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1.
Sci Adv ; 6(2): eaax9605, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31934629

RESUMO

Overnutrition results in adiposity and chronic inflammation with expansion of white adipose tissue (WAT). However, genetic factors controlling fat mass and adiposity remain largely undetermined. We applied whole-exome sequencing in young obese subjects and identified rare gain-of-function mutations in CTNNB1/ß-catenin associated with increased obesity risk. Specific ablation of ß-catenin in mature adipocytes attenuated high-fat diet-induced obesity and reduced sWAT mass expansion with less proliferated Pdgfrα+ preadipocytes and less mature adipocytes. Mechanistically, ß-catenin regulated the transcription of serum amyloid A3 (Saa3), an adipocyte-derived chemokine, through ß-catenin-TCF (T-Cell-Specific Transcription Factor) complex in mature adipocytes, and Saa3 activated macrophages to secrete several factors, including Pdgf-aa, which further promoted the proliferation of preadipocytes, suggesting that ß-catenin/Saa3/macrophages may mediate mature adipocyte-preadipocyte cross-talk and fat expansion in sWAT. The identification of ß-catenin as a key regulator in fat expansion and human adiposity provides the basis for developing drugs targeting Wnt/ß-catenin pathway to combat obesity.

2.
Liver Int ; 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31820847

RESUMO

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) has been considered as a risk factor of adverse cardiovascular prognosis, but the relationship between subclinical atherosclerosis and NAFLD remains controversy. We aimed to investigate the impact of subclinical atherosclerosis on incident NAFLD and liver fibrosis. METHODS: We included 3433 subjects aged ≥ 40 years and free of NAFLD. Brachial-ankle pulse wave velocity (ba-PWV) and carotid intima-media thickness (CIMT) were measured at baseline to assess subclinical atherosclerosis status. At follow-up visit, NAFLD was diagnosed by hepatic ultrasound and fibrosis was assessed by NAFLD fibrosis score (NFS), fibrosis-4 score (FIB-4) and aspartate aminotransferase to platelet ratio index (APRI). RESULTS: A total of 654 (19.1%) subjects developed NAFLD during the follow-up of 4.3 years. In the multivariate logistic regression models, each standard deviation (SD) increment of ba-PWV was associated with 20% (95% confidence interval [CI] 1.07-1.33), 22% (95% CI 1.08-1.39), 17% (95% CI 1.04-1.32) and 37% (95% CI 1.07-1.75) higher risk of incident NAFLD, higher NFS, FIB-4 and APRI, respectively. Compared with the lowest quartile of ba-PWV, the highest quartile ba-PWV had 63% (95% CI 1.20-2.22), 112% (95% CI 1.42-3.17), 86% (95% CI 1.28-2.69) and 201% (95% CI 1.29-7.04) higher risk of incident NAFLD, higher NFS, FIB-4 and APRI, respectively. Besides, per SD increase of CIMT was associated with a 12% (95% CI 1.01-1.24) higher risk of incident NAFLD. CONCLUSIONS: Increased ba-PWV was independently associated with incident NAFLD and higher probability of fibrosis, whereas CIMT was associated with incident NAFLD but not with fibrosis.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31879247

