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1.
Medicine (Baltimore) ; 98(39): e17298, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574854

RESUMO

Recently, studies have shown significant association between the rs2000999 polymorphism in the haptoglobin-encoding gene (HP) and low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels, which are important risk factors for cardiovascular diseases. However, the association of rs2000999 with serum lipids in Latin American diabetic populations is still uncharacterized. Here, we analyzed the association of rs2000999 with TC, high-density lipoprotein cholesterol (HDL-C), and LDL-C levels in 546 Mexican adults with type 2 diabetes (T2D) and in 654 controls without T2D. In this observational case-control study we included adults from 4 centers of the Mexican Social Security Institute in Mexico City recruited from 2012 to 2015. TC, HDL-C, LDL-C, triglycerides (TG), and glucose levels were measured by an enzymatic colorimetric method. The variant rs2000999 was genotyped using TaqMan real time polymerase chain reaction. The percentage of Native-American ancestry showed a negative association with the rs2000999 A allele. In contrast, the rs2000999 A allele had a strong positive association with European ancestry, and to a lesser extent, with African ancestry. Linear regression was used to estimate the association between the variant rs2000999 and lipid concentrations, using different genetic models. Under codominant and recessive models, rs2000999 was significantly associated with TC and LDL-C levels in the T2D group and in controls without T2D. In addition, the group with T2D showed a significant association between the variant and HDL-C levels. In summary, the rs2000999 A allele in Mexican population is positively associated with the percentage of European and negatively associated with Native American ancestry. Carriers of the A allele have increased levels of TC and LDL-C, independently of T2D diagnosis, and also increased concentrations of HDL-C in the T2D sample.


Assuntos
Doenças Cardiovasculares , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Colesterol/sangue , Diabetes Mellitus Tipo 2 , Haptoglobinas , Adulto , Biomarcadores/análise , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Feminino , Haptoglobinas/análise , Haptoglobinas/genética , Humanos , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
2.
Exp Suppl ; 111: 385-416, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588541

RESUMO

In addition to the common types of diabetes mellitus, two major monogenic diabetes forms exist. Maturity-onset diabetes of the young (MODY) represents a heterogenous group of monogenic, autosomal dominant diseases. MODY accounts for 1-2% of all diabetes cases, and it is not just underdiagnosed but often misdiagnosed to type 1 or type 2 diabetes. More than a dozen MODY genes have been identified to date, and their molecular classification is of great importance in the correct treatment decision and in the judgment of the prognosis. The most prevalent subtypes are HNF1A, GCK, and HNF4A. Genetic testing for MODY has changed recently due to the technological advancements, as contrary to the sequential testing performed in the past, nowadays all MODY genes can be tested simultaneously by next-generation sequencing. The other major group of monogenic diabetes is neonatal diabetes mellitus which can be transient or permanent, and often the diabetes is a part of a syndrome. It is a severe monogenic disease appearing in the first 6 months of life. The hyperglycemia usually requires insulin. There are two forms, permanent neonatal diabetes mellitus (PNDM) and transient neonatal diabetes mellitus (TNDM). In TNDM, the diabetes usually reverts within several months but might relapse later in life. The incidence of NDM is 1:100,000-1:400,000 live births, and PNDM accounts for half of the cases. Most commonly, neonatal diabetes is caused by mutations in KCNJ11 and ABCC8 genes encoding the ATP-dependent potassium channel of the ß cell. Neonatal diabetes has experienced a quick and successful transition into the clinical practice since the discovery of the molecular background. In case of both genetic diabetes groups, recent guidelines recommend genetic testing.


Assuntos
Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus/genética , Doenças do Recém-Nascido/genética , Testes Genéticos , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/genética , Humanos , Recém-Nascido , Mutação , Canais de Potássio Corretores do Fluxo de Internalização/genética , Proteínas Serina-Treonina Quinases/genética , Receptores Sulfonilureia/genética
3.
Adv Exp Med Biol ; 1121: 7-20, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31392648

RESUMO

Common Non communicable diseases (NCDs), such as cardiovascular disease, cancer, schizophrenia, and diabetes, have become the major cause of death in the world. They result from an interaction between genetics, lifestyle and environmental factors. The prevalence of NCDs are increasing, and researchers hopes to find efficient strategies to predict, prevent and treat them. Given the role of epigenome in the etiology of NCDs, insight into epigenetic mechanisms may offer opportunities to predict, detect, and prevent disease long before its clinical onset.Epigenetic alterations are exerted through several mechanisms including: chromatin modification, DNA methylation and controlling gene expression by non-coding RNAs (ncRNAs). In this chapter, we will discuss about NCDs, with focus on cancer, diabetes and schizophrenia. Different epigenetic mechanisms, categorized into two main groups DNA methylation and chromatin modifications and non-coding RNAs, will be separately discussed for these NCDs.


