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1.
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
2.
J Sleep Res ; : e13046, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32293774

RESUMO

There is now increasing evidence demonstrating that obstructive sleep apnea (OSA) contributes to microvascular disorder. However, whether OSA is associated with impaired coronary flow reserve is still unclear. Therefore, we conducted this systematic review and meta-analysis to summarize current evidence. In a systematic review, PubMed, Embase, the Cochrane Library and Web of Science were searched; five observational studies fulfilled the selection criteria and were included in this study. Data were extracted from selected studies and meta-analysis was performed using random-effects modelling. In all, 829 OSA patients and 507 non-OSA subjects were included and assessed for coronary flow reserve (CFR), the clinical indicator of coronary microvascular dysfunction (CMD). For all studies, OSA was significantly associated with reduced CFR. The pooled weighted mean difference (WMD) of CFR was -0.78 (95% confidence interval [CI] -1.25 to -0.32, p ï¼œ 0.001, I2  = 84.4%). The difference in the apnea-hypopnea index (AHI) between studies can explain 89% of heterogeneity (coef = -0.05, 95% CI -0.12 to 0.02, p = .078) in a meta-regression, indicating the CFR tended to negatively correlate with severity of OSA. The Egger regression test did not show statistical significance (p = .49). In conclusion, there are plausible biological mechanisms linking OSA and CMD, and the preponderance of evidence from this systematic review suggests that OSA, especially severe OSA, is associated with reduced CFR. Future studies are warranted to further delineate the exact role of OSA in CMD occurrence and development in a prospective setting.

3.
Medicine (Baltimore) ; 99(11): e18052, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32176024

RESUMO

The objective of the present study was to explore the association between intercellular adhesion molecule 1 (ICAM1) polymorphisms (rs5498 and rs3093030) and diabetic foot (DF) susceptibility in a Chinese Han population.128 type 2 diabetes mellitus (T2DM) patients with DF, 147 T2DM patients without DF, and 155 healthy individuals were enrolled in this study. ICAM1 polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The genotypes and alleles of the polymorphisms were compared by χ test between the 2 groups. Association between ICAM1 polymorphisms and DF susceptibility was expressed through odds ratio (OR) with corresponding 95% confidence interval (95%CI). Effects of ICAM1 polymorphisms on DF clinical characteristics were analyzed by t test.GG genotype of rs5498 polymorphism was distinctly correlated with decreased T2DM risk (OR = 0.369, 95%CI = 0.152-0.895) and reduced susceptibility to DF among healthy controls (OR = 0.316, 95%CI = 0.119-0.837). Similar results were discovered between rs5498 G allele and decreased risk of T2DM (OR = 0.676, 95%CI = 0.475-0.963) and DF (OR = 0.656, 95%CI = 0.453-0.950) among healthy controls. Individuals carrying rs3093030 T allele had low susceptibility to DF developed from T2DM (OR = 0.634, 95%CI = 0.412-0.974). DF patients carrying rs5498 AA genotype had significantly higher serum creatinine levels than GG genotype carriers (P = .003).ICAM1 rs3093030 polymorphism may act as a protective factor against DF developed from T2DM, moreover, rs5498 may be involved in onset of T2DM.Clinical trial number: ChiCTR-INR-18010231.


Assuntos
Pé Diabético/genética , Predisposição Genética para Doença/genética , Molécula 1 de Adesão Intercelular/genética , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Molécula 1 de Adesão Intercelular/fisiologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
4.
Can J Diabetes ; 44(4): 327-334.e3, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31902718