RESUMO

BACKGROUND: National investigations on the interaction of insulin resistance, ß-cell dysfunction, and obesity with the development of diabetes are scarce in China. We aimed to investigate the individual and joint associations of insulin resistance and ß-cell dysfunction with incident diabetes, and to examine the modifying effect of BMI and waist circumference on these associations among adults with normal glucose tolerance and with prediabetes. METHODS: In this nationwide, population-based, prospective cohort study, we analysed data from the China Cardiometabolic Disease and Cancer Cohort Study, which recruited adults aged 40 years or older during 2011-12 (baseline) and invited participants to attend follow-up visits in 2014-16. Patients with diabetes at baseline, missing data for baseline measures of glucose tolerance status, missing data for baseline homoeostasis model assessment (HOMA) indexes, missing data for baseline covariates, and missing data for measures of glucose tolerance status at follow-up visits were excluded. At baseline and follow-up visits, a comprehensive set of questionnaires, clinical measurements, oral glucose tolerance tests, and laboratory examinations were carried out following standardised protocols. Glucose tolerance status and prediabetes were defined according to the American Diabetes Association 2010 criteria. In the main analysis, we examined the contributions of insulin resistance (HOMA of insulin resistance [HOMA-IR]) and ß-cell dysfunction (HOMA of ß-cell function [HOMA-B]) to diabetes risk, and evaluated the impact of obesity on these associations. FINDINGS: 94 952 participants (31 517 men and 63 435 women) were included in the analysis. High HOMA-IR was associated with a greater hazard of diabetes (quartile 4 vs 1: hazard ratio [HR] 6·70, 95% CI 6·08-7·39; per unit increase in Z score: HR 2·17, 95% CI 2·10-2·24) than low HOMA-B (quartile 1 vs 4: 4·08, 3·72-4·48; per unit decrease in Z score: 1·92, 1·85-2·00). Approximately 24·4% (95% CI 23·6-25·2) of the incident diabetes could be attributed to insulin resistance and 12·4% (11·2-13·7) could be attributed to ß-cell dysfunction. The HRs for diabetes were 1·83 (95% CI 1·72-1·95) per unit increase in Z score of HOMA-IR and 2·03 (1·86-2·21) per unit decrease in Z score of HOMA-B among participants with normal weight; the corresponding HRs for diabetes were 2·02 (1·93-2·11) and 1·88 (1·79-1·98) among participants with obesity (pinteraction=0·0091). These associations and interactions were similar for participants with normal glucose tolerance or prediabetes. INTERPRETATION: Insulin resistance shows a stronger association with incident diabetes than does ß-cell dysfunction in Chinese adults, and this association pattern was more prominent among adults with obesity. Given the limitations of HOMA indexes as surrogate measures of insulin resistance and ß-cell dysfunction, these findings should be interpreted with caution. FUNDING: National Natural Science Foundation of China.

5.
J Diabetes ; 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31846221

RESUMO

Geographically, the Qinling Mountain-Huai River line divides China into two parts, Northern and Southern. Surprisingly, the line also divides the high prevalence of obesity and metabolic syndromes in Northern China from the low prevalence of Southern China. In past decades, the diet-center hypothesis has gained much support from the apparent cardiometabolic disease-protection effect of the Mediterranean diet. Questions include the following: Does the diet pattern explain the disease prevalence difference between two parts with similar genetic background? Which kind of diet pattern is suitable for future national diet recommendation for Chinese, as Mediterranean diet does for the Western countries? Here, we review the main healthy diet components, which the native inhabitants in the Yangtze River Delta region have eaten for several hundreds of years, and refer this healthy diet as "Southern River ()-style dietary pattern" or "Jiangnan Diet". This article is protected by copyright. All rights reserved.

6.
Int J Endocrinol ; 2019: 5069578, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781210

RESUMO

Introduction: Obesity has an unclear pathogenesis. MicroRNAs (miRNAs) may function as biologically active molecules for obesity through regulating adipocyte differentiation. This study aimed to identify how miR-129-5p (a specific miRNA) regulates adipogenesis in vitro and explore its possible role in the pathogenesis of obesity in humans. Materials and Methods: The miR-129-5p expression was detected in obese mouse models. The effect of miR-129-5p on adipocyte differentiation was observed, and the adipose markers were analyzed. Bioinformatics and dual-luciferase reporter assay were applied to predict and confirm the target genes of miR-129-5p. The human serum samples were detected and analyzed. Results: miR-129-5p is highly expressed in adipose tissues of db/db mice. Gain- and loss-of-function studies show that miR-129-5p could significantly inhibit adipocyte differentiation and white adipocyte browning in vitro and decreases the level of specific markers, such as FABP4, UCP1, and PPARγ, in mature white and brown adipocytes. miR-129-5p directly targets ATG7 which is predicted with bioinformatics and confirmed by dual-luciferase reporter assay. Serum miR-129-5p level was evidently elevated in patients with simple obesity (p < 0.01) and correlates with obesity indices, including BMI (r = 0.407, p < 0.029) and fat percentage (r = 0.394, p < 0.038). Conclusion: miR-129-5p might target on the ATG7-related autophagy signaling network that regulates white and brown adipogenesis. Importantly, the aforementioned results suggest serum miR-129-5p might be a potential biomarker and therapeutic target for obesity.