Assuntos
Epigênese Genética , Doenças não Transmissíveis , Metilação de DNA , Diabetes Mellitus Tipo 2/genética , Humanos , Neoplasias/genética , Esquizofrenia/genética
4.
Gene ; 715: 144011, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31357022

RESUMO

BACKGROUND: An association between Apolipoprotein E (Apo E) alleles and genotypes and diabetic nephropathy (DN) was suggested, but with inconsistent results. We tested the relationship between serum lipids, Apo E alleles and genotypes with type 2 diabetes (T2DM), and DN pathogenesis. METHODS: Study subjects comprised 1389 normoglycemic controls, and 1422 T2DM patients, of whom 825 were normoalbuminuric (DWN), and 597 presented with nephropathy (DN). RESULTS: Significantly lower Apo ε2, and higher Apo ε4 allele frequencies was seen among T2DM patients than controls. Significantly higher frequency of ε3/ε4, and lower frequencies of ε3/ε3, ε2/ε3, and ε4/ε4 carriers was seen among T2DM cases. Apo ε2-carrying individuals were more frequently found in controls than in patients, while significantly higher frequency of ε4-carrying genotypes was seen in T2DM cases. Significantly higher ε2, and lower ε3 allele frequencies were noted for DN group compared to DWN group. Significantly higher frequency of ε2-containing ε2/ε3 and ε2/ε4, and lower frequencies of ε3/ε3 carriers was seen among DN cases. Apo ε3/ε3 was associated with higher total cholesterol, LDL-cholesterol, and triglyceride levels in DN patients, and significantly higher triglyceride levels were seen in ε2/ε3-carrying DN patients. Logistic regression analysis confirmed the association of Apo ε3-containing ε3/ε3, ε2/ε3, and ε3/ε4, and Apo ε2-containing ε2/ε4 with DN, after controlling for key covariates. CONCLUSION: The results of this case-control study provide evidence that the ε2 and ε3 alleles of APOE modify lipid profile, and constitute independent risk factors of DN in type 2 diabetes. The molecular mechanisms underlying this risk is discussed.


Assuntos
Alelos , Apolipoproteínas E/genética , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/genética , Frequência do Gene , Predisposição Genética para Doença , Idoso , Apolipoproteínas E/sangue , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/sangue , Nefropatias Diabéticas/sangue , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Fatores de Risco
5.
BMJ ; 366: l4292, 2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31345923