RESUMO

OBJECTIVES: Maternal diabetes mellitus (including pre-existing and gestational diabetes mellitus) is linked with adverse infant outcomes. However, the question of whether maternal diabetes increases the risk of persistent pulmonary hypertension of the newborn (PPHN) is unclear. Herein, we conducted a systematic review and meta-analysis to summarize clinical evidence to determine the association between maternal diabetes mellitus and PPHN. METHODS: In this systematic review and meta-analysis, we systematically searched PubMed, Embase, Cochrane Library, Web of Science and Google Scholar to identify relevant studies according to predefined criteria. Data from selected studies were extracted, and meta-analysis was performed using fixed effects modelling. RESULTS: In all, we included 7 unique studies with aggregated data on 2 million individuals and >5,000 cases of PPHN. Maternal diabetes was significantly associated with a higher risk of PPHN (risk ratio [RR], 1.37; 95% confidence interval [CI], 1.23 to 1.51). Both case-control and cohort studies exhibited that the presence of maternal diabetes increased the risk of PPHN (case-control: RR, 1.91; 95% CI, 1.02 to 2.79; cohort: RR, 1.36; 95% CI, 1.22 to 1.50). By omitting 1 study at a time, sensitivity analysis made sure that no individual study was entirely responsible for the combined results. CONCLUSIONS: Maternal diabetes was associated with increased risk of PPHN. For babies with refractory hypoxemia, with mothers with diabetes, PPHN should be taken into consideration in clinical practice.

5.
Horm Metab Res ; 51(11): 729-734, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31683343

RESUMO

Contrasting data about the association between proliferative diabetic retinopathy (PDR) and vitamin D status remain unknown. First, a hospital-based cross-sectional study consisting of 889 diabetic retinopathy (DR) and non-DR (NDR) patients was admitted. Further the accumulated evidence was performed to explore the association and dose-response relationship. Our study indicated that the odd ratio for PDR in vitamin D deficiency (VDD) individuals was significantly increased (1.60, 95% CI 1.06-2.42), compared with NDR in vitamin D sufficiency individuals, adjusted by age, sex, diabetic duration, and HbA1c. Four studies plus our study with data on vitamin D levels in 4970 patients with PDR and NDR subjects are compared. Association between vitamin D deficiency and risk of PDR exists (OR=1.69, 95% CI 1.40-2.05; I2=0%, p=0.61). Association between a nonlinear trend for vitamin D decrease with risk of DR was significant (chi2=16.53, p=0.0003). No significant heterogeneity in identified studies was found (goodness of fit chi2=2.98, p=0.225). It is concluded that vitamin D deficiency is significantly associated with risk of proliferative diabetic retinopathy.

6.
Lipids Health Dis ; 18(1): 207, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31775868

RESUMO

OBJECTIVE: Endoplasmic reticulum (ER) stress and mitochondrial function affected intramuscular fat accumulation. However, there is no clear evident on the effect of the regulation of ER stress and mitochondrial function by Angiotensin-converting enzyme 2 (ACE2) on the prevention of intramuscular fat metabolism. We investigated the effects of ACE2 on ER stress and mitochondrial function in skeletal muscle lipid metabolism. METHODS: The triglyceride (TG) content in skeletal muscle of ACE2 knockout mice and Ad-ACE2-treated db/db mice were detected by assay kits. Meanwhile, the expression of lipogenic genes (ACCα, SREBP-1c, LXRα, CPT-1α, PGC-1α and PPARα), ER stress and mitochondrial function related genes (GRP78, eIF2α, ATF4, BCL-2, and SDH6) were analyzed by RT-PCR. Lipid metabolism, ER stress and mitochondrial function related genes were analyzed by RT-PCR in ACE2-overexpression C2C12 cell. Moreover, the IKKß/NFκB/IRS-1 pathway was determined using lysate sample from skeletal muscle of ACE2 knockout mice. RESULTS: ACE2 deficiency in vivo is associated with increased lipid accumulation in skeletal muscle. The ACE2 knockout mice displayed an elevated level of ER stress and mitochondrial dysfunctions in skeletal muscle. In contrast, activation of ACE2 can ameliorate ER stress and mitochondrial function, which slightly accompanied by reduced TG content and down-regulated the expression of skeletal muscle lipogenic proteins in the db/db mice. Additionally, ACE2 improved skeletal muscle lipid metabolism and ER stress genes in the C2C12 cells. Mechanistically, endogenous ACE2 improved lipid metabolism through the IKKß/NFκB/IRS-1 pathway in skeletal muscle. CONCLUSIONS: ACE2 was first reported to play a notable role on intramuscular fat regulation by improving endoplasmic reticulum and mitochondrial function. This study may provide a strategy for treating insulin resistance in skeletal muscle.

