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1.
Rev Med Chil ; 147(8): 965-976, 2019 Aug.
Artigo em Espanhol | MEDLINE | ID: mdl-31859960

RESUMO

BACKGROUND: Type 2 diabetes etiology has a strong genetic component. More than 20 genetic variants have been associated with diabetes and other metabolic markers. However, the polymorphism rs7903146 of the TCF7L2 gene has shown the strongest association. AIM: To investigate the association of TCF7L2 (rs7903146) genotype with adiposity and metabolic markers in the Chilean adult population. MATERIAL AND METHODS: The association of TCF7L2 (rs7093146) with adiposity and metabolic markers was studied in 301 participants. The outcomes of the study were adiposity markers (body weight, body mass index (BMI), fat mass and waist circumference) and metabolic markers (blood glucose, insulin, HOMA-IR, lipid profile, high sensitivity C-reactive protein (CRP), alanine aminotransferase (ALT), gamma glutamyl transpeptidase (GGT) and leptin). RESULTS: There was an association between the polymorphism TCF7L2 genotype and fasting blood glucose. The latter increased by 4.86 mg/dl per each copy of the risk allele [(95% confidence intervals (CI): 0.48; 9.24), p = 0.03] in the unadjusted adjusted model. However, this association was slightly attenuated in the fully adjusted model [4.38 mg/dl (95% IC: 0.16; 8.60), p = 0.04)]. There were no associations between the TCF7L2 genotype and any other metabolic or adiposity outcome. CONCLUSIONS: These findings confirm the association between the TCF7L2 (rs7903146) and fasting glucose in the Chilean population. However, further studies are needed to confirm the association between the TCF7L2 and diabetes risk in the Chilean population.


Assuntos
Adiposidade/genética , Diabetes Mellitus Tipo 2/genética , Polimorfismo de Nucleotídeo Único , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Adiposidade/etnologia , Adulto , Alelos , Antropometria , Glicemia/genética , Chile , Estudos Transversais , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Frequência do Gene , Estudos de Associação Genética , Marcadores Genéticos , Genótipo , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Valores de Referência , Fatores de Risco , Adulto Jovem
2.
Nat Commun ; 10(1): 5765, 2019 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-31852892

RESUMO

Body composition is often altered in psychiatric disorders. Using genome-wide common genetic variation data, we calculate sex-specific genetic correlations amongst body fat %, fat mass, fat-free mass, physical activity, glycemic traits and 17 psychiatric traits (up to N = 217,568). Two patterns emerge: (1) anorexia nervosa, schizophrenia, obsessive-compulsive disorder, and education years are negatively genetically correlated with body fat % and fat-free mass, whereas (2) attention-deficit/hyperactivity disorder (ADHD), alcohol dependence, insomnia, and heavy smoking are positively correlated. Anorexia nervosa shows a stronger genetic correlation with body fat % in females, whereas education years is more strongly correlated with fat mass in males. Education years and ADHD show genetic overlap with childhood obesity. Mendelian randomization identifies schizophrenia, anorexia nervosa, and higher education as causal for decreased fat mass, with higher body fat % possibly being a causal risk factor for ADHD and heavy smoking. These results suggest new possibilities for targeted preventive strategies.


Assuntos
Glicemia/genética , Composição Corporal/genética , Transtornos Mentais/genética , Sobrepeso/genética , Fatores Etários , Comorbidade , Escolaridade , Feminino , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Transtornos Mentais/epidemiologia , Transtornos Mentais/prevenção & controle , Pessoa de Meia-Idade , Herança Multifatorial/genética , Sobrepeso/epidemiologia , Fenótipo , Aptidão Física , Fatores de Risco , Fatores Sexuais
3.
Nutrients ; 11(7)2019 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-31284621