RESUMO

OBJECTIVE: To investigate whether the genetic burden of type 2 diabetes modifies the association between the quality of dietary fat and the incidence of type 2 diabetes. DESIGN: Individual participant data meta-analysis. DATA SOURCES: Eligible prospective cohort studies were systematically sourced from studies published between January 1970 and February 2017 through electronic searches in major medical databases (Medline, Embase, and Scopus) and discussion with investigators. REVIEW METHODS: Data from cohort studies or multicohort consortia with available genome-wide genetic data and information about the quality of dietary fat and the incidence of type 2 diabetes in participants of European descent was sought. Prospective cohorts that had accrued five or more years of follow-up were included. The type 2 diabetes genetic risk profile was characterized by a 68-variant polygenic risk score weighted by published effect sizes. Diet was recorded by using validated cohort-specific dietary assessment tools. Outcome measures were summary adjusted hazard ratios of incident type 2 diabetes for polygenic risk score, isocaloric replacement of carbohydrate (refined starch and sugars) with types of fat, and the interaction of types of fat with polygenic risk score. RESULTS: Of 102 305 participants from 15 prospective cohort studies, 20 015 type 2 diabetes cases were documented after a median follow-up of 12 years (interquartile range 9.4-14.2). The hazard ratio of type 2 diabetes per increment of 10 risk alleles in the polygenic risk score was 1.64 (95% confidence interval 1.54 to 1.75, I2=7.1%, τ2=0.003). The increase of polyunsaturated fat and total omega 6 polyunsaturated fat intake in place of carbohydrate was associated with a lower risk of type 2 diabetes, with hazard ratios of 0.90 (0.82 to 0.98, I2=18.0%, τ2=0.006; per 5% of energy) and 0.99 (0.97 to 1.00, I2=58.8%, τ2=0.001; per increment of 1 g/d), respectively. Increasing monounsaturated fat in place of carbohydrate was associated with a higher risk of type 2 diabetes (hazard ratio 1.10, 95% confidence interval 1.01 to 1.19, I2=25.9%, τ2=0.006; per 5% of energy). Evidence of small study effects was detected for the overall association of polyunsaturated fat with the risk of type 2 diabetes, but not for the omega 6 polyunsaturated fat and monounsaturated fat associations. Significant interactions between dietary fat and polygenic risk score on the risk of type 2 diabetes (P>0.05 for interaction) were not observed. CONCLUSIONS: These data indicate that genetic burden and the quality of dietary fat are each associated with the incidence of type 2 diabetes. The findings do not support tailoring recommendations on the quality of dietary fat to individual type 2 diabetes genetic risk profiles for the primary prevention of type 2 diabetes, and suggest that dietary fat is associated with the risk of type 2 diabetes across the spectrum of type 2 diabetes genetic risk.


Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/etiologia , Dieta/efeitos adversos , Gorduras na Dieta/efeitos adversos , Adulto , Alelos , Diabetes Mellitus Tipo 2/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco
6.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 48(2): 200-203, 2019 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-31309759

RESUMO

Maturity onset diabetes of the young (MODY) is a monogenic autosomal dominant inherited disease. Its clinical manifestations are asymptomatic with slightly elevated fasting blood glucose and few complications. This paper reports a novel mutation W257R in glucokinase (GCK) gene from a Chinese patient with MODY. Heterozygous mutation c.769T>C (p.W257R) in exon 7 of GCK gene (Chr744187343) was found in the proband, her father and brother. This W257R mutation was first reported in Chinese population.


Assuntos
Diabetes Mellitus Tipo 2 , Glucoquinase , Mutação , China , Diabetes Mellitus Tipo 2/genética , Feminino , Glucoquinase/genética , Humanos , Masculino , Linhagem
7.
Nat Commun ; 10(1): 2474, 2019 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171772

RESUMO

Diabetes is a global health problem caused primarily by the inability of pancreatic ß-cells to secrete adequate levels of insulin. The molecular mechanisms underlying the progressive failure of ß-cells to respond to glucose in type-2 diabetes remain unresolved. Using a combination of transcriptomics and proteomics, we find significant dysregulation of major metabolic pathways in islets of diabetic ßV59M mice, a non-obese, eulipidaemic diabetes model. Multiple genes/proteins involved in glycolysis/gluconeogenesis are upregulated, whereas those involved in oxidative phosphorylation are downregulated. In isolated islets, glucose-induced increases in NADH and ATP are impaired and both oxidative and glycolytic glucose metabolism are reduced. INS-1 ß-cells cultured chronically at high glucose show similar changes in protein expression and reduced glucose-stimulated oxygen consumption: targeted metabolomics reveals impaired metabolism. These data indicate hyperglycaemia induces metabolic changes in ß-cells that markedly reduce mitochondrial metabolism and ATP synthesis. We propose this underlies the progressive failure of ß-cells in diabetes.


Assuntos
Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 2/genética , Glucose/metabolismo , Células Secretoras de Insulina/metabolismo , Mitocôndrias/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Perfilação da Expressão Gênica , Gluconeogênese , Glicólise , Secreção de Insulina , Metabolômica , Camundongos , Camundongos Transgênicos , NAD/metabolismo , Fosforilação Oxidativa , Consumo de Oxigênio , Canais de Potássio Corretores do Fluxo de Internalização/genética , Proteômica
8.
BMC Complement Altern Med ; 19(1): 136, 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31215434