7.
Artigo em Inglês | MEDLINE | ID: mdl-31781763

RESUMO

CONTEXT: ß cell dedifferentiation was recently proposed as a mechanism of ß cell dysfunction, but whether it can be a trigger of ß cell failure preceding hyperglycemia in human is uncertain. Pancreatic cancer can cause new-onset diabetes, yet the underlying mechanism is unknown. OBJECTIVE: To investigate whether ß cell dedifferentiation is present in non-diabetic pancreatic ductal adenocarcinoma (PDAC) patients, we examined pancreatic islets from 15 non-diabetic patients with benign tumor (Control) and 15 non-diabetic PDAC patients. DESIGN: We calculated the number of hormone-negative endocrine cells and evaluated important markers of ß cell dedifferentiation and function in the paraneoplastic islets. We assessed tumor-related inflammatory changes under pancreatic cancer microenvironment, and their influence on ß cell identity. RESULTS: We found nearly 10% of non-hormone expressing endocrine cells in non-diabetic PDAC subjects. PDAC islets were dysfunctional, evidenced by low expression of GLUT2 and UCN3, and concomitant upregulation of ALDH1A3 expression and proinsulin accumulation. Pancreatic cancer caused paraneoplastic inflammation with enhanced tissue fibrosis, monocytes/macrophages infiltration and elevated inflammatory cytokines. Moreover, we detected ß cell dedifferentiation and defects in GSIS in islets exposed to PANC-1-conditioned medium. In a larger cohort, we showed high prevalence of new-onset diabetes in PDAC subjects, and FBG was found to be an additional useful parameter for early diagnosis of PDAC. CONCLUSIONS: Our data provide a rationale for ß cell dedifferentiation in the pathogenesis of pancreatic cancer associated diabetes. We propose that ß cell dedifferentiation can be a trigger for ß cell failure in human, before hyperglycemia occurs.

8.
Endocrinology ; 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31761936

RESUMO

MicroRNAs are essential for the regulation of development, proliferation and functions of pancreatic ß-cells. The conserved miR-221/222 cluster is an important regulator in multiple cellular processes. Here we investigated the functional role of miR-221/222 in the regulation of ß-cell proliferation and functions in transgenic mouse models. We generated two pancreatic ß-cell-specific miR-221/222 transgenic mouse models on a C57BL/6J background. The glucose metabolic phenotypes, ß-cell mass and ß-cell functions were analyzed in the mouse models. Adenovirus-mediated overexpression of miR-221/222 was performed on ß-cells and MIN6 cells to explore the effect and mechanisms of miR-221/222 on ß-cell proliferation and functions. Luciferase reporter assay, histological analysis and quantitative PCR were carried out to study the direct target genes of miR-221/222 in ß-cells. The expression of miR-221/222 was significantly upregulated in ß-cells from the high-fat-diet-fed mice and db/db mice. Overexpression of miR-221/222 impaired the insulin production and secretion of ß-cells and resulted in glucose intolerance in vivo. The ß-cell mass and proliferation were increased by miR-221/222 expression via Cdkn1b and Cdkn1c. MiR-221/222 repressed insulin transcription activity through targeting Nfatc3 and lead to reduction of insulin in ß-cells. Our findings demonstrate that miR-221/222 are important regulator of ß-cell proliferation and insulin production. The expression of miR-221/222 in ß-cells could regulate glucose metabolism in physiological and pathological processes.

9.
J Diabetes ; 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31769936

RESUMO

BACKGROUND: The relationship between albuminuria and insulin resistance (IR) has not been clarified in previous studies. This study was conducted to examine whether IR is associated with albuminuria in subjects with diverse blood pressure and glycometabolism statuses. METHODS: This study included 34136 participants whose data were drawn from a cross-sectional survey named the 2011 REACTION study. The participants were divided into six groups. The urinary albumin-creatinine ratio (UACR) and glomerular filtration rate (GFR) were used as markers of chronic kidney disease (CKD). Variance tests and logistic regression models were performed for homeostatic model assessment of insulin resistance (HOMA-IR) in relation to UACR and eGFR. RESULTS: First, UACR levels and HOMA-IR exhibited a positive correlation among participants (P<0.05), and a negative correlation existed between GFR and HOMA-IR (P<0.05). Second, in the hypertension with diabetes group, in individuals whose BMI was 18.5-24.0 kg/m2 , age was 50-60 years old, LDL-C was 2.6-3.4 mmol/L or HDL-C was 0.9-1.55 mmol/L, HOMA-IR was positively associated with UACR (P<0.05). However, there was a negative correlation between GFR and HOMA-IR in the hypertension with diabetes group in individuals whose BMI was 18.5-24.0 kg/m2 or whose age was over 65 years old (P<0.05). CONCLUSIONS: In the context of different blood pressure and glycometabolism statuses, the positive correlation between UACR levels and HOMA-IR was affected by BMI, age, LDL-C, HDL-C, and GFR. In patients with hypertension and diabetes, the early detection and intervention of IR and related risk factors in patients with normal BMI may reduce the occurrence of microalbuminuria and delay the progression of CKD. This article is protected by copyright. All rights reserved.