8.
BMC Cardiovasc Disord ; 19(1): 145, 2019 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-31208330

RESUMO

BACKGROUND: The relationship between vitamin D levels and peripheral arterial disease (PAD) remains unclear. We assessed the association of serum 25-hydroxyvitamin D (25(OH)D) levels with the prevalence of PAD in patients with type 2 diabetes mellitus(T2DM). METHODS: A total of 1018 T2DM patients participated in this cross-sectional study. Serum 25(OH)D levels were measured and risk factors of PAD were recorded. PAD was diagnosed as an ankle-brachial index (ABI) < 0.9. RESULTS: The mean age of the diabetic patients was 58.59 ± 11.34 years. Of all the patients, only 20.1% had a 25(OH)D level ≥ 20 ng/mL. Compared to patients without PAD, serum 25(OH)D levels were significantly lower in those with PAD (14.81 ± 8.43 vs. 11.55 ± 5.65 ng/mL, P < 0.001). The overall prevalence of PAD was 7.7%. From the highest level (≥ 20 ng/mL) to the lowest level (< 10 ng/mL) of serum 25(OH)D, the prevalence of PAD was 2.8, 7.5 and 10.7% respectively. After adjustment for age, sex, body mass index (BMI), smoking status and season, compared to patients with serum 25(OH)D levels ≥20 ng/mL, the odds ratios of PAD in patients with a level of 10 to < 20 ng/mL and < 10 ng/mL was 3.587(95% CI: 1.314-9.790) and 5.540(95% CI: 2.004-15.320), respectively. When further considering the influence of coronary heart disease (CHD), hypertension and cerebral infarction, the ratios changed to 3.824(95% CI: 1.378-10.615) and 5.729(95% CI: 2.028-16.187), respectively. And after further adjustment for the duration of diabetes, glycated hemoglobin (HbA1c) and glomerular filtration rate (GFR), the ratios changed to 3.489(95% CI: 1.100-11.062) and 3.872(95% CI: 1.168-12.841), respectively. CONCLUSIONS: Reduced serum vitamin D levels were associated with an increased risk of PAD in T2DM patients. Randomized interventive clinical studies are required to verify the effects of vitamin D supplementation on PAD.

9.
Nutr Metab (Lond) ; 16: 37, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31160916

RESUMO

Background: Proliferative diabetic retinopathy (PDR), a sight-threatening retinopathy, is the leading cause of irreversible blindness in adults. Despite strict control of systemic risk factors, a fraction of patients with diabetes develop PDR, suggesting the existence of other potential pathogenic factors underlying PDR. This study aimed to investigate the plasma metabotype of patients with PDR and to identify novel metabolite markers for PDR. Biomarkers identified from this study will provide scientific insight and new strategies for the early diagnosis and intervention of diabetic retinopathy. Methods: A total of 1024 patients with type 2 diabetes were screened. To match clinical parameters between case and control subjects, patients with PDR (PDR, n = 21) or those with a duration of diabetes of ≥10 years but without diabetic retinopathy (NDR, n = 21) were assigned to the present case-control study. Distinct metabolite profiles of serum were examined using liquid chromatography-mass spectrometry (LC-MS). Results: The distinct metabolites between PDR and NDR groups were significantly enriched in 9 KEGG pathways (P < 0.05, impact > 0.1), namely, alanine, aspartate and glutamate metabolism, caffeine metabolism, beta-alanine metabolism, purine metabolism, cysteine and methionine metabolism, sulfur metabolism, sphingosine metabolism, and arginine and proline metabolism. A total of 63 altered metabolites played important roles in these pathways. Finally, 4 metabolites were selected as candidate biomarkers for PDR, namely, fumaric acid, uridine, acetic acid, and cytidine. The area under the curve for these biomarkers were 0.96, 0.95, 1.0, and 0.95, respectively. Conclusions: This study suggested that impairment in the metabolism of pyrimidines, arginine and proline were identified as metabolic dysregulation associated with PDR. And fumaric acid, uridine, acetic acid, and cytidine might be potential biomarkers for PDR. Fumaric acid was firstly reported as a novel metabolite marker with no prior reports of association with diabetes or diabetic retinopathy, which might provide insights into potential new pathogenic pathways for diabetic retinopathy.