RESUMO

OBJECTIVE: The Nile rat (Arvicanthis niloticus) is a superior model for Type-II Diabetes Mellitus (T2DM) induced by diets with a high glycemic index (GI) and glycemic load (GLoad). To better define the age and gender attributes of diabetes in early stages of progression, weanling rats were fed a high carbohydrate (hiCHO) diet for between 2 to 10 weeks. Methods. Data from four experiments compared two diabetogenic semipurified diets (Diet 133 (60:20:20, as % energy from CHO, fat, protein with a high glycemic load (GLoad) of 224 per 2000 kcal) versus Diets 73MBS or 73MB (70:10:20 with or without sucrose and higher GLoads of 259 or 295, respectively). An epidemiological technique was used to stratify the diabetes into quintiles of blood glucose (Q1 to Q5), after 2-10 weeks of dietary induction in 654 rats. The related metagenetic physiological growth and metabolic outcomes were related to the degree of diabetes based on fasting blood glucose (FBG), random blood glucose (RBG), and oral glucose tolerance test (OGTT) at 30 minutes and 60 minutes. Results. Experiment 1 (Diet 73MBS) demonstrated that the diabetes begins aggressively in weanlings during the first 2 weeks of a hiCHO challenge, linking genetic permissiveness to diabetes susceptibility or resistance from an early age. In Experiment 2, ninety male Nile rats fed Diet 133 (60:20:20) for 10 weeks identified two quintiles of resistant rats (Q1,Q2) that lowered their RBG between 6 weeks and 10 weeks on diet, whereas Q3-Q5 became progressively more diabetic, suggesting an ongoing struggle for control over glucose metabolism, which either stabilized or not, depending on genetic permissiveness. Experiment 3 (32 males fed 70:10:20) and Experiment 4 (30 females fed 60:20:20) lasted 8 weeks and 3 weeks respectively, for gender and time comparisons. The most telling link between a quintile rank and diabetes risk was telegraphed by energy intake (kcal/day) that established the cumulative GLoad per rat for the entire trial, which was apparent from the first week of feeding. This genetic permissiveness associated with hyperphagia across quintiles was maintained throughout the study and was mirrored in body weight gain without appreciable differences in feed efficiency. This suggests that appetite and greater growth rate linked to a fiber-free high GLoad diet were the dominant factors driving the diabetes. Male rats fed the highest GLoad diet (Diet 73MB 70:10:20, GLoad 295 per 2000 kcal for 8 weeks in Experiment 3], ate more calories and developed diabetes even more aggressively, again emphasizing the Cumulative GLoad as a primary stressor for expressing the genetic permissiveness underlying the diabetes. Conclusion: Thus, the Nile rat model, unlike other rodents but similar to humans, represents a superior model for high GLoad, low-fiber diets that induce diabetes from an early age in a manner similar to the dietary paradigm underlying T2DM in humans, most likely originating in childhood.


Assuntos
Glicemia/genética , Diabetes Mellitus Tipo 2/genética , Carboidratos da Dieta , Interação Gene-Ambiente , Carga Glicêmica , Fatores Etários , Fenômenos Fisiológicos da Nutrição Animal , Animais , Biomarcadores/sangue , Glicemia/metabolismo , Composição Corporal , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Modelos Animais de Doenças , Progressão da Doença , Ingestão de Energia , Feminino , Predisposição Genética para Doença , Masculino , Estado Nutricional , Fenótipo , Roedores , Fatores Sexuais , Especificidade da Espécie , Fatores de Tempo
4.
Genes (Basel) ; 10(6)2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31141985

RESUMO

To address how skeletal muscle contributes to postprandial hyperglycemia, we performed skeletal muscle transcriptome analysis of diabetic Goto-Kakizaki (GK) and control Wistar rats by RNA sequencing (RNA-Seq). We obtained 600 and 1785 differentially expressed genes in GK rats compared to those Wistar rats at three and four weeks of age, respectively. Specifically, Tbc1d4, involved in glucose uptake, was significantly downregulated in the skeletal muscle of GK aged both three and four weeks compared to those of age-matched Wistar rats. Pdk4, related to glucose uptake and oxidation, was significantly upregulated in the skeletal muscle of GK aged both three and four weeks compared to that of age-matched Wistar rats. Genes (Acadl, Acsl1 and Fabp4) implicated in fatty acid oxidation were significantly upregulated in the skeletal muscle of GK aged four weeks compared to those of age-matched Wistar rats. The overexpression or knockout of Tbc1d4, Pdk4, Acadl, Acsl1 and Fabp4 has been reported to change glucose uptake and fatty acid oxidation directly in rodents. By taking the results of previous studies into consideration, we speculated that dysregulation of key dysregulated genes (Tbc1d4, Pdk4, Acadl, Acsl1 and Fabp4) may lead to a decrease in glucose uptake and oxidation, and an increase in fatty acid oxidation in GK skeletal muscle at three and four weeks, which may, in turn, contribute to postprandial hyperglycemia. Our research revealed transcriptome changes in GK skeletal muscle at three and four weeks. Tbc1d4, Acadl, Acsl1 and Fabp4 were found to be associated with early diabetes in GK rats for the first time, which may provide a new scope for pathogenesis of postprandial hyperglycemia.


Assuntos
Diabetes Mellitus Tipo 2/genética , Hiperglicemia/genética , Músculo Esquelético/metabolismo , Transcriptoma/genética , Animais , Glicemia/genética , Diabetes Mellitus Tipo 2/patologia , Regulação da Expressão Gênica/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hiperglicemia/patologia , Insulina/genética , Músculo Esquelético/patologia , Fosforilação , Ratos , Sequenciamento Completo do Exoma
5.
PLoS Genet ; 15(4): e1008009, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30951530