RESUMO

BACKGROUND: Tomato fruit (Lycopersicon esculentum Mill.) has been suggested to be useful for the prevention of diabetes. Esculeoside A is the main saponin compounds in tomatoes. This study investigated the hypoglycemic effects and the underlying mechanism of esculeoside A in C57BLKS/Leprdb (db/db) mice. METHODS: Wild-type C57BLKS (db/dm) mice were used in the db/dm mouse group and db/db mice were randomly divided into 2 groups: untreated and treated db/db mouse groups. Esculeoside A (100 mg/kg) was administered by gavage for 56 days to the treated db/db mouse group. Distilled water was administered to the db/dm mouse group and the untreated db/db mouse group. The blood and liver biochemical parameters and the expression of liver insulin signaling-related proteins were examined. RESULTS: The results showed that esculeoside A reduced the fasting blood glucose (FBG) levels and improved the glucose tolerance. Further investigation revealed that hepatic protein expressions of total AMP-activated protein kinase (T-AMPK), phosphorylated AMP-activated protein kinase (p-AMPK), insulin receptor substrate-1 (IRS-1), and glucokinase (GCK) were significantly upregulated after esculeoside A treatment. In contrast, the hepatic protein expression of phosphoenolpyruvate carboxykinase (PEPCK) was significantly downregulated by esculeoside A treatment. CONCLUSION: These findings suggested that esculeoside A has a potential of alleviating the metabolic abnormalities in db/db mice via regulation of AMPK/IRS-1 pathway. Our findings supported a possible application of esculeoside A as a functional supplement for diabetes treatment.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Proteínas Substratos do Receptor de Insulina/genética , Sapogeninas/administração & dosagem , Proteínas Quinases Ativadas por AMP/genética , Animais , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Glucoquinase/genética , Glucoquinase/metabolismo , Humanos , Insulina/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Regulação para Cima
9.
Nat Commun ; 10(1): 2757, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31227697

RESUMO

Inappropriate expansion of the adipose cells in the subcutaneous adipose tissue (SAT) is a characteristic of hypertrophic obesity and of individuals with genetic predisposition for T2D (first-degree relatives; FDR). It is associated with insulin resistance, a dysfunctional, adipose tissue and reduced adipogenesis. We examined the regulation of adipogenesis in human SAT precursor cells and found ZNF521 to be a critical regulator of early adipogenic commitment and precursor cells leaving the cell cycle. However, neither altered upstream signalling nor lack of SAT progenitor cells could explain the reduced adipogenesis in hypertrophic obesity. Instead, we show that progenitor cells undergoing poor differentiation are characterized by senescence, inability to suppress p53/P16INK4 and secretion of factors reducing adipogenesis in non-senescent cells. We found aging, FDR and established T2D to be associated with increased progenitor cell senescence, reduced adipogenesis and hypertrophic expansion of the SAT adipose cells.


Assuntos
Adipogenia , Senescência Celular/fisiologia , Proteínas de Ligação a DNA/metabolismo , Obesidade/patologia , Gordura Subcutânea/patologia , Adipócitos , Adulto , Idoso , Envelhecimento/fisiologia , Biópsia por Agulha , Células Cultivadas , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Proteínas de Ligação a DNA/genética , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Feminino , Predisposição Genética para Doença , Humanos , Hipertrofia/patologia , Masculino , Pessoa de Meia-Idade , Obesidade/etiologia , Cultura Primária de Células , Transdução de Sinais/fisiologia , Células-Tronco/fisiologia , Gordura Subcutânea/citologia , Proteína Supressora de Tumor p53/metabolismo , Adulto Jovem
10.
Vasc Health Risk Manag ; 15: 101-107, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31190848

RESUMO

Introduction: Theoretically, first-degree relatives (FDRs) of type 2 diabetes mellitus (T2DM) are predisposed to have earlier and more severe atherosclerosis than non-FDR due to hereditary insulin resistance. A previous study reported that atherosclerotic plaques were found in 45.2% of young adults FDR of T2DM, but the study did not include non-FDR as control group. The aim of this study was to compare subclinical atherosclerosis (carotid intima-media thickness, CIMT) between FDR of T2DM and non-FDR. Method: This was a cross-sectional study involving 16 FDR subjects and 16 age-sex matched non-FDR subjects, aged 19-40 years, with normal glucose tolerance and no hypertension. Collected data included demographic characteristic, anthropometric measurement (BMI and waist circumference), laboratory analysis (fasting blood glucose, HbA1c, lipid profile), and CIMT examination (using B-mode ultrasound). Results: The mean of CIMT in the FDR group was higher than that in the non-FDR group (0.44 mm vs 0.38 mm, p=0.005). After adjusting for waist circumference, BMI, low-density lipoprotein cholesterol, and triglyceride, CIMT maintained significant difference between FDR and non-FDR subjects. BMI and waist circumference showed moderate correlation with CIMT. Conclusion: CIMT in young adult FDR of T2DM is thicker than that in age-and sex-matched non-FDR population.