10.
Ren Fail ; 41(1): 446-454, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31162999

RESUMO

Objectives: Urine neutrophil gelatinase-associated lipocalin (NGAL) was found to increase in diabetic kidney disease (DKD). However, the clinical value of urine NGAL as diagnostic indicators in DKD remains to be clarified. Methods: Relevant studies were systematically retrieved from PubMed, Embase, Web of Science, and the Cochrane Library. Stratified analyses and regression analyses were performed. Results: Fourteen studies with 1561 individuals were included in our analysis, including 1204 cross-sectional participants and 357 cohort participants. For the cross-sectional studies, the pooled sensitivity and specificity of NGAL in the diagnosis of DKD were 0.82 (95% confidence interval (CI): 0.75-0.87) and 0.81 (95% CI: 0.68-0.90), respectively. The pooled diagnostic odds ratio was 19 (95% CI: 11-33), and the overall area under the curve was 0.88 (95% CI: 0.84-0.90). For the cohort studies, the pooled sensitivity and specificity of NGAL in the diagnosis of DKD were 0.96 (95% CI: 0.91-0.98) and 0.89 (95% CI: 0.84-0.92), respectively. The overall area under the curve was 0.98, indicating good discriminative ability of NGAL as biomarkers for DKD. Conclusions: Urine NGAL, as the early diagnostic marker of DKD, might have the high diagnostic value, especially in cohort studies.


Assuntos
Nefropatias Diabéticas/diagnóstico , Lipocalina-2/urina , Adolescente , Adulto , Idoso , Biomarcadores/urina , Criança , Estudos de Coortes , Estudos Transversais , Nefropatias Diabéticas/urina , Diagnóstico Precoce , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Observacionais como Assunto , Sensibilidade e Especificidade
11.
Asian Pac Isl Nurs J ; 4(1): 34-46, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31037271

RESUMO

Aims: Neck circumference (NC) was found to be related to the risk factors for coronary heart disease (CHD). However, the effects of NC on CHD are still controversial. To evaluate the relationship between NC and CHD, a meta-analysis of observational studies was performed. Method: Eligible studies on the association between NC and CHD were searched in Medline, Embase, Ovid, and Web of Science databases published in English from January 1980 to December 2016. Moreover, studies published in Chinese in Wanfang and China Hospital Knowledge databases were also searched. Random effects models in the metafor package in statistical analysis software R 3.3.3 were used for the meta-analysis. Heterogeneity was analyzed with Q statistics. Results: Eight studies were selected for the meta-analysis. A larger NC was associated with a higher prevalence of CHD (OR = 1.18, 95% CI 1.04-1.34, p = 0.0108). The eight studies were further divided into three subgroups according to the criteria for diagnosing CHD. In the subgroup of coronary angiography, NC was also found to be associated with the prevalence of CHD with low heterogeneity (OR = 1.17, 95% CI 1.07-1.28, p = 0.0007, I 2 = 17.02%). However, in the subgroup of computed tomography or past history, no association between NC and CHD was found. In addition, subgroup analyses were also conducted according to the regions of the study. No association between NC and CHD was identified in either Chinese studies or Brazil studies (OR = 1.20, 95% CI 0.96-1.49; OR = 1.31, 95% CI 0.82-2.09, respectively). Conclusion: Larger NC is associated with increased risk of CHD, especially when coronary angiography was taken to diagnose CHD.

