital fasting glucose 24-72 hours postpartum cannot replace the OGTT 4-12 weeks postpartum. Pragmatic solutions for low postpartum return rates in women with HFDP should be pursued.


Assuntos
Glicemia/análise , Glucose/metabolismo , Hiperglicemia/fisiopatologia , Adulto , Estudos de Coortes , Diabetes Mellitus Tipo 2/sangue , Diabetes Gestacional/sangue , Jejum/sangue , Jejum/fisiologia , Feminino , Intolerância à Glucose/sangue , Teste de Tolerância a Glucose , Humanos , Período Pós-Parto/sangue , Gravidez , Prognóstico , Estudos Prospectivos , Fatores de Risco , África do Sul
7.
Phytomedicine ; 78: 153319, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32950951

RESUMO

BACKGROUND: Inflammation and oxidative stress play essential roles in the occurrence and progression of diabetic cardiomyopathy (DCM). Isoliquiritigenin (ISL), a natural chalcone, exhibits strong anti-inflammatory and antioxidant activities. HYPOTHESIS/PURPOSE: In this study, we aimed to investigate the protective effects of ISL on DCM using high glucose (HG)-challenged cultured cardiomyocytes and streptozotocin (STZ)-induced diabetic mice. STUDY DESIGN AND METHODS: Embryonic rat heart-derived H9c2 cells challenged with a high concentration of glucose were used to evaluate the anti-inflammatory and antioxidant effects of ISL. STZ-induced diabetic mice were used to study the effects of ISL in DCM in vivo. Furthermore, cardiac fibrosis, hypertrophy, and apoptosis were explored both in vitro and in vivo. RESULTS: ISL effectively inhibited HG-induced hypertrophy, fibrosis, and apoptosis probably by alleviating the inflammatory response and oxidative stress in H9c2 cells. Results from in vivo experiments showed that ISL exhibited anti-inflammatory and antioxidant stress activities that were characterized by the attenuation of cardiac hypertrophy, fibrosis, and apoptosis, which resulted in the maintenance of cardiac function. The protective effects of ISL against inflammation and oxidative stress were mediated by the inhibition of mitogen-activated protein kinases (MAPKs) and induction of nuclear factor-erythroid 2 related factor 2 (Nrf2) signaling pathway, respectively. CONCLUSION: Our results provided compelling evidence that ISL, by virtue of neutralizing excessive inflammatory response and oxidative stress, could be a promising agent in the treatment of DCM. Targeting the MAPKs and Nrf2 signaling pathway might be an effective therapeutic strategy for the prevention and treatment of DCM.


Assuntos
Antioxidantes/farmacologia , Chalconas/farmacologia , Cardiomiopatias Diabéticas/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Apoptose/efeitos dos fármacos , Cardiotônicos/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/fisiopatologia , Glucose/metabolismo , Glucose/farmacologia , Hiperglicemia/tratamento farmacológico , Hiperglicemia/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Estreptozocina
8.
PLoS One ; 15(9): e0238750, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32886728

RESUMO

PURPOSE: The purpose of this study was to use a mouse model of diet-induced obesity to determine if corneal dysfunction begins prior to the onset of sustained hyperglycemia and if the dysfunction is ameliorated by diet reversal. METHODS: Six-week-old male C57BL/6 mice were fed a high fat diet (HFD) or a normal diet (ND) for 5-15 weeks. Diet reversal (DiR) mice were fed a HFD for 5 weeks, followed by a ND for 5 or 10 weeks. Corneal sensitivity was determined using aesthesiometry. Corneal cytokine expression was analyzed using a 32-plex Luminex assay. Excised corneas were prepared for immunofluorescence microscopy to evaluate diet-induced changes and wound healing. For wounding studies, mice were fed a HFD or a ND for 10 days prior to receiving a central 2mm corneal abrasion. RESULTS: After 10 days of HFD consumption, corneal sensitivity declined. By 10 weeks, expression of corneal inflammatory mediators increased and nerve density declined. While diet reversal restored nerve density and sensitivity, the corneas remained in a heightened inflammatory state. After 10 days on the HFD, corneal circadian rhythms (limbal neutrophil accumulation, epithelial cell division and Rev-erbα expression) were blunted. Similarly, leukocyte recruitment after wounding was dysregulated and accompanied by delays in wound closure and nerve recovery. CONCLUSION: In the mouse, obesogenic diet consumption results in corneal dysfunction that precedes the onset of sustained hyperglycemia. Diet reversal only partially ameliorated this dysfunction, suggesting a HFD diet may have a lasting negative impact on corneal health that is resistant to dietary therapeutic intervention.