RESUMO

Recent and classical work has revealed biologically and medically significant subtypes in complex diseases and traits. However, relevant subtypes are often unknown, unmeasured, or actively debated, making automated statistical approaches to subtype definition valuable. We propose reverse GWAS (RGWAS) to identify and validate subtypes using genetics and multiple traits: while GWAS seeks the genetic basis of a given trait, RGWAS seeks to define trait subtypes with distinct genetic bases. Unlike existing approaches relying on off-the-shelf clustering methods, RGWAS uses a novel decomposition, MFMR, to model covariates, binary traits, and population structure. We use extensive simulations to show that modelling these features can be crucial for power and calibration. We validate RGWAS in practice by recovering a recently discovered stress subtype in major depression. We then show the utility of RGWAS by identifying three novel subtypes of metabolic traits. We biologically validate these metabolic subtypes with SNP-level tests and a novel polygenic test: the former recover known metabolic GxE SNPs; the latter suggests subtypes may explain substantial missing heritability. Crucially, statins, which are widely prescribed and theorized to increase diabetes risk, have opposing effects on blood glucose across metabolic subtypes, suggesting the subtypes have potential translational value.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Modelos Genéticos , Herança Multifatorial , Fenótipo , Algoritmos , Glicemia/efeitos dos fármacos , Glicemia/genética , Análise por Conglomerados , Simulação por Computador , Doença das Coronárias/sangue , Doença das Coronárias/tratamento farmacológico , Doença das Coronárias/genética , Transtorno Depressivo Maior/classificação , Transtorno Depressivo Maior/genética , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Lipídeos/sangue , Polimorfismo de Nucleotídeo Único , Estado Pré-Diabético/genética , Locos de Características Quantitativas
6.
Diabetes Metab Res Rev ; 35(5): e3155, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30892801

RESUMO

Diabetic kidney disease is one of the most serious microvascular complications and among the leading causes of end stage renal disease. Persistently increasing albuminuria has been considered to be the central hallmark of nephropathy. However, albuminuria can indicate kidney damage for clinicians; it is not a specific biomarker for prediction of diabetic kidney disease prior to the onset of this devastating complication, and in fact all individuals with microalbuminuria do not progress to overt nephropathy. Controlled glycemia is unable to prevent nephropathy in all diabetic individuals indicating the role of other factors in progression of diabetic kidney disease. There are numerous cellular and molecular defects persisting prior to appearance of clinical symptoms. So, there is an urgent need to look for easy, novel, and accurate way to detect diabetic kidney disease prior to its beginning or at the infancy stage so that its progression can be slowed or arrested. It is now accepted that initiation and progression of diabetic kidney disease are a result of complex interactions between genetic and environmental factors. Environmental signals can alter the intracellular pathways by chromatin modifiers and regulate gene expression patterns leading to diabetes and its complications. In the present review, we have discussed a possible link between aberrant DNA methylation and altered gene expression in diabetic kidney disease. Drugs targeting to reverse epigenetic alteration can retard or stop the development of this devastating disease, just by breaking the chain of events occurring prior to the development of this microvascular complication in patients with diabetes.


Assuntos
Biomarcadores , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/genética , Técnicas de Diagnóstico Endócrino , Epigênese Genética/fisiologia , Animais , Biomarcadores/análise , Biomarcadores/sangue , Glicemia/genética , Glicemia/metabolismo , Nefropatias Diabéticas/sangue , Humanos , Prognóstico
7.
Artigo em Inglês | MEDLINE | ID: mdl-30872147

RESUMO

A 10-week feeding trial was conducted to investigate the response of glucosensing system to glucose in Japanese flounder Paralichthys olivaceus (initial body weight: 7.14 ±â€¯0.10 g) fed diets with different carbohydrate content. Two experimental diets were designed as carbohydrate free (CF) and suitable carbohydrate (SC) supplementation, respectively. The dietary carbohydrate contents were 0.93% and 15.6%, respectively. After a 10-week feeding trial, a glucose tolerance test (GTT) was performed. Results showed that after the last meal in the feeding trial, the blood glucose of fish fed with diet CF peaked at 3 h (4.64 ±â€¯0.29 mM), the duration of hyperglycemia was about 5 h (1-6 h). The blood glucose in SC group peaked at 9 h (3.28 ±â€¯0.66 mM), and the duration of hyperglycemia was approximately 6 h (6-12 h). After GTT, blood glucose reached the first peak at 6 h both in the two groups, and the duration of hyperglycemia was obvious 24 h. During the 3-12 h after injection, blood glucose level in SC group was significantly higher than that in CF group. However, blood glucose level in group SC was significantly lower than that in group CF at 24 h. The blood glucose level decreased to half of the peak at 10.97 h after injection of glucose in SC group and at 27.26 h in CF group. The 6-24 h clearance ability in SC group (6.57 ±â€¯1.68%/h) was significantly higher than that in CF group (2.81 ±â€¯1.11%/h). Compared with CF diet, SC diet significantly increase the expression of glucosensing-related genes including glucose facilitative transporter type 2, glucokinase, inward rectifier K+ channel pore type 6.2, sulfonylurea receptor, carnitine palmitoyltransferase 1b, hydroxyacyl-CoA dehydrogenase, cytochrome c oxidase subunit 4, mitochondrial uncoupling protein 2a, liver X receptor, sodium/glucose co-transporter 1, a heterodimer of type 1 receptor subunits depending on T1R2 + T1R3 in liver and intestine. Meanwhile, activities of glucokinase, pyruvate kinase and glycogen synthase in liver, and hepatic glycogen content were also increased. In conclusion, glucosensing systems in Japanese flounder are responsive to dietary carbohydrate levels, especially the suitable dietary carbohydrate level, at which the glucose tolerance capacity of Japanese flounder was improved.