12.
Metab Syndr Relat Disord ; 17(7): 367-373, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31145036

RESUMO

Background: Patients with type 2 diabetes are prone to the asymptomatic obstructive coronary artery disease (AO-CAD). The association of proliferative diabetic retinopathy (PDR) with AO-CAD is unknown. The aim of the study is to explore the specific relationship of PDR with AO-CAD. Methods: We performed coronary angiography and retinal photographs in 1332 participants with unknown CAD status in a retrospective discovery set and 252 patients with non-CAD enrolled in a prospective validation cohort. Main outcome measures are prediction of PDR to AO-CAD. Results: In the case-control retrospective discovery set, investigation included 211 nondiabetic retinopathy (NDR) and 140 PDR. Individuals with PDR had a 2.16 times higher risk of AO-CAD compared with individuals without diabetic retinopathy (P < 0.01). Relative risk between individuals with PDR and the risk of AO-CAD varied by different adjusted covariates, 2.53 (1.48-4.32) by age and gender; 2.16 (1.10-4.31) by additionally other covariates. In the prospective validation set, after adjustment for covariates, the cumulative risk of AO-CAD was significantly higher in the PDR group compared with NDR group, followed up for a median of 4.3 years (hazard ratio = 3.07, 95% confidence interval 1.81-5.21, P < 0.001). Conclusions: PDR showed superior identification performance over traditional risk factors in screening for AO-CAD. PDR may predict persons at high risk of AO-CAD.

13.
BMC Infect Dis ; 19(1): 157, 2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30764765

RESUMO

BACKGROUND: Helicobacter pylori infection is associated with several extragastric conditions including dyslipidemia and metabolic syndrome. This study aimed to investigate additional metabolic parameters associated with H. pylori infection in a Chinese population. METHODS: Using a case-control approach we studied 617 subjects with 13C-urea breath test (13C-UBT) values ≥10‰ who were defined as being positive for H. pylori (cases), while 617 sex and age- matched subjects with 13C-UBT values ≤1‰ were defined as H. pylori negative (controls) in Beijing Tongren Hospital from March 2016 to May 2017. Biochemical parameters including serum bilirubin and lipids were tested. RESULTS: A total of 1982 subjects participated in this study. The H. pylori infected subjects had significantly lower serum direct bilirubin concentrations (2.34 ± 0.38 vs. 2.47 ± 0.90 µmol/L, P = 0.008). H. pylori infection was independently associated with lower direct bilirubin levels (OR = 1.497, 95% CI =1.121-1.999, P = 0.006) or total bilirubin levels (OR = 1.322, 95% CI =1.005-1.738, P = 0.046) after adjustment for age, sex, body mass index (BMI), alanine aminotransferase (ALT), aspartate aminotransferase (AST), high-density lipoprotein cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), total cholesterol (TC) and triglycerides(TG). In addition, the H. pylori infected subjects had higher LDL-C levels (2.98 ± 0.76 vs. 2.89 ± 0.75 mmol/L, P = 0.033) and lower HDL-C levels (1.39 ± 0.37 vs. 1.44 ± 0.41 mmol/L, P = 0.044). LDL-C was negatively correlated with direct bilirubin concentration (R = - 0.260, P < 0.0001). CONCLUSIONS: Bilirubin has been found to be a potent endogenous antioxidant and negatively associated with metabolic syndrome. Our results suggest that H. pylori infection is an independent risk factor for serum bilirubin reduction and less favorable lipid profiles.


Assuntos
Bilirrubina/sangue , Dislipidemias/etiologia , Infecções por Helicobacter/sangue , Infecções por Helicobacter/complicações , Lipídeos/sangue , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , China/epidemiologia , Dislipidemias/epidemiologia , Dislipidemias/metabolismo , Feminino , Inquéritos Epidemiológicos , Infecções por Helicobacter/epidemiologia , Infecções por Helicobacter/metabolismo , Helicobacter pylori/isolamento & purificação , Hospitais/estatística & dados numéricos , Humanos , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/complicações , Síndrome Metabólica/epidemiologia , Pessoa de Meia-Idade , Fatores de Risco , Adulto Jovem
14.
Diabetes Metab Res Rev ; 35(4): e3123, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30604460