Assuntos
Córnea/fisiopatologia , Dieta Hiperlipídica/efeitos adversos , Hiperglicemia/fisiopatologia , Obesidade/induzido quimicamente , Obesidade/complicações , Animais , Composição Corporal/efeitos dos fármacos , Córnea/efeitos dos fármacos , Modelos Animais de Doenças , Homeostase/efeitos dos fármacos , Hiperglicemia/complicações , Leucócitos/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Tempo , Cicatrização/efeitos dos fármacos
11.
Curr Opin Endocrinol Diabetes Obes ; 27(4): 215-224, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32618633

RESUMO

PURPOSE OF REVIEW: Emerging data have suggested that ß-cell dysfunction may exacerbate the development and progression of type 1 diabetes (T1D). In this review, we highlight clinical and preclinical studies suggesting a role for ß-cell dysfunction during the evolution of T1D and suggest agents that may promote ß-cell health in T1D. RECENT FINDINGS: Metabolic abnormalities exist years before development of hyperglycemia and exhibit a reproducible pattern reflecting progressive deterioration of ß-cell function and increases in ß-cell stress and death. Preclinical studies indicate that T1D may be prevented by modification of pathways impacting intrinsic ß-cell stress and antigen presentation. Recent findings suggest that differences in metabolic phenotypes and ß-cell stress may reflect differing endotypes of T1D. Multiple pathways representing potential drug targets have been identified, but most remain to be tested in human populations with preclinical disease. SUMMARY: This cumulative body of work shows clear evidence that ß-cell stress, dysfunction, and death are harbingers of impending T1D and likely contribute to progression of disease and insulin deficiency. Treatment with agents targeting ß-cell health could augment interventions with immunomodulatory therapies but will need to be tested in intervention studies with endpoints carefully designed to capture changes in ß-cell function and health.


Assuntos
Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 1/fisiopatologia , Células Secretoras de Insulina/fisiologia , Diabetes Mellitus Tipo 1/metabolismo , Progressão da Doença , Humanos , Hiperglicemia/sangue , Hiperglicemia/complicações , Hiperglicemia/patologia , Hiperglicemia/fisiopatologia , Insulina/deficiência , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia
12.
Invest Ophthalmol Vis Sci ; 61(5): 36, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32437549

RESUMO

Purpose: Retinal vasomotor activity can be regulated by two major endothelial enzymes, nitric oxide synthase (NOS) and cyclooxygenase (COX). The vascular arginase also consumes a NOS substrate and thus impedes NOS-mediated vasodilation. Diabetes mellitus exhibits vascular complications in the retina with elevated oxidative stress and compromised NOS-mediated vasodilation. However, the underlying molecular mechanisms remain unclear, and the effect of diabetes on COX-mediated vasodilation is unknown. Herein, we examined the relative impact of diabetes on retinal arteriolar dilations to COX and NOS activation and the roles of arginase and superoxide in diabetes-induced vasomotor dysfunction. Methods: Retinal arterioles were isolated from streptozocin-induced diabetic pigs (2 weeks of hyperglycemia, 433 ± 27 mg/dL) or age-matched control pigs (97 ± 4 mg/dL). The vasodilations to bradykinin (NOS activator) and histamine (NOS/COX activator) were examined in vitro. Results: Retinal arteriolar dilations to histamine and bradykinin were significantly reduced after 2 weeks of diabetes. The NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME) attenuated the dilations of control vessels, but not diabetic vessels, to histamine. In the presence of L-NAME and COX inhibitor indomethacin, histamine-induced dilations of control and diabetic vessels were reduced similarly. Treatment of diabetic vessels with arginase inhibitor nor-NOHA, but not superoxide dismutase mimetic TEMPOL, preserved both histamine- and bradykinin-induced dilations in an L-NAME-sensitive manner. Conclusions: Arginase, rather than superoxide, impairs endothelium-dependent NOS-mediated dilation of retinal arterioles during diabetes, whereas vasodilation mediated by COX remains intact. Blockade of vascular arginase may improve endothelial function of retinal arterioles during early onset of diabetes.