Assuntos
Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/diagnóstico por imagem , Espessura Intima-Media Carotídea , Diabetes Mellitus Tipo 2/genética , Adulto , Doenças Assintomáticas , Biomarcadores/sangue , Glicemia/análise , Pressão Sanguínea , Artérias Carótidas/patologia , Doenças das Artérias Carótidas/genética , Doenças das Artérias Carótidas/patologia , Estudos de Casos e Controles , Estudos Transversais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Predisposição Genética para Doença , Hereditariedade , Humanos , Masculino , Linhagem , Fenótipo , Placa Aterosclerótica , Valor Preditivo dos Testes , Fatores de Risco , Adulto Jovem
11.
Nat Commun ; 10(1): 2581, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31197173

RESUMO

Despite existing reports on differential DNA methylation in type 2 diabetes (T2D) and obesity, our understanding of its functional relevance remains limited. Here we show the effect of differential methylation in the early phases of T2D pathology by a blood-based epigenome-wide association study of 4808 non-diabetic Europeans in the discovery phase and 11,750 individuals in the replication. We identify CpGs in LETM1, RBM20, IRS2, MAN2A2 and the 1q25.3 region associated with fasting insulin, and in FCRL6, SLAMF1, APOBEC3H and the 15q26.1 region with fasting glucose. In silico cross-omics analyses highlight the role of differential methylation in the crosstalk between the adaptive immune system and glucose homeostasis. The differential methylation explains at least 16.9% of the association between obesity and insulin. Our study sheds light on the biological interactions between genetic variants driving differential methylation and gene expression in the early pathogenesis of T2D.


Assuntos
Metilação de DNA/fisiologia , Diabetes Mellitus Tipo 2/genética , Glucose/metabolismo , Insulina/metabolismo , Obesidade/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Simulação por Computador , Ilhas de CpG/genética , Diabetes Mellitus Tipo 2/metabolismo , Epigênese Genética/fisiologia , Epigenômica/métodos , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/genética , Estudo de Associação Genômica Ampla/métodos , Homeostase/genética , Humanos , Masculino , Redes e Vias Metabólicas/genética , Pessoa de Meia-Idade , Obesidade/metabolismo , Polimorfismo de Nucleotídeo Único/fisiologia , Adulto Jovem
12.
Anim Genet ; 50(4): 319-325, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31179570

RESUMO

The recent extension of genetic tools to the domestic cat, together with the serendipitous consequences of selective breeding, have been essential to the study of the genetic diseases that affect them. Cats are increasingly presented for veterinary surveillance and share many of human's heritable diseases, allowing them to serve as natural models of these conditions. Feline diabetes mellitus is a common condition in domestic cats that bears close pathological and clinical resemblance to type 2 diabetes in humans, including pancreatic ß-cell dysfunction and peripheral insulin resistance. In Australia, New Zealand and Europe, diabetes mellitus is almost four times more common in cats of the Burmese breed than in other breeds. This geographically based breed predisposition parallels familial and population clustering of type 2 diabetes in humans. As a genetically isolated population, the Australian Burmese breed provides a spontaneous, naturally occurring genetic model of type 2 diabetes. Genetically isolated populations typically exhibit extended linkage disequilibrium and increased opportunity for deleterious variants to reach high frequencies over many generations due to genetic drift. Studying complex diseases in such populations allows for tighter control of confounding factors including environmental heterogeneity, allelic frequencies and population stratification. The homogeneous genetic background of Australian Burmese cats may provide a unique opportunity to either refine genetic signals previously associated with type 2 diabetes or identify new risk factors for this disease.