Assuntos
Ração Animal , Glicemia/metabolismo , Carboidratos da Dieta/farmacologia , Proteínas de Peixes/metabolismo , Linguado/metabolismo , Animais , Glicemia/genética , Proteínas de Peixes/genética , Linguado/genética
8.
Proc Natl Acad Sci U S A ; 116(15): 7449-7454, 2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30910968

RESUMO

When mice are subjected to 60% calorie restriction for several days, they lose nearly all of their body fat. Although the animals lack energy stores, their livers produce enough glucose to maintain blood glucose at viable levels even after a 23-hour fast. This adaptation is mediated by a marked increase in plasma growth hormone (GH), which is elicited by an increase in plasma ghrelin, a GH secretagogue. In the absence of ghrelin, calorie-restricted mice develop hypoglycemia, owing to diminished glucose production. To determine the site of GH action, in the current study we used CRISPR/Cas9 and Cre recombinase technology to produce mice that lack GH receptors selectively in liver (L-Ghr -/- mice) or in adipose tissue (Fat-Ghr-/- mice). When subjected to calorie restriction and then fasted for 23 hours, the L-Ghr -/- mice, but not the Fat-Ghr-/- mice, developed hypoglycemia. The fall in blood glucose in L-Ghr-/- mice was correlated with a profound drop in hepatic triglycerides. Hypoglycemia was prevented by injection of lactate or octanoate, two sources of energy to support gluconeogenesis. Electron microscopy revealed extensive autophagy in livers of calorie-restricted control mice but not in L-Ghr -/- mice. We conclude that GH acts through its receptor in the liver to activate autophagy, preserve triglycerides, enhance gluconeogenesis, and prevent hypoglycemia in calorie-restricted mice, a model of famine.


Assuntos
Autofagia , Glicemia/metabolismo , Restrição Calórica , Hormônio do Crescimento/sangue , Hipoglicemia/sangue , Fígado/metabolismo , Inanição/sangue , Animais , Glicemia/genética , Doença Crônica , Modelos Animais de Doenças , Hormônio do Crescimento/genética , Hipoglicemia/genética , Fígado/patologia , Camundongos , Camundongos Knockout , Inanição/genética , Inanição/patologia
9.
Biomed Res Int ; 2019: 7398063, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30805369

RESUMO

Background: Solute carrier family 2 member 4- (SLC2A4-) retinol binding protein-4- (RBP4-) phosphoenolpyruvate carboxykinase 1 (PCK1)/phosphoinositide 3-kinase (PI3K) is an adipocyte derived "signalling pathway" that may contribute to the pathogenesis of type 2 diabetes mellitus (T2DM). We explored whether single nucleotide polymorphisms (SNPs) of these "signalling pathway" genes are associated with gestational diabetes mellitus (GDM). Methods: Case-control studies were conducted to compare GDM and control groups. A total of 334 cases and 367 controls were recruited. Seventeen candidate SNPs of the pathway were selected. Chi-square tests, logistic regression, and linear regression were used to estimate the relationships of SNPs with GDM risk and oral glucose tolerance test (OGTT), fasting insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) levels. Model-based multifactor dimensionality reduction was used to estimate the adjusted interactions between genes. Regression and interaction analyses were adjusted by maternal age, prepregnancy BMI, and weekly BMI growth. The Bonferroni correction was applied for multiple comparisons. Results: RBP4 rs7091052 was significantly associated with GDM risk. SLC2A4 rs5435, RBP4 rs7091052, PCK1 rs1042531 and rs2236745, and PIK3R1 (coding gene of the PI3K P85 subunit) rs34309 were associated with OGTT, fasting insulin, and HOMA-IR levels in the linear regression analysis. The gene-gene interaction analysis showed that, compared with pregnant women with other genotype combinations, women with SLC2A4 rs5435 (CC/CT), RBP4 rs7091052 (CC), PCK1 rs1042531 (TT/TG) and rs2236745 (TT), and PIK3R1 rs34309 (AA) had lower GDM risk. Conclusion: SLC2A4, RBP4, PCK1, and PIK3R1 genes may be involved in the pathogenesis of GDM.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Diabetes Gestacional/genética , Transportador de Glucose Tipo 4/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Fosfatidilinositol 3-Quinases/genética , Fosfoenolpiruvato Carboxiquinase (GTP)/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas Plasmáticas de Ligação ao Retinol/genética , Adulto , Glicemia/genética , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/genética , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , Insulina/genética , Resistência à Insulina/genética , Gravidez , Transdução de Sinais/genética
10.
Mol Med Rep ; 19(3): 2245-2253, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30664213