Assuntos
Arginase/fisiologia , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 1/fisiopatologia , Endotélio Vascular/enzimologia , Óxido Nítrico Sintase Tipo III/metabolismo , Artéria Retiniana/fisiologia , Vasodilatação/fisiologia , Animais , Arteríolas/fisiologia , Glicemia/metabolismo , Bradicinina/farmacologia , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Tipo 1/enzimologia , Inibidores Enzimáticos/farmacologia , Histamina/farmacologia , Hiperglicemia/fisiopatologia , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Prostaglandina-Endoperóxido Sintases/metabolismo , Sus scrofa
13.
Am J Physiol Regul Integr Comp Physiol ; 319(1): R11-R18, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32401628

RESUMO

Consumption of a single, sugar-sweetened beverage (SSB) impairs vascular endothelial function. Regular aerobic exercise improves endothelium-dependent vasodilation; however, it is unknown whether these beneficial effects persist with frequent SSB consumption. Therefore, the purpose of this study was twofold; we studied the effects of repetitive SSB consumption (75 g d-glucose, 3 times/day) for 1 wk (Glu, n = 13, 23 ± 4 yr, 23.5 ± 3.4 kg/m2) on endothelium-dependent vasodilation (FMD). Then, in a separate cohort, we investigated whether 45 min of moderate-intensity aerobic exercise on five separate days offset the hypothesized decrease in FMD during the Glu protocol (Glu+Ex, n = 11, 21 ± 3 yr, 23.8 ± 2.4 kg/m2). Baseline, fasting [glucose] (P = 0.15), [insulin] (P = 0.25), %FMD (P = 0.48), absolute FMD (P = 0.66), and shear rate area under the curve (SRAUC; P = 0.82) were similar between groups. Following the interventions, fasting [glucose] (Glu: 94 ± 6 to 92 ± 6 mg/dL, Glu+Ex: 89 ± 8 to 87 ± 6 mg/dL, P = 0.74) and [insulin] (Glu: 11.3 ± 6.2 to 11.8 ± 8.9 µU/mL, Glu+Ex: 8.7 ± 2.9 to 9.4 ± 3.2 µU/mL, P = 0.89) were unchanged. %FMD was reduced in Glu (6.1 ± 2.2 to 5.1 ± 1.3%) and increased in Glu+Ex (6.6 ± 2.2 to 7.8 ± 2.4%, P < 0.05 for both). SRAUC increased similarly in both Glu [17,715 ± 8,275 to 22,922 ± 4,808 arbitrary units (A.U.)] and Glu+Ex (18,216 ± 4,516 to 21,666 ± 5,392 A.U., main effect of time P < 0.05). When %FMD was adjusted for SRAUC, attenuation was observed in Glu (0.41 ± 0.18 to 0.23 ± 0.08%/s × 103, P < 0.05) but not Glu+Ex (0.38 ± 0.14 to 0.38 ± 0.13%/s × 103, P = 0.88). Despite unchanged fasting [glucose] and [insulin], repeated consumption of SSBs impaired conduit artery vascular endothelial function. Additionally, subjects who engaged in regular moderate-intensity aerobic exercise did not demonstrate the same SSB-induced endothelial dysfunction. Collectively, these data suggest aerobic exercise may offset the deleterious effects of repetitive SSB consumption.