10.
Genome Res ; 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31722958

RESUMO

Construction of a genome-wide transgenic UAS-cDNA/ORF library in Drosophila based on the binary GAL4/UAS system has been severely hampered by technical difficulties, although genome-wide cDNA or ORF resources of Drosophila, human and mouse have been publicly available for over a decade. Here, we developed a new method named CRISPR-based modular assembly (CRISPRmass) for the high-throughput construction of a genome-wide UAS-cDNA/ORF library from publicly available cDNA/ORF resources. Through cleavage of shared vector sequences of cDNA/ORF plasmids by CRISPR/Cas9 and subsequent insertion of UAS modules by Gibson assembly, the procedure of construction of such a library by CRISPRmass is standardized as massively parallel two-step test tube reactions prior to bacterial transformation. Using CRISPRmass, we generated 5,551 UAS-cDNA/ORF constructs covering 83% of the Drosophila genes conserved in humans in the Drosophila Genomics Resource Center (DGRC) Gold Collection, and among them, 5,518 were generated within three months by three people. Our results demonstrate that CRISPRmass allows modulization, simplicity, efficiency and adaptability in the generation of a genome-wide UAS-cDNA/ORF plasmid library by using publicly available cDNA/ORF resources. CRISPRmass can be applied to editing various genome-wide libraries in general and is an alternative to Gateway technology in high-throughput plasmid library editing. Furthermore, the over 5,500 UAS-cDNA/ORF plasmids of Drosophila genes serve as a powerful resource for gain-of-function (GOF) screening in cultured cells and for generation of a transgenic UAS-cDNA/ORF library in Drosophila.

11.
Endocrine ; 66(3): 666-672, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31606865

RESUMO

PURPOSE: Up to 40% of patients with pheochromocytomas or paragangliomas (PPGLs) carry a germline mutation. This study aimed to build a nomogram using clinical information to predict the probability of germline mutation in PPGLs. METHODS: The data were collected from 563 patients who were diagnosed with PPGLs between 2002 and 2015. Clinical and pathologic features were assessed with a multivariable logistic regression analysis to predict the presence of germline mutations. A nomogram to predict the probability of germline mutation was constructed with R software. Discrimination and calibration were employed to evaluate the performance of the nomogram. RESULTS: By multivariate analysis, age at manifestation, bilateral, or multifocal tumors and family history were identified as independent predictors of the presence of any germline mutation. The nomogram was then developed using these three variables. The nomogram showed an area under the receiver operating characteristic curve (AUC) of 0. 841 (95% confidence interval [CI], 0.809-0.871). The calibration plot indicated that the nomogram-predicted probabilities compared very well with the actual probabilities (Hosmer-Lemeshow test: P = 0.888). CONCLUSION: The nomogram is a valuable predictive tool for the presence of germline mutations in patients with PPGLs.