RESUMO

Diabetic nephropathy (DN) is among the most common complications of diabetes mellitus. The disorder is associated with a decrease in the activity of the nitric oxide synthase/nitric oxide system. Piperazine ferulate (PF) is widely used for the treatment of kidney disease in China. The aim of the present study was to examine the effects of PF on streptozotocin (STZ)­induced DN and the underlying mechanism of this process. STZ­induced diabetic mice were intragastrically administered PF (100, 200 and 400 mg/kg/body weight/day) for 12 weeks. At the end of the treatment period, the parameters of 24­h albuminuria and blood urea nitrogen, creatinine and oxidative stress levels were measured. Hematoxylin and eosin staining, periodic acid­Schiff staining and electron microscopy were used to evaluate the histopathological alterations. mRNA and protein expression of endothelial nitric oxide synthase (eNOS) were measured by quantitative polymerase chain reaction and western blotting, respectively. PF significantly decreased blood urea nitrogen and creatinine levels and 24­h albuminuria, and it alleviated oxidative stress, improved glomerular basement membrane thickness and caused an upregulation in eNOS expression and activity levels in diabetic mice. In addition, high glucose decreased eNOS expression levels, whereas PF caused a reversal in the nitric oxide (NO) levels of glomerular endothelial cells. The present results suggested that PF exhibited renoprotective effects on DN. The mechanism of its action was associated with the regulation of eNOS expression and activity.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Óxido Nítrico Sintase Tipo III/genética , Piperazina/administração & dosagem , Animais , Glicemia/genética , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Modelos Animais de Doenças , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Camundongos , Óxido Nítrico/genética , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/genética
11.
PLoS One ; 14(1): e0210114, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30629617

RESUMO

BACKGROUND: PPP1R3B has been suggested as a candidate gene for monogenic forms of diabetes as well as type 2 diabetes (T2D) due to its association with glycaemic trait and its biological role in glycogen synthesis. OBJECTIVES: To study if rare missense variants in PPP1R3B increase the risk of maturity onset diabetes of the young (MODY), T2D or affect measures of glucose metabolism. METHOD: Targeted resequencing of PPP1R3B was performed in 8,710 samples; MODY patients with unknown etiology (n = 54), newly diagnosed patients with T2D (n = 2,930) and population-based control individuals (n = 5,726, of whom n = 4,569 had normal glucose tolerance). All population-based sampled individuals were examined using an oral glucose tolerance test. RESULTS: Among n = 396 carriers, we identified twenty-three PPP1R3B missense mutations, none of which segregated with MODY. The burden of likely deleterious PPP1R3B variants was significantly increased with a total of 17 carriers among patients with T2D (0.58% (95% CI: 0.36-0.93)) compared to 18 carriers among non-diabetic individuals (0.31% (95% CI: 0.20-0.49)), resulting in an increased risk of T2D (OR (95% CI) = 2.57 (1.14-5.79), p = 0.02 (age and sex adjusted)). Furthermore, carriers with diabetes had less abdominal fat and a higher serum concentration of LDL-cholesterol compared to patients with T2D without rare missense PPP1R3B variants. In addition, non-diabetic carriers had a higher birth weight compared to non-carriers. CONCLUSION: Rare missense PPP1R3B variants may predispose to T2D.


Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Proteína Fosfatase 1/genética , Idoso , Glicemia/genética , Dinamarca , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Feminino , Teste de Tolerância a Glucose , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto
12.
Transplant Proc ; 51(1): 164-166, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30655132

RESUMO

The fat mass and obesity-associated (FTO) gene is one of the most important obesity susceptibility genes. Some FTO gene polymorphisms have been associated with obesity, diabetes, and hypertension, all conditions for which, after transplant, there is increased susceptibility, due to effects of immunosuppressive regimens. To evaluate whether FTO could be a candidate for targeted preventive intervention in the transplant setting, we investigated whether the common genetic variation, FTO rs9939609T>A, could affect weight gain and risk of cardiovascular complications in kidney transplantation. METHODS: In 198 kidney transplant recipients, FTO rs9939609 was investigated in association with body mass index (BMI)/obesity and with other clinical markers of posttransplant risk, then monitored up to 5 years after transplantation. Genotyping was performed using an allelic discrimination method on a real-time polymerase chain (PCR) system. Associations were analyzed using the chi-square test; differences between genotypes were examined with analysis of variance or Kruskal-Wallis test; tests for repeated measures and a general linear model analysis controlling for age and gender were also utilized. RESULTS: Allele and genotype frequencies of FTO rs9939609 in recipients (T/T, 29.8%; T/A, 49.0%; A/A, 21.2%; A, 45.7%; T, 54.3%) reflect those present in healthy Caucasian populations. In the face of pre-/posttransplant differences in total cholesterol, triglycerides, or fasting glucose, results did not show significant changes in these factors among genotypes either before or after transplantation. CONCLUSION: This study highlights a lack of association of FTO rs9939609T>A genotypes and posttransplant weight gain, plasma lipids, and fasting blood glucose in kidney transplantation.


Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Transplante de Rim , Obesidade/genética , Ganho de Peso/genética , Adulto , Glicemia/genética , Índice de Massa Corporal , Colesterol/sangue , Colesterol/genética , Feminino , Genótipo , Humanos , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Obesidade/induzido quimicamente , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Triglicerídeos/sangue , Triglicerídeos/genética
13.
Gene ; 681: 93-98, 2019 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-30273662

RESUMO

BACKGROUND: Fat mass and obesity-associated protein gene variants have shown diverse influence on body weight and metabolism across different populations. Overweight, obesity and metabolic syndrome are multifactorial major health problems in the UAE and worldwide. Insulin resistance represents the link between overweight and development of metabolic syndrome and type 2 diabetes mellitus. We investigated two (FTO) variants in Emirati population, in relation to insulin resistance and different parameters of metabolic syndrome. METHODS: We recruited 259 Emiratis through the UAE National Diabetes and Lifestyle Project. Ethical approval was obtained. Besides basic data collection, venous blood samples were collected. Fasting blood glucose, Lipid profile, and insulin levels were measured. Genotyping for (FTO) rs9939609 (A>T) and rs9930506 (G>A) were performed using real time-PCR. Insulin resistance were identified using HOMA2-IR calculation; with a cut-off point of 1.4 for female and 1.18 for male subjects. RESULTS: The study included 259 Emiratis (age range 30-53 years, mean 41.76 years, 54.4% females), 24.5% are diabetic and 30.8% are hypertensive, with body mass index of 28.4 ±â€¯5.9 and 28.7 ±â€¯5.7 kg/m2 in female and male subjects, respectively. Homozygous A of rs9939609 showed significantly higher fasting glucose compared to other genotypes (p = 0.04) with a trend of higher insulin level and HOMA-2IR. The A/A diabetic patients (n = 13) showed significantly higher insulin levels compared to other genotypes. G allele of rs9930506 showed a trend of higher fasting glucose and HOMA-2IR, but lower insulin level and HbA1c. No association of genotypes was detected with other components of metabolic syndrome. CONCLUSION: There is an association of FTO rs9939609 A/A genotype and impaired fasting glucose and insulin resistance. Homozygous A genotype diabetic patients may be more vulnerable to blood glucose fluctuation. Focused genotyping can help the health care providers to identify high risk groups of both normal population and diabetic patients to intervene accordingly.


Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Glicemia/genética , Intolerância à Glucose/genética , Resistência à Insulina/genética , Polimorfismo de Nucleotídeo Único , Adulto , Alelos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Jejum/sangue , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Intolerância à Glucose/sangue , Intolerância à Glucose/epidemiologia , Humanos , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/genética , Pessoa de Meia-Idade , Sobrepeso/sangue , Sobrepeso/epidemiologia , Sobrepeso/genética , Estado Pré-Diabético/sangue , Estado Pré-Diabético/epidemiologia , Estado Pré-Diabético/genética , Emirados Árabes Unidos/epidemiologia
14.
J Clin Neurosci ; 61: 36-43, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30470649

RESUMO

Both post-traumatic stress disorder (PTSD) and estrogen receptor alpha (ESR1) gene rs2234693 were reported to influence serum glucose and lipids profiles. However, their interactions on serum glucose and lipids profiles have not been reported. A total of 708 Chinese Han high school students were recruited at 6th months after the 2008 Wenchuan Earthquake. Serum concentrations of fasting blood glucose (FBG), fasting blood insulin (FBI), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were detected. Body mass index (BMI) and homeostatic model assessment of insulin resistance (HOMA-IR) were calculated. PTSD was assessed by the PTSD Checklist Civilian Version (PCL-C). Variants of ESR1 rs2234693 was analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analyses and verified by DNA sequencing. The male subjects with PTSD had a trend of higher FBG (p = 0.077) and significantly higher FBI and HOMA-IR than male controls. The PTSD subjects had significantly higher levels of FBG, FBI, HOMA-IR and HDL-C than the controls only in the male C allele carriers irrespective of adjustment for age and BMI. In the male controls group, the C allele carriers had significantly lower HDL-C than the TT homozygotes regardless of adjustment for age and BMI. In female PTSD group, the C allele carriers had significantly higher TC/HDL-C and LDL-C/HDL-C than the TT homozygotes after adjustment for age and BMI. These results suggest the interplays of ESR1 rs2234693 with PTSD influence serum glucose and lipids profiles with a gender dependent manner.