Assuntos
Endotélio Vascular/fisiologia , Exercício Físico/fisiologia , Bebidas Adoçadas com Açúcar/efeitos adversos , Adolescente , Adulto , Glicemia/análise , Estudos de Coortes , Dieta , Humanos , Hiperglicemia/induzido quimicamente , Hiperglicemia/fisiopatologia , Hiperinsulinismo/induzido quimicamente , Hiperinsulinismo/fisiopatologia , Insulina/sangue , Masculino , Vasodilatação/efeitos dos fármacos , Adulto Jovem
14.
Invest Ophthalmol Vis Sci ; 61(4): 40, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32340032

RESUMO

Purpose: To determine whether high glucose (HG) compromises internalization of lysyl oxidase (LOX) through excess binding of LOX with extracellular matrix (ECM) proteins. Methods: To determine whether HG promotes binding of LOX with ECM proteins, fibronectin (FN) and collagen IV (Coll IV), total or ECM-only proteins from rat retinal endothelial cells grown in normal (N; 5 mM) or HG (30 mM) medium were analyzed by coimmunoprecipitation and Western blot (WB). In parallel, coimmunostaining was performed to determine changes in LOX binding to FN or Coll IV. To determine the effect of HG on extracellular LOX levels, medium in which cells were grown for 1, 3, 5, and 7 days were assessed for LOX levels. Results: WB analysis using total protein showed LOX overexpression and elevated levels of LOX bound to Coll IV or FN in HG condition. Similarly, a significant increase in LOX bound to FN or Coll IV was observed in ECM-only protein. These data were supported by Z-stack confocal microscopy images from coimmunostaining. Furthermore, immunostaining performed on ECM layer revealed increased presence of LOX bound to Coll IV or FN. Additionally, when media from cells grown in HG was monitored, a maximal increase in LOX level was observed by day 3, which declined by day 7. Conclusions: Findings indicate that HG promotes binding of LOX to FN and Coll IV extracellularly that results in reduced LOX internalization, attenuation of negative feedback, and upregulation of LOX expression associated with diabetic retinopathy.


Assuntos
Retinopatia Diabética/metabolismo , Matriz Extracelular/genética , Hiperglicemia/metabolismo , Proteína-Lisina 6-Oxidase/genética , Regulação para Cima/genética , Animais , Western Blotting/métodos , Células Cultivadas , Colágeno Tipo IV/metabolismo , Diabetes Mellitus Experimental/metabolismo , Retinopatia Diabética/patologia , Modelos Animais de Doenças , Células Endoteliais , Fibronectinas/metabolismo , Regulação da Expressão Gênica/genética , Humanos , Hiperglicemia/fisiopatologia , Ligação Proteica/genética , Ratos
15.
Medicine (Baltimore) ; 99(17): e19663, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32332610

RESUMO

Hyperglycemia in pregnancy (HIP) is related to adverse pregnancy outcomes. However, women with hyperglycemia in the second and third trimester of pregnancy (HISTTP) were not been observed. We aim to reveal associations between HISTTP and prematurity. To confirm which risk factor is better in predicting preterm delivery.This retrospective study included 660 patients, of which 132 have HISTTP and 528 have euglycemia. Univariate analysis was used to extract risk factors and multivariates logistic regression analysis to obtain odds ratio (OR) for prematurity. Mean decrease gini (MDG) in random forest algorithm was used to rank the risk factors.HISTTP women have higher prepregnancy BMI and a higher percentage of family history of hypertension, maternal adiposity, maternal anemia, gestational diabetes mellitus (GDM), prematurity, neonatal asphyxia in 1-minute (P < .05). Univariate analysis of prematurity showed that preterm women had higher rate of HISTTP (P < .01), second births, elderly pregnancy, hypertention, family history of hypertention and multiple perinatal infant (P < .05). Multivariate logistic regression analysis indicates that HISTTP (OR = 2.984, P = .0017), maternal hypertension (OR = 5.208, P = .001) and multiple perinatal infants (OR = 59.815, P < .0001) are independent risk factors for prematurity. After ranked the MDG, the top 3 risk factors were multiple perinatal infants, maternal hypertension, HISTTP. MDG of HISTTP is higher than that of GDM.Women with HISTTP deserve to be concerned, whose prematurity rate are increased. HISTTP is an independent risk factor and a better predictor of prematurity.