Assuntos
Doenças do Gato/genética , Gatos , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/veterinária , Modelos Animais de Doenças , Amiloidose , Animais , Doenças do Gato/patologia , Gatos/classificação , Gatos/genética , Diabetes Mellitus Tipo 2/patologia , Dislipidemias/genética , Dislipidemias/patologia , Dislipidemias/veterinária , Predisposição Genética para Doença , Resistência à Insulina , Células Secretoras de Insulina
13.
Zhonghua Er Ke Za Zhi ; 57(6): 440-444, 2019 Jun 02.
Artigo em Chinês | MEDLINE | ID: mdl-31216801

RESUMO

Objective: To explore the gene mutation characteristics and detailed clinical presentations of hyperglycemia caused by GCK mutations in 10 patients. Methods: The clinical and follow-up data of 10 patients with hyperglycemia caused by mutation of GCK gene were reviewed. The patients were ascertained between January 1, 2014 and August 31, 2018 at the Department of Pediatrics, the First Affiliated Hospital of Zhejiang University and Ningbo Women & Children's Hospital. Clinical data were collected, including age, gender, main complaint, family history, fasting blood glucose, fasting blood insulin, 2-hour blood glucose, 2-hour blood insulin after oral glucose tolerance test, glycosylated hemoglobin, anti-glutamic acid decarboxylase antibody and body mass index. Mutations of GCK gene were detected by Sanger sequencing or high-throughput sequencing of diabetes-related genes in the patients and their family members. Results: There were ten patients, 8 of them were male, 2 were female.The ages at diagnosis varied between 4.7 to 12.3 years. The patients usually did not have obvious clinical symptoms of diabetes mellitus. Most of them were unexpectedly found to have hyperglycemia and with impaired glucose metabolism in three consecutive generations. The fasting blood glucose of patients was 6.8-7.7 mmol/L, 2-hour postprandial blood glucose was 7.8-11.6 mmol/L. Fasting blood insulin was 0.5-8.5 mU/L, glucose tolerance test results showed that 2 h postprondial blood insulin was 1.3-55.4 mU/L. The level of glycosylated hemoglobin was 6.1%-6.8%. Anti-glutamic acid decarboxylase antibody was negative in all patients. The GCK mutations identified in patients and one of their parents were located at exon5 (4 cases), exon9 (2 cases), exon2 (1 case), exon4 (1 case), exon6 (1 case) and exon7 (1 case). Conclusions: Most of the hyperglycemia patients caused by GCK mutations did not have typical clinical symptoms of diabetes. The fasting blood glucose was slightly elevated. Abnormal glucose tolerance test results were found in all 10 patients. Three consecutive generations of family had impaired glucose metabolism. GCK mutations located at exon 5 were common in 10 cases. There was no correlation between type of mutations and plasma glucose levels in domestic and international researches. When fasting glucose was found abnormal in clinic, a complete family history should be taken and the GCK gene should be sequenced to confirm the diagnosis in time.


Assuntos
Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Glucoquinase/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Hiperglicemia/genética , Glicemia , Criança , Pré-Escolar , Feminino , Marcadores Genéticos , Teste de Tolerância a Glucose , Humanos , Hiperglicemia/diagnóstico , Masculino , Mutação
14.
BMC Genomics ; 20(Suppl 6): 434, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31189471

RESUMO

BACKGROUND: Biological networks describes the mechanisms which govern cellular functions. Temporal networks show how these networks evolve over time. Studying the temporal progression of network topologies is of utmost importance since it uncovers how a network evolves and how it resists to external stimuli and internal variations. Two temporal networks have co-evolving subnetworks if the evolving topologies of these subnetworks remain similar to each other as the network topology evolves over a period of time. In this paper, we consider the problem of identifying co-evolving subnetworks given a pair of temporal networks, which aim to capture the evolution of molecules and their interactions over time. Although this problem shares some characteristics of the well-known network alignment problems, it differs from existing network alignment formulations as it seeks a mapping of the two network topologies that is invariant to temporal evolution of the given networks. This is a computationally challenging problem as it requires capturing not only similar topologies between two networks but also their similar evolution patterns. RESULTS: We present an efficient algorithm, Tempo, for solving identifying co-evolving subnetworks with two given temporal networks. We formally prove the correctness of our method. We experimentally demonstrate that Tempo scales efficiently with the size of network as well as the number of time points, and generates statistically significant alignments-even when evolution rates of given networks are high. Our results on a human aging dataset demonstrate that Tempo identifies novel genes contributing to the progression of Alzheimer's, Huntington's and Type II diabetes, while existing methods fail to do so. CONCLUSIONS: Studying temporal networks in general and human aging specifically using Tempo enables us to identify age related genes from non age related genes successfully. More importantly, Tempo takes the network alignment problem one huge step forward by moving beyond the classical static network models.