RESUMO

BACKGROUND: Previous works indicated that the stress on the endoplasmic reticulum (ER) affected nonalcoholic fatty liver disease (NAFLD). However, there is no clear evident on the effect of the regulation of ER stress by angiotensin-converting enzyme 2 (ACE2) on the prevention of NAFLD. METHODS: HepG2 cells were treated with thapsigargin (Tg) or palmitic acid (PA). We analysed ACE2 expression using Western-blotting analyses. ER stress-related proteins were detected in ACE2 knockout mice and Ad-ACE2-treated db/db mice by immunofluorescence or Western-blotting analyses. In ACE2-overexpression HepG2 cells, the triglyceride (TG), total cholesterol (TC), and glycogen content were detected by assay kits. Meanwhile, the expression of hepatic lipogenic proteins (ACCα, SREBP-1c, FAS, and LXRα), enzymes for gluconeogenesis (PEPCK, G6Pase, and IRS2), and IKKß/NFκB/IRS1/Akt pathway were analysed by Western-blotting analyses. RESULTS: ACE2 was significantly increased in Tg/PA-induced cultured hepatocytes. Additionally, ACE2 knockout mice displayed elevated levels of ER stress, while Ad-ACE2-treated db/db mice showed reduced ER stress in liver. Furthermore, activation of ACE2 can ameliorate ER stress, accompanied by decreased TG content, increased intracellular glycogen, and downregulated expression of hepatic lipogenic proteins and enzymes for gluconeogenesis in Tg/PA-induced hepatocytes. As a consequence of anti-ER stress, the activation of ACE2 led to improved glucose and lipid metabolism through the IKKß/NFκB/IRS1/Akt pathway. CONCLUSIONS: This is the first time documented that ACE2 had a notable alleviating role in ER stress-induced hepatic steatosis and glucose metabolism via the IKKß/NFκB/IRS1/Akt-mediated pathway. This study may further provide insight into a novel underlying mechanism and a strategy for treating NAFLD.


Assuntos
Estresse do Retículo Endoplasmático , Gluconeogênese , Metabolismo dos Lipídeos , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Peptidil Dipeptidase A/fisiologia , Transdução de Sinais , Animais , Células Hep G2 , Humanos , Masculino , Camundongos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/enzimologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Triglicerídeos/metabolismo
15.
Biochem Biophys Res Commun ; 508(2): 556-562, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30509498

RESUMO

Regulatory Factor X-box binding transcriptional factor 6 (Rfx6) plays an important role in the differentiation and development of pancreas in mammals. However, the direct target genes of Rfx6 to regulate this process were largely unknown. The present study aimed to investigate the function of Rfx6 on regulating pancreatic differentiation and development in a physiologically-relevant context. We performed the chromatin immunoprecipitation followed by the next generation sequencing analysis (ChIP-seq) using whole pancreatic tissue harvested from C57/BL6 adult mice to find target genes of Rfx6. We captured 4146 unique peaks in the genome region of the adult murine pancreas. Among all these binding peaks, a majority were located in intron or intergenic regions. We further annotated all peaks to their nearest gene, and over 1000 genes were captured as Rfx6-binding genes in the pancreas. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis found that Rfx6-binding genes to be associated with the pancreas developmental process. A portion of selected ChIP-seq targets related with pancreas differentiation including Pdx1, Neurod1, Hnf1a, Nkx6-1, St18 and Shox2 were selected and validated as true targets by independent qPCR experiments. In addition, Rfx6 can directly bind to upstream of MiR-145, MiR-195, and possibly other non-protein-coding functional RNAs to control adult mouse pancreatic differentiation. Interestingly, our study revealed that Rfx6 played an important role in insulin translation by binding to the Eif2ak1, Upf1, and Eif5. Our data provide direct target genes of Rfx6 during pancreas development and point to Rfx6 as a potential therapeutic target for improving insulin protein content.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Insulina/biossíntese , Pâncreas/crescimento & desenvolvimento , Fatores de Transcrição de Fator Regulador X/genética , Animais , Diferenciação Celular , Regulação da Expressão Gênica , Insulina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Organogênese , Pâncreas/química , Ligação Proteica , Fatores de Transcrição de Fator Regulador X/metabolismo
16.
Cell Rep ; 25(13): 3800-3810.e6, 2018 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-30590050