Assuntos
Hiperglicemia/complicações , Adulto , Índice de Massa Corporal , Feminino , Idade Gestacional , Humanos , Hiperglicemia/sangue , Hiperglicemia/fisiopatologia , Recém-Nascido , Modelos Logísticos , Razão de Chances , Gravidez , Complicações na Gravidez/sangue , Complicações na Gravidez/epidemiologia , Complicações na Gravidez/fisiopatologia , Segundo Trimestre da Gravidez/sangue , Segundo Trimestre da Gravidez/metabolismo , Terceiro Trimestre da Gravidez/sangue , Terceiro Trimestre da Gravidez/metabolismo , Nascimento Prematuro/sangue , Nascimento Prematuro/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Estatísticas não Paramétricas
16.
Metabolism ; 107: 154231, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32298723

RESUMO

BACKGROUND: The mechanism of pyruvate kinase M2 (PKM2)-mediated inflammatory signalling in macrophages when plaques rupture and the impact of hyperglycaemia on the signalling are unclear. The present study aimed to explore the impact of hyperglycaemia on PKM2-mediated NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome/stress granule signalling in macrophages and its correlation with plaque vulnerability in vivo and in vitro. METHODS: From July to December 2019, 80 patients with coronary heart disease (CHD) were divided into acute ST-segment elevation myocardial infarction (STEMI) (n = 57) (DM-STEMI, n = 21; non-DM-STEMI, n = 36) and stable CHD (SCHD) groups (n = 23). Circulating mononuclear cells were isolated. The value of peak troponin I (TnI), the Global Registry of Acute Coronary Events (GRACE) risk score, and the expression levels of the related markers were quantified and compared. In vitro studies on the THP-1 cells were also performed. RESULTS: The DM-STEMI group had a higher value of peak TnI and a higher GRACE risk score than the non-DM-STEMI group (p < 0.05). The highest expression levels of PKM2, NLRP3, interleukin (IL)-1ß, and IL-18 and the lowest expression level of GTPase activating protein (SH3 domain)-binding protein 1 (G3BP1) (a stress granule marker protein) were observed in the DM-STEMI group, and they were followed by the non-DM-STEMI group and the SCHD group (p < 0.05). In vitro studies showed similar results and that TEPP-46 (a PKM2 activator) and 2-deoxy-d-glucose (a toxic glucose analogue) reversed the hyperglycaemia-induced increase in the NLRP3 inflammasome and decrease in G3BP1 expression. CONCLUSION: Hyperglycaemia might increase the activation of PKM2-mediated NLRP3 inflammasome/stress granule signalling and increase plaque vulnerability, associating it with worse prognosis. PKM2 may be a novel prognostic indicator and a new target for the treatment of patients with CHD and DM.


Assuntos
Proteínas de Transporte/metabolismo , Grânulos Citoplasmáticos , Hiperglicemia/fisiopatologia , Inflamassomos , Macrófagos/metabolismo , Proteínas de Membrana/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Placa Aterosclerótica/metabolismo , Hormônios Tireóideos/metabolismo , Idoso , Linhagem Celular , Doença das Coronárias/metabolismo , DNA Helicases/sangue , Feminino , Humanos , Hiperglicemia/induzido quimicamente , Interleucinas/sangue , Masculino , Pessoa de Meia-Idade , Proteínas de Ligação a Poli-ADP-Ribose/sangue , RNA Helicases/sangue , Proteínas com Motivo de Reconhecimento de RNA/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/metabolismo , Troponina I/metabolismo
17.
Am J Physiol Endocrinol Metab ; 318(6): E1014-E1021, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32286881