Assuntos
Receptor alfa de Estrogênio/genética , Transtornos de Estresse Pós-Traumáticos/sangue , Transtornos de Estresse Pós-Traumáticos/genética , Adolescente , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Glicemia/genética , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Terremotos , Feminino , Genótipo , Humanos , Lipídeos , Masculino , Polimorfismo de Fragmento de Restrição , Caracteres Sexuais , Triglicerídeos/sangue
16.
Acta Diabetol ; 56(3): 365-371, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30539233

RESUMO

AIMS: Bone morphogenetic proteins (BMPs) are involved in the development and homeostasis of multiple organs and tissues. There has been a significant focus on understanding the role of BMPs in pancreatic ß-cell dysfunction associated with type 2 diabetes (T2D). Our objective was to investigate the relationship between BMP6 and glucose homeostasis. METHODS: Ob/ob mice were treated with BMP6 for 6 days and analyzed for insulin release, body weight, lipid parameters and glucose tolerance. Quantitative real-time PCR, chromatin immunoprecipitation and glucose output assays were used to assess BMP6 effect on gluconeogenesis in rat hepatoma H4IIE cells. Specificity of BMP6 receptors was characterized by the utilization of various receptor Fc fusion proteins in luciferase reporter gene and glucose output assays in INS1 and H4IIE cells. RESULTS: Treatment of ob/ob mice with BMP6 for 6 days resulted in a reduction of circulating glucose and lipid levels, followed by a significantly elevated plasma insulin level in a dose-dependent manner. In addition, BMP6 improved the glucose excursion during an oral glucose tolerance test, lowering the total glycemic response by 21%. In rat H4IIE hepatoma cells, BMP6 inhibited gluconeogenesis and glucose output via downregulation the PepCK expression. Moreover, BMP6 inhibited glucose production regardless of the presence of cAMP, antagonizing its glycogenolytic effect. BMP6 acted on pancreatic and liver cells utilizing Alk3, Alk6 and ActRIIA serine/threonine kinase receptors. CONCLUSIONS: Collectively, we demonstrate that BMP6 improves glycaemia in T2D mice and regulates glucose metabolism in hepatocytes representing an exciting prospect for future treatments of diabetes.


Assuntos
Proteína Morfogenética Óssea 6/farmacologia , Diabetes Mellitus Experimental/metabolismo , Glucose/metabolismo , Homeostase/efeitos dos fármacos , Animais , Glicemia/genética , Glicemia/metabolismo , Proteína Morfogenética Óssea 6/fisiologia , Células CHO , Células Cultivadas , Cricetinae , Cricetulus , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Homeostase/genética , Insulina/metabolismo , Masculino , Camundongos , Camundongos Obesos , Ratos , Proteínas Recombinantes/farmacologia
17.
Diabetologia ; 62(2): 286-291, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30413829

RESUMO

AIMS/HYPOTHESIS: The aim of this study was to investigate the modifying effect of the glucose transporter (GLUT2) gene SLC2A2 (rs8192675) variant on the glycaemic response to metformin in individuals recently diagnosed with type 2 diabetes. METHODS: Individuals with type 2 diabetes (n = 508) from the prospective German Diabetes Study (age [mean ± SD] 53 ± 10 years; 65% male; BMI 32 ± 6 kg/m2, metformin use 57%) underwent detailed metabolic characterisation (hyperinsulinaemic-euglycaemic clamp, IVGTT) during the first year after diagnosis. Participants provided self-reported data from the time of diagnosis. The change in fasting glucose was assessed in relation to SLC2A2 genotype and glucose-lowering treatment using two-way ANCOVA with gene×treatment interactions adjusted for age, sex, BMI and diabetes duration. RESULTS: The C variant allele of rs8192675 was associated with a higher prevalence of diabetes symptoms at diabetes diagnosis. In the metformin monotherapy group only, patients with a C allele showed a larger adjusted blood glucose reduction during the first year after diabetes diagnosis than patients with the TT genotype (6.3 mmol/l vs 3.9 mmol/l; genotype difference 2.4 mmol/l, p = 0.02; p value for genotype interaction [metformin monotherapy vs non-pharmacological therapy] <0.01). The greater decline in fasting glucose (CC/CT vs TT) in metformin monotherapy persisted after further adjusting for glucose values at diagnosis (genotype difference 1.0 mmol/l, p = 0.01; genotype×treatment interaction p = 0.06). CONCLUSIONS/INTERPRETATION: The variant rs8192675 in the SLC2A2 gene (C allele) is associated with an improved glucose response to metformin monotherapy during the first year after diagnosis in type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01055093.


Assuntos
Glicemia/genética , Diabetes Mellitus Tipo 2/genética , Transportador de Glucose Tipo 2/genética , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Adulto , Alelos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Genótipo , Técnica Clamp de Glucose , Humanos , Masculino , Pessoa de Meia-Idade , Farmacogenética , Polimorfismo de Nucleotídeo Único
18.
Int J Biol Macromol ; 123: 576-580, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30414419

RESUMO

The ACE INDEL gene polymorphisms are strongly associated with CAD. Therefore, the present study was undertaken to investigate the relationship between ACE INDEL polymorphism and CAD in Turkish Cypriots whose are expected to have Mediterranean-style diet. 273 Turkish Cypriot descent volunteer subjects (186 controls and 87 CAD patients) participated in this study. Genotyping for the ACE INDEL polymorphism was performed by PCR-RFLP analysis. Biochemical parameters except the glucose and triglyceride lipid level were all within normal limits. Glucose level was found significant (p = 0.019) and triglyceride level was observed at the borderline for significance (p = 0.050) in participants according to WHO guidelines. With the respect to the genotype and allele distributions of ACE INDEL, the results showed statistically significant in CAD patients (p = 0.034) and not significant (p = 0.190) in controls. Haplotype analysis showed that D allele was more frequent in patients compared to controls. Thus, there is a statistically significant association with CAD disease with DD genotypes (p = 0.030) in Turkish Cypriot population. The results indicated that ACE INDEL polymorphism is an important predictor of coronary artery disease in Turkish Cypriots. Although 47% of the studied Turkish Cypriot population carry the D allele (p = 0.07), protocols should be developed for prevention strategies immediately.