12.
J Diabetes Res ; 2019: 9718370, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31534974

RESUMO

Objective: In general population, resting heart rate (RHR) is associated with cardiovascular disease. However, its relation to chronic kidney disease (CKD) is debated. We therefore investigated the relationship between RHR and urinary albumin/creatinine ratio (UACR, an indicator of early kidney injury) in general population at different levels of blood pressure and blood glucose. Methods: We screened out 32,885 subjects from the REACTION study after excluding the subjects with primary kidney disease, heart disease, tumor history, related drug application, and important data loss. The whole group was divided into four groups (Q1: RHR ≤ 71, Q2: 72 ≤ RHR ≤ 78, Q3: 79 ≤ RHR ≤ 86, and Q4: 87 ≤ RHR) according to the quartile of average resting heart rate. The renal function was evaluated by UACR (divided by quartiles of all data in the center to which the subject belonged). Ordinary logistic regression was carried out to explore the association between RHR and UACR at diverse blood pressure and blood glucose levels. Results: The subjects with higher RHR quartile tend to have a higher UACR, even multifactors were adjusted. After stratifying the subjects according to blood pressure and blood glucose, the positive relationship between RHR and UACR remained in the subjects with normal blood pressure and normal glucose tolerance, while in the hypertension (SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg) group and the diabetic mellitus (FPG ≥ 7.0 mmol/L and/or PPG ≥ 11.1 mmol/L) group, the relationship disappeared. In the subjects without hypertension, compared with the Q1 group, the UACR is significant higher in the Q3 group (OR: 1.11) and the Q4 group (OR: 1.22). In the subjects with normal glucose tolerance (NGT), compared with the Q1 group, the UACR is significantly higher in the Q3 group (OR: 1.13) and the Q4 group (OR: 1.19). Conclusions: The population with higher RHR tend to have a higher UACR in the normal blood pressure group and the normal glucose tolerance group.

13.
Diabetes Care ; 42(11): 2117-2126, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31455687

RESUMO

OBJECTIVE: Comprehensive assessment of serum lipidomic aberrations before type 2 diabetes mellitus (T2DM) onset has remained lacking in Han Chinese. We evaluated changes in lipid coregulation antecedent to T2DM and identified novel lipid predictors for T2DM in individuals with normal glucose regulation (NGR). RESEARCH DESIGN AND METHODS: In the discovery study, we tested 667 baseline serum lipids in subjects with incident diabetes and propensity score-matched control subjects (n = 200) from a prospective cohort comprising 3,821 Chinese adults with NGR. In the validation study, we tested 250 lipids in subjects with incident diabetes and matched control subjects (n = 724) from a pooled validation cohort of 14,651 individuals with NGR covering five geographical regions across China. Differential correlation network analyses revealed perturbed lipid coregulation antecedent to diabetes. The predictive value of a serum lipid panel independent of serum triglycerides and 2-h postload glucose was also evaluated. RESULTS: At the level of false-discovery rate <0.05, 38 lipids, including triacylglycerols (TAGs), lyso-phosphatidylinositols, phosphatidylcholines, polyunsaturated fatty acid (PUFA)-plasmalogen phosphatidylethanolamines (PUFA-PEps), and cholesteryl esters, were significantly associated with T2DM risk in the discovery and validation cohorts. A preliminary study found most of the lipid predictors were also significantly associated with the risk of prediabetes. Differential correlation network analysis revealed that perturbations in intraclass (i.e., non-PUFA-TAG and PUFA-TAGs) and interclass (i.e., TAGs and PUFA-PEps) lipid coregulation preexisted before diabetes onset. Our lipid panel further improved prediction of incident diabetes over conventional clinical indices. CONCLUSIONS: These findings revealed novel changes in lipid coregulation existing before diabetes onset and expanded the current panel of serum lipid predictors for T2DM in normoglycemic Chinese individuals.