RESUMO

Glucose-stimulated insulin secretion from islet ß cells is mediated by KATP channels. However, the role of non-KATP K+ channels in insulin secretion is largely unknown. Here, we show that a non-KATP K+ channel, KCNH6, plays a key role in insulin secretion and glucose hemostasis in humans and mice. KCNH6 p.P235L heterozygous mutation co-separated with diabetes in a four-generation pedigree. Kcnh6 knockout (KO) or Kcnh6 p.P235L knockin (KI) mice had a phenotype characterized by changing from hypoglycemia with hyperinsulinemia to hyperglycemia with insulin deficiency. Islets from the young KO mice had increased intracellular calcium concentration and increased insulin secretion. However, islets from the adult KO mice not only had increased intracellular calcium levels but also had remarkable ER stress and apoptosis, associated with loss of ß cell mass and decreased insulin secretion. Therefore, dysfunction of KCNH6 causes overstimulation of insulin secretion in the short term and ß cell failure in the long term.


Assuntos
Diabetes Mellitus/patologia , Canais de Potássio Éter-A-Go-Go/metabolismo , Hiperinsulinismo/patologia , Secreção de Insulina , Potenciais de Ação , Adolescente , Adulto , Animais , Sequência de Bases , Diabetes Mellitus/genética , Canais de Potássio Éter-A-Go-Go/genética , Feminino , Genes Dominantes , Células HEK293 , Humanos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Ativação do Canal Iônico , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação/genética , Linhagem , Adulto Jovem
17.
Int J Mol Sci ; 19(10)2018 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-30297647

RESUMO

Significant growth hormone (GH) reductions have been reported in diabetic animal models with disturbed metabolic balance coinciding with GH deficiency. Therefore, enhanced GH secretion may have beneficial effects in controlling diabetes. Thus, we aim to investigate the effect of hexarelin, a synthetic GH secretagogue (GHS), on GH secretion in streptozotocin (STZ, 65 mg/kg)-induced diabetic rats. Daily hexarelin (100 µg/kg) treatment was performed for two weeks in four-week-long STZ-diabetic and vehicle control rats. Pulsatile GH secretion in STZ-rats was significantly reduced in total, pulsatile, basal, and mass of GH secretion per burst. In addition, impaired GH secretion was followed by an increase in fasting-level free fatty acids (FFAs) and a decrease in insulin-like growth factor 1 (IGF-1) compared to control rats. After hexarelin treatment, pulsatile GH secretion in STZ-rats was significantly increased in total, pulsatile, and basal, but not in the mass GH secretion per burst, compared to STZ-rats without hexarelin treatment. However, there was no significant elevation in GH secretion in the hexarelin-treated control group. In addition, hexarelin-treated STZ-rats showed a significant decrease in fasting level FFAs, whereas suppression of fasting level for IGF-1 was maintained. These results suggest that STZ-induced diabetic rats have impaired pulsatile GH secretion, causing increased FFAs and decreased IGF-1 levels in circulation. Hexarelin injections for two weeks is able to normalize impaired pulsatile GH secretion with normal fasting levels of FFAs, but fails to recover IGF-1 levels.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Hormônio do Crescimento/sangue , Substâncias de Crescimento/farmacologia , Oligopeptídeos/farmacologia , Secretagogos/farmacologia , Animais , Ácidos Graxos/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Neurossecreção/efeitos dos fármacos , Ratos , Ratos Wistar
18.
Medicine (Baltimore) ; 97(41): e12767, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30313088

RESUMO

Serum alanine aminotransferase (ALT) is a biomarker of hepatocyte damage. However, the relationship between normal range of serum ALT level and metabolic syndrome (MetS) has not been completely understood. This study aimed to investigate the correlation between normal range of serum ALT level and MetS.A total of 2453 participants from the Beijing Community Pre-Diabetes study were enrolled. Multiple linear regression analysis was performed to calculate the regression coefficient. Normal serum ALT levels were divided into quartiles. Logistic regression model was used to compare the relative risk of MetS, and the receiver operating characteristic (ROC) curve to calculate the optimal ALT boundary value for predicting MetS.The frequency of MetS increased with the ALT level within the normal range. Compared with the first group, the risk of MetS was greater in the other quartiles of ALT level in males, the difference was significant for the fourth group. For females, the risk of MetS increased with ALT level within the normal range as well, with all differences showing statistical significance. The optimal ALT boundary value of the ROC curve for males and females was 24.5 and 14.5 U/L, respectively.ALT was related to metabolic factors and used as one of the indicators to assess the morbidity risk of metabolic diseases.