RESUMO

Oral glucose ingestion leads to impaired muscle microvascular blood flow (MBF), which may contribute to acute hyperglycemia-induced insulin resistance. We investigated whether incorporating lipids and protein into a high-glucose load would prevent postprandial MBF dysfunction. Ten healthy young men (age, 27 yr [24, 30], mean with lower and upper bounds of the 95% confidence interval; height, 180 cm [174, 185]; weight, 77 kg [70, 84]) ingested a high-glucose (1.1 g/kg glucose) mixed-nutrient meal (10 kcal/kg; 45% carbohydrate, 20% protein, and 35% fat) in the morning after an overnight fast. Femoral arterial blood flow was measured via Doppler ultrasound, and thigh MBF was measured via contrast-enhanced ultrasound, before meal ingestion and 1 h and 2 h postprandially. Blood glucose and plasma insulin were measured at baseline and every 15 min throughout the 2-h postprandial period. Compared with baseline, thigh muscle microvascular blood volume, velocity, and flow were significantly impaired at 60 min postprandial (-25%, -27%, and -46%, respectively; all P < 0.05) and to a greater extent at 120 min postprandial (-37%, -46%, and -64%; all P < 0.01). Heart rate and femoral arterial diameter, blood velocity, and blood flow were significantly increased at 60 min and 120 min postprandial (all P < 0.05). Higher blood glucose area under the curve was correlated with greater MBF dysfunction (R2 = 0.742; P < 0.001). Ingestion of a high-glucose mixed-nutrient meal impairs MBF in healthy individuals for up to 2 h postprandial.


Assuntos
Glicemia/metabolismo , Artéria Femoral/fisiopatologia , Glucose/administração & dosagem , Hiperglicemia/fisiopatologia , Insulina/metabolismo , Microcirculação/fisiologia , Músculo Esquelético/irrigação sanguínea , Fluxo Sanguíneo Regional/fisiologia , Adulto , Velocidade do Fluxo Sanguíneo/fisiologia , Artéria Femoral/diagnóstico por imagem , Voluntários Saudáveis , Frequência Cardíaca/fisiologia , Humanos , Hiperglicemia/diagnóstico por imagem , Masculino , Refeições , Músculo Esquelético/diagnóstico por imagem , Período Pós-Prandial , Coxa da Perna , Ultrassonografia , Adulto Jovem
18.
Vascul Pharmacol ; 130: 106678, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32229255

RESUMO

BACKGROUND: Hyperglycemia plays a role in promoting insulin resistance in adipocytes, hepatocytes and myocytes. Its effects on insulin signaling in endothelial cells remain, however, incompletely understood. AIM: To investigate the proteomic and metabolomic profiles of human aortic endothelial cells (HAECs) exposed to insulin, normal glucose (NG), high glucose (HG) or its hyperosmolar control high mannitol (HM), and to examine whether and how HG or HM may promote insulin resistance. METHODS AND RESULTS: We exposed HAECs to HG and HM in shorter (3 h) and longer-term experiments (24 h), followed by insulin treatment for 45 min. Label-free proteomics and network analysis showed a downregulation of proteins linked to the PI3K-Akt/mTOR/eNOS signaling pathway in HAECs. Metabolomic profiling showed decreased levels of "odd-chain acylcarnitines" such as C3. At immunoblotting, HG or HM blunted insulin ability to activate the PI3K/AKT/eNOS pathway, which was reverted through a silencing of aquaporin 1 (AQP1) and Tonicity enhancer binding protein (TonEBP), while inducing p-P38 and pERK1/2. CONCLUSIONS: HG impairs the PI3K/AKT/eNOS pathway and shifts insulin signaling towards the activation of mitogenic and pro-inflammatory effectors, such as p38 and ERK1/2. These effects may explain the progression of insulin resistance as a result of endothelial glucotoxicity.