14.
JAMA Cardiol ; 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31365039

RESUMO

Importance: Whether optimal cardiovascular health metrics may counteract the risk of cardiovascular events among patients with prediabetes or diabetes is unclear. Objective: To investigate the associations of ideal cardiovascular health metrics (ICVHMs) with subsequent development of cardiovascular disease (CVD) among participants with prediabetes or diabetes as compared with participants with normal glucose regulation. Design, Setting, and Participants: The China Cardiometabolic Disease and Cancer Cohort Study was a nationwide, population-based, prospective cohort study of 20 communities from various geographic regions in China. The study included 111 765 participants who were free from CVD or cancer at baseline. Data were analyzed between 2011 and 2016. Exposures: Prediabetes and diabetes were defined according to the American Diabetes Association 2010 criteria. Seven ICVHMs were adapted from the American Heart Association recommendations. Main Outcomes and Measures: The composite of incident fatal or nonfatal CVD, including cardiovascular death, myocardial infarction, stroke, and hospitalized or treated heart failure. Results: Of the 111 765 participants, 24 881 (22.3%) had normal glucose regulation, 61 024 (54.6%) had prediabetes, and 25 860 (23.1%) had diabetes. Mean (SD) age ranged from 52.9 (8.6) years to 59.4 (8.7) years. Compared with participants with normal glucose regulation, among participants with prediabetes, the multivariable-adjusted hazard ratio for CVD was 1.34 (95% CI, 1.16-1.55) for participants who had 1 ICVHM or less and 0.57 (95% CI, 0.43-0.75) for participants who had at least 5 ICVHMs; among participants with diabetes, the hazard ratios for CVD were 2.05 (95% CI, 1.76-2.38) and 0.80 (95% CI, 0.56-1.15) for participants who had 1 ICVHM or less and at least 5 ICVHMs, respectively. Such pattern of association between ICVHM and CVD was more prominent for participants younger than 55 years (prediabetes and at least 5 ICVHMs: hazard ratio [HR], 0.32; 95% CI, 0.16-0.63; 1 ICVHM or less: HR, 1.58, 95% CI, 1.13-2.21; diabetes and at least 5 ICVHMs: HR, 0.99; 95% CI, 0.44-2.26; 1 ICVHM or less: HR, 2.46; 95% CI, 1.71-3.54; compared with normal glucose regulation) than for participants 65 years or older (prediabetes and at least 5 ICVHMs: HR, 0.80; 95% CI, 0.50-1.26; 1 ICVHM or less: HR, 1.01; 95% CI, 0.79-1.31; diabetes and at least 5 ICVHMs: HR, 0.79; 95% CI, 0.46-1.35; 1 ICVHM or less: HR, 1.73; 95% CI, 1.36-2.22, compared with normal glucose regulation; P values for interaction ≤.02). Additionally, the hazard ratio for CVD per additional ICVHM was 0.82 (95% CI, 0.79-0.86) among participants with prediabetes and was 0.85 (95% CI, 0.80-0.89) among participants with diabetes. Conclusions and Relevance: Participants with prediabetes or diabetes who had 5 or more ICVHMs exhibited lower or no significant excess CVD risks compared with the participants with normal glucose regulation.

15.
Biomed Environ Sci ; 32(7): 477-485, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31331432

RESUMO

OBJECTIVE: The association between lipoprotein (a) [Lp(a)] levels and metabolic syndrome (MetS) remains uncertain, especially in the Asian population. The purpose of this study was to demonstrate the association between Lp(a) levels and MetS in a middle-aged and elderly Chinese cohort. METHODS: A cross-sectional study of 10,336 Chinese adults aged 40 years or older was conducted in Jiading District, Shanghai, China. Logistic regression analysis was used to evaluate the association between serum Lp(a) levels and MetS. RESULTS: In the overall population, 37.5% of participants had MetS. Compared with individuals in the lowest quartile of serum Lp(a) levels, those in the highest quartile had a lower prevalence of MetS (30.9% vs. 46.9%, P for trend < 0.0001). Multivariate logistic regression analyses showed that compared with participants in the bottom quartile of serum Lp(a) levels, those in the top quartile had decreased odds ratio (OR) for prevalent MetS [multivariate-adjusted OR 0.45 (95% confidence interval 0.39-0.51); P < 0.0001]. Additionally, Lp(a) level was conversely associated with the risk of central obesity, high fasting glucose, high triglycerides, and low HDL cholesterol, but not with hypertension. Stratified analyses suggested that increasing levels of Lp(a) was associated with decreased risk of MetS in all the subgroups. CONCLUSION: Serum Lp(a) level was inversely associated with the risk of prevalent MetS in a middle-aged and elderly Chinese cohort.