Assuntos
Alanina Transaminase/sangue , Síndrome Metabólica/enzimologia , Adulto , Pequim/epidemiologia , Biomarcadores/sangue , China/epidemiologia , Feminino , Humanos , Modelos Logísticos , Masculino , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/etiologia , Pessoa de Meia-Idade , Curva ROC , Valores de Referência , Fatores de Risco , Fatores Sexuais
19.
Diabetes Ther ; 9(5): 2015-2027, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30171589

RESUMO

INTRODUCTION: To explore the accumulated evidence concerning the effect of intensive blood pressure control on the incidence and progression of diabetic retinopathy (DR), proliferative diabetic retinopathy (PDR) and macular edema (ME). METHODS: A number of electronic databases were searched including PubMed, EMBASE, CINAHL, Cochrane Library, conferences and proceedings. Randomized controlled trials comparing intensive blood pressure targets with conventional blood pressure targets in patients with type 2 diabetes were included. The definition of intensive versus conventional blood pressure targets was from the pertinent original studies. Meta-analyses and trial sequential analyses of randomized trials were analyzed in STATA. RESULTS: Eight trials randomizing 6989 patients were assessed and reviewed in full text; 3749 vs. 3240 were in each arm (intensive vs. conventional). All trials had a low risk of bias. Intensive blood pressure control supported a 17% reduction in the incidence of DR (relative risk 0.83, 95% confidence interval 0.72-0.95). Trial sequential analyses confirmed that sufficient evidence indicated a relative risk reduction above 17% for the incidence of DR when intensive blood pressure control was targeted. Heterogeneity was absent (I2 = 0%; P = 0.56). No statistically significant effect was found for intensive blood pressure targeting on the progress of DR (relative risk 0.94, 95% confidence interval 0.81-1.08). TSA showed that insufficient evidence had been found, although the Z value line appeared to have a tendency of approaching the futility boundaries. There were also no statistically significant effects on the incidence of PDR and ME (TSA-adjusted CI 0.84-1.12). CONCLUSION: Intensive blood pressure control reduced the relative risk of incidence of DR by 17%. The available data were insufficient to prove or refute a relative risk reduction for the progression of DR or incidence of PDR and ME at a magnitude of 15%.

20.
Diabetes ; 67(11): 2397-2409, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30131393

RESUMO

Profound loss and senescence of adipose tissues are hallmarks of advanced age, but the underlying cause and their metabolic consequences remain obscure. Proper function of the murine double minute 2 (MDM2)-p53 axis is known to prevent tumorigenesis and several metabolic diseases, yet its role in regulation of adipose tissue aging is still poorly understood. In this study, we show that the proximal p53 inhibitor MDM2 is markedly downregulated in subcutaneous white and brown adipose tissues of mice during aging. Genetic disruption of MDM2 in adipocytes triggers canonical p53-mediated apoptotic and senescent programs, leading to age-dependent lipodystrophy and its associated metabolic disorders, including type 2 diabetes, nonalcoholic fatty liver disease, hyperlipidemia, and energy imbalance. Surprisingly, this lipodystrophy mouse model also displays premature loss of physiological integrity, including impaired exercise capacity, multiple organ senescence, and shorter life span. Transplantation of subcutaneous fat rejuvenates the metabolic health of this aging-like lipodystrophy mouse model. Furthermore, senescence-associated secretory factors from MDM2-null adipocytes impede adipocyte progenitor differentiation via a non-cell-autonomous manner. Our findings suggest that tight regulation of the MDM2-p53 axis in adipocytes is required for adipose tissue dynamics and metabolic health during the aging process.


Assuntos
Adipócitos/metabolismo , Envelhecimento/metabolismo , Lipodistrofia/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Calorimetria Indireta , Regulação para Baixo , Metabolismo Energético/genética , Teste de Tolerância a Glucose , Camundongos , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteína Supressora de Tumor p53/genética
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