Assuntos
Doença da Artéria Coronariana/dietoterapia , Dieta Mediterrânea , Peptidil Dipeptidase A/genética , Adulto , Biomarcadores/sangue , Glicemia/genética , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/patologia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Mutação INDEL/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Fragmento de Restrição , Fatores de Risco , Triglicerídeos/sangue
19.
Hum Antibodies ; 27(2): 99-104, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30594920

RESUMO

BACKGROUND: Conventional coronary artery disease (CAD) is the leading cause of morbidity and mortality in the general population. In recent years, multiple CAD promising risk factors have been reported and used for risk stratification. Lipoprotein(a) [LPA] concentration in plasma was shown associated with CAD risk and LPA genetic variants in different ethnic groups remains less clear. METHODS: We obtained data from 100 affected patients with established CAD and 100 healthy controls. We tested Body mass index (BMI), total cholesterol level (TC), systolic blood pressure (SBP), diastolic blood pressure (DBP), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides (TG), fasting blood sugar (FBS) and two LPA (rs10455872 and rs3798220 SNPs) between cases and healthy controls. TaqMan SNP genotyping assays were performed to detect variants. RESULTS: Obtained data for BMI, TC, SBP, DBP, and LDL have significantly difference between two groups. Individually, the single SNPs were not associated with CAD in different analysis models. Also there was no significant difference in the incidence of CAD among cases carrying different genotypes of the two variants in LPA with p> 0.05. DISCUSSION: In this study patients with CAD, lipoprotein(a) concentrations and genetic variants showed no associations and we conclude that these variables are not useful risk factors to predict progression to disease is Iranian population. However, the prevalence and association of LPA SNPs with size of LPA and isoforms are highly variable and genetic background-specific. CONCLUSION: Our data did not indicate a relationship between genomic LPA variants (rs10455872 and rs3798220) and subsequent cardiovascular events in Iranian CAD patients. We did not confirm the association of the theses SNPs with CAD in our samples of Iranian patients. For the studied variants, our finding is consistent with reports which showed the lack of this genetic association in other populations.


Assuntos
Doença da Artéria Coronariana/genética , Predisposição Genética para Doença/genética , Lipoproteína(a)/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Glicemia/genética , Pressão Sanguínea/genética , Índice de Massa Corporal , Estudos de Casos e Controles , Colesterol/sangue , Feminino , Genótipo , Humanos , Irã (Geográfico) , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Masculino , Fatores de Risco , Triglicerídeos/sangue , Adulto Jovem
20.
J Cell Mol Med ; 22(12): 6294-6303, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30320493

RESUMO

Diabetic nephropathy (DN) is one of general and common complication of diabetes, which severely affects the physical and mental health of diabetic patients. Fibroblast growth factor 1 (FGF1), an effective control agent of blood glucose, plays an effective treatment role on diabetes-induced renal injury. But the specific molecule mechanism underlying it is still unclear. Since induction of cellular stress is the main and common mechanism of diabetes-induced complication, we hypothesized that reduction of cellular stress is also the molecular mechanism of FGF1 treatment for DN. Here, we have further confirmed that FGF1 significantly ameliorated the diabetes-induced renal interstitial fibrosis and glomerular damage. The expression levels of collagen and α-smooth muscle actin (α-SMA) also dramatically induced in kidney from db/db mice, but these effects were blocked by FGF1 administration. Our mechanistic investigation had further revealed that diabetes significantly induced oxidative stress, nitrosative stress, and endoplasmic reticulum (ER) stress with upregulation of malondialdehyde (MDA), nitrotyrosine level, ER stress makers and downregulation of antioxidant capacity (AOC). FGF1 treatment significantly attenuated the effect of diabetes on cellular stress. We conclude that FGF1-associated glucose decreases and subsequent reduction of cellular stress is the another potential molecule mechanism underlying FGF1 treatment for DN.


Assuntos
Diabetes Mellitus Experimental/genética , Nefropatias Diabéticas/genética , Fator 1 de Crescimento de Fibroblastos/genética , Fibrose/genética , Animais , Antioxidantes/metabolismo , Glicemia/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Estresse do Retículo Endoplasmático/genética , Fibrose/metabolismo , Fibrose/patologia , Regulação da Expressão Gênica/genética , Humanos , Rim/metabolismo , Rim/patologia , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Malondialdeído/metabolismo , Camundongos , Estresse Oxidativo/genética
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