Assuntos
Lipoproteína(a)/sangue , Síndrome Metabólica/sangue , Idoso , Grupo com Ancestrais do Continente Asiático , China/epidemiologia , Estudos Transversais , Feminino , Humanos , Masculino , Síndrome Metabólica/epidemiologia , Pessoa de Meia-Idade
16.
J Diabetes ; 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31290214

RESUMO

BACKGROUND: Unhealthy diet is one of the important risk factors of diabetes, which is one of the major public health problems in China. The Internet tools provide large-scale passively collected data that show people's dietary preferences and their relationship with diabetes risk. METHODS: 212 341 708 individuals' dietary preference labels were created based on Internet data from online search and shopping software. Metabolic data obtained from the 2010 China Noncommunicable Disease Surveillance, which had 98 658 participants, was used to estimate the relation between dietary preferences geographical distribution and diabetes risk. RESULTS: Chinese dietary preferences had different geographical distribution, which is related to the local climate and consumption level. Fried food preference proportion distribution was significantly positively correlated with diabetes prevalence, hypertension prevalence and body mass index (BMI). Similarly, grilled food preference proportion distribution had significantly positive correlation with the prevalence of diabetes and hypertension. In contrast, spicy food preference proportion distribution was negatively correlated with diabetes prevalence. Sweet food preference proportion distribution was positively related to diabetes prevalence. Using dietary preferences data to predict regional prevalence of diabetes, hypertension and BMI, the average values of error (95% CI) between the three paired predicted and observed values were 9.8% (6.9%-12.7%), 7.5% (5.0%-10.0%) and 1.6% (1.2%-2.0%), respectively. CONCLUSIONS: Fried food, grilled food, and sweet food preferences were positively related to diabetes risk whereas spicy food preference was negatively correlated with diabetes risk. Dietary preferences based on passively collected Internet data could be used to predict regional prevalence of diabetes, hypertension, and BMI and showed good value for public health monitoring.

17.
Diabetes ; 68(10): 1950-1964, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31345937

RESUMO

Immature pancreatic ß-cells are highly proliferative, and the expansion of ß-cells during the early neonatal period largely determines functional ß-cell mass; however, the mechanisms are poorly characterized. We generated Ngn3RapKO mice (ablation of Raptor, an essential component of mechanistic target of rapamycin [mTORC1] in Ngn3+ endocrine progenitor cells) and found that mTORC1 was dispensable for endocrine cell lineage formation but specifically regulated both proliferation and identity maintenance of neonatal ß-cells. Ablation of Raptor in neonatal ß-cells led to autonomous loss of cell identity, decelerated cell cycle progression, compromised proliferation, and caused neonatal diabetes as a result of inadequate establishment of functional ß-cell mass at postnatal day 14. Completely different from mature ß-cells, Raptor regulated G1/S and G2/M phase cell cycle transition, thus permitting a high proliferation rate in neonatal ß-cells. Moreover, Ezh2 was identified as a critical downstream target of mTORC1 in neonatal ß-cells, which was responsible for G2/M phase transition and proliferation. Our discovery of the dual effect of mTORC1 in immature ß-cells has revealed a potential target for replenishing functional ß-cell pools by promoting both expansion and functional maturation of newly formed immature ß-cells.

18.
J Diabetes ; 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31170331

RESUMO

BACKGROUND: This study investigated the association between birth weight and diabetes in a Chinese population, and the effects of body mass index (BMI) and lifestyle factors in later life on this association. METHODS: Data from 49 118 participants aged ≥40 years with recalled birth weight from the Risk Evaluation of cAncers in Chinese diabeTic Individuals: a lONgitudinal (REACTION) study, a nationwide population-based cohort, were used. Diabetes diagnosis was based on oral glucose tolerance tests and HbA1c measurements. Logistic regression models were used to evaluate the association of birth weight and risk of diabetes in later life. RESULTS: Increased risk of diabetes was associated with lower or higher birth weight. Compared with individuals with a birth weight of 2500 to 3499 g, the odds ratios (ORs) and 95% confidence intervals (CIs) of diabetes for individuals with a birth weight of <2500, between 3500 and 3999, and ≥4000 g were 1.28 (1.11-1.47), 1.11 (1.04-1.19), and 1.20 (1.07-1.34), respectively. Significant associations were prominent in participants with a current BMI ≥24 kg/m2 , but not detected in those with a normal BMI (OR 1.20 [95% CI 0.96-1.49], 1.11 [95% CI 0.98-1.25], and 1.10 [95% CI 0.89-1.37], respectively). Moreover, there was no increased risk of diabetes in individuals with a low birth weight but with healthy dietary habits (OR 0.94; 95% CI 0.68-1.29) or ideal physical activity (OR 1.41; 95% CI 0.97-2.04). CONCLUSIONS: A U-shaped association was observed between birth weight and the risk of diabetes. Healthy lifestyles (healthy dietary habits or ideal physical activity) may eliminate the negative effects of low birth weight in the development of diabetes, but not the effect of high birth weight.