Assuntos
Células Endoteliais/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Glucose/toxicidade , Hiperglicemia/metabolismo , Resistência à Insulina , Insulina/farmacologia , Aquaporina 1/genética , Aquaporina 1/metabolismo , Células Cultivadas , Células Endoteliais/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Hiperglicemia/genética , Hiperglicemia/fisiopatologia , Manitol/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Concentração Osmolar , Pressão Osmótica/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/metabolismo , Fosforilação , Mapas de Interação de Proteínas , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
19.
Biol Res Nurs ; 22(2): 197-204, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32008368

RESUMO

OBJECTIVE: Fatigue is a pervasive and serious complaint among aging adults with type 2 diabetes. Anecdotally, hyperglycemia was thought to cause fatigue, but prior cross-sectional analyses failed to find any relationship between glucose levels and fatigue. However, study methodology may have caused this relationship to be missed. Our aim was to use concurrent and continuous data across 5 days to examine real-time momentary relationships between glucose and fatigue levels by week, day, and time of day. Additionally, we explored how these relationships differed by sex. METHOD: Participants (N = 54, 51% male, 54% non-White) wore continuous glucose monitors and wrist actigraphy into which they inputted fatigue ratings 6-8 times daily during waking hours across 5 days. Generalized estimation equation models were used to explore the relationship between glucose and fatigue when averaged by week, day, and time of day. Differences by sex were also explored. RESULTS: HbA1c and baseline and real-time fatigue were higher in women than in men. Baseline HbA1c and self-reported general fatigue were unrelated. Fatigue levels averaged by day and time of day were higher in women than in men (p < .05). Glucose and fatigue were significantly related at all levels of data (weekly, daily, and time of day) in women but not men. CONCLUSIONS: Our findings suggest that, when measured concurrently, glucose excursions may affect fatigue levels in women.


Assuntos
Glicemia/análise , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Fadiga/etiologia , Fadiga/fisiopatologia , Hiperglicemia/fisiopatologia , Actigrafia , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Fatores de Tempo
20.
Rev. clín. esp. (Ed. impr.) ; 220(1): 57-68, ene.-feb. 2020. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-198405

RESUMO

Para alcanzar un control glucémico adecuado, la hiperglucemia posprandial y basal debe reducirse. Diversos estudios epidemiológicos sugieren una asociación de las fluctuaciones de glucemia posprandial con el riesgo cardiovascular. Sin embargo, los estudios de intervención realizados hasta el momento no demuestran que el control selectivo de la hiperglucemia posprandial se asocie con beneficios cardiovasculares. En consecuencia, una adecuada combinación de fármacos, que controlen tanto la hiperglucemia basal como la posprandial, de forma individualizada según las características de cada paciente, es la mejor estrategia para alcanzar un buen control glucémico. Esta revisión pretende acercar a los clínicos el concepto de hiperglucemia posprandial, analizando las causas, cómo puede medirse, su prevalencia, sus consecuencias y, finalmente, qué estrategias terapéuticas existen para el control preferente de la misma junto a la hiperglucemia basal


To achieve appropriate glycaemic control, postprandial and baseline hyperglycaemia should be reduced. Various epidemiological studies have suggested an association between fluctuations in postprandial blood glucose and cardiovascular risk. However, studies of interventions performed to date have not shown that selective control of postprandial hyperglycaemia is associated with cardiovascular benefits. Accordingly, an appropriate combination of drugs that control both baseline and postprandial hyperglycaemia (individually based on each patient's characteristics) is the best strategy for achieving good glycaemic control. This review seeks to impart to clinicians the concept of postprandial hyperglycaemia, analysing its causes, how to measure it, its prevalence, its consequences and, ultimately, the available therapeutic strategies for the preferential control of the postprandial hyperglycaemia along with baseline hyperglycaemia


Assuntos
Humanos , Hiperglicemia/fisiopatologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Período Pós-Prandial , Complicações do Diabetes , Hiperglicemia/tratamento farmacológico , Hiperglicemia/epidemiologia , Hemoglobina A Glicada , Algoritmos , Prevalência , Doenças Cardiovasculares/prevenção & controle
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