19.
Diabetes ; 68(9): 1730-1746, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31167878

RESUMO

Recent studies implicate a strong association between elevated plasma branched-chain amino acids (BCAAs) and insulin resistance (IR). However, a causal relationship and whether interrupted BCAA homeostasis can serve as a therapeutic target for diabetes remain to be established experimentally. In this study, unbiased integrative pathway analyses identified a unique genetic link between obesity-associated IR and BCAA catabolic gene expression at the pathway level in human and mouse populations. In genetically obese (ob/ob) mice, rate-limiting branched-chain α-keto acid (BCKA) dehydrogenase deficiency (i.e., BCAA and BCKA accumulation), a metabolic feature, accompanied the systemic suppression of BCAA catabolic genes. Restoring BCAA catabolic flux with a pharmacological inhibitor of BCKA dehydrogenase kinase (BCKDK) ( a suppressor of BCKA dehydrogenase) reduced the abundance of BCAA and BCKA and markedly attenuated IR in ob/ob mice. Similar outcomes were achieved by reducing protein (and thus BCAA) intake, whereas increasing BCAA intake did the opposite; this corroborates the pathogenic roles of BCAAs and BCKAs in IR in ob/ob mice. Like BCAAs, BCKAs also suppressed insulin signaling via activation of mammalian target of rapamycin complex 1. Finally, the small-molecule BCKDK inhibitor significantly attenuated IR in high-fat diet-induced obese mice. Collectively, these data demonstrate a pivotal causal role of a BCAA catabolic defect and elevated abundance of BCAAs and BCKAs in obesity-associated IR and provide proof-of-concept evidence for the therapeutic validity of manipulating BCAA metabolism for treating diabetes.

20.
Diabetes Care ; 42(8): 1539-1548, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31152120

RESUMO

OBJECTIVE: Uncertainty remains regarding the predictive value of various glycemic measures as they relate to the risk of diabetes and its complications. Using the cutoffs recommended by the American Diabetes Association's 2010 criteria, we determined the associations of fasting plasma glucose (FPG), 2-h postload glucose (2h-PG), and HbA1c with the outcomes. RESEARCH DESIGN AND METHODS: Baseline medical history, FPG, 2h-PG, and HbA1c were obtained from a population-based cohort of 193,846 adults aged ≥40 years in China during 2011-2012. A follow-up visit was conducted during 2014-2016 in order to assess incident diabetes, cardiovascular disease (CVD), cancer, and mortality. RESULTS: We documented 8,063 cases of diabetes, 3,014 CVD-related events, 1,624 cases of cancer, and 2,409 deaths during up to 5 years of follow-up. Multivariable-adjusted risk ratios (95% CIs) of diabetes associated with prediabetes based on FPG of 100-125 mg/dL, 2h-PG of 140-199 mg/dL, or HbA1c of 5.7-6.4% (39-47 mmol/mol) were 1.60 (1.43-1.79), 2.72 (2.43-3.04), and 1.49 (1.36-1.62), respectively. Restricted cubic spline analyses suggested J-shaped associations of FPG, 2h-PG, and HbA1c levels with CVD, cancer, and mortality. Multivariable-adjusted hazard ratios (95% CIs) associated with untreated diabetes based on FPG ≥126 mg/dL, 2h-PG ≥200 mg/dL, or HbA1c ≥6.5% (48 mmol/mol) were 1.18 (1.05-1.33), 1.31 (1.18-1.45), and 1.20 (1.07-1.34) for CVD; 1.10 (0.92-1.32), 1.44 (1.25-1.67), and 1.08 (0.92-1.28) for cancer; and 1.37 (1.20-1.57), 1.57 (1.41-1.76), and 1.33 (1.17-1.52) for mortality, respectively. 2h-PG remained significantly associated with outcomes in models including FPG and HbA1c as spline terms. Furthermore, 2h-PG significantly improved the ability of the C statistic to predict diabetes, CVD, and mortality. CONCLUSIONS: 2h-PG remains independently predictive of outcomes in models including FPG and HbA1c. Therefore, in addition to FPG and HbA1c, routine testing of 2h-PG should be considered in order to better assess the risks of outcomes.

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