Assuntos
Algoritmos , Evolução Molecular , Redes Reguladoras de Genes , Redes e Vias Metabólicas , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Biologia Computacional/métodos , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Doença de Huntington/genética , Doença de Huntington/metabolismo , Pessoa de Meia-Idade , Mapeamento de Interação de Proteínas , Adulto Jovem
15.
BMC Med Genet ; 20(1): 107, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31195986

RESUMO

BACKGROUND: Type 2 diabetes mellitus is believed to be a polygenic disorder that develops as a result of a complex interaction between multiple genes and environmental factors. KCNJ11 gene encodes a Kir6.2 protein which forms the inner section of the potassium channels in pancreatic beta cells. Several studies found that KCNJ11 polymorphism increases T2DM risk. Our study aimed to investigate the association between rs5219 polymorphism of the KCNJ11 gene and T2DM in Syrian patients. METHODS: This case-control study involved 75 T2DM patients and 63 healthy controls. The KCNJ11 rs5219 polymorphism was genotyped by Restriction Fragment Length Polymorphism (RFLP). RESULTS: The frequency of the risk allele K was similar between the two groups (38.7% vs. 38.1%, P = 0.132). The frequency of the KK genotype was higher among the patients' group (16% vs. 4.8%), and the frequency of the EK genotype was higher among the control group (45.3% vs. 66.6%); however, the differences were statistically insignificant. The KK genotype was significantly associated with T2DM in the recessive model with an OR of 3.81 (95% CI 1.024-14.17, P = 0.035). CONCLUSIONS: This study showed that rs5219 polymorphism of the KCNJ11 gene is an important risk factor for type 2 diabetes mellitus in a sample of the Syrian population.


Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Canais de Potássio Corretores do Fluxo de Internalização/genética , Adulto , Alelos , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudos de Associação Genética , Genética Populacional , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Síria
16.
BMC Bioinformatics ; 20(Suppl 12): 320, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31216985

RESUMO

BACKGROUND: As Genome-Wide Association Studies (GWAS) have been increasingly used with data from various populations, it has been observed that data from different populations reveal different sets of Single Nucleotide Polymorphisms (SNPs) that are associated with the same disease. Using Type II Diabetes (T2D) as a test case, we develop measures and methods to characterize the functional overlap of SNPs associated with the same disease across populations. RESULTS: We introduce the notion of an Overlap Matrix as a general means of characterizing the functional overlap between different SNP sets at different genomic and functional granularities. Using SNP-to-gene mapping, functional annotation databases, and functional association networks, we assess the degree of functional overlap across nine populations from Asian and European ethnic origins. We further assess the generalizability of the method by applying it to a dataset for another complex disease - Prostate Cancer. Our results show that more overlap is captured as more functional data is incorporated as we go through the pipeline, starting from SNPs and ending at network overlap analyses. We hypothesize that these observed differences in the functional mechanisms of T2D across populations can also explain the common use of different prescription drugs in different populations. We show that this hypothesis is concordant with the literature on the functional mechanisms of prescription drugs. CONCLUSION: Our results show that although the etiology of a complex disease can be associated with distinct processes that are affected in different populations, network-based annotations can capture more functional overlap across populations. These results support the notion that it can be useful to take ethnicity into account in making personalized treatment decisions for complex diseases.


Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único/genética , Grupo com Ancestrais do Continente Asiático , Diabetes Mellitus Tipo 2/tratamento farmacológico , Grupos Étnicos , Genoma Humano , Humanos , Masculino , Neoplasias da Próstata/genética , Mapas de Interação de Proteínas/genética
17.
Genome Biol ; 20(1): 110, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31159854

RESUMO

BACKGROUND: Single-cell RNA sequencing (scRNA-seq) plays a pivotal role in our understanding of cellular heterogeneity. Current analytical workflows are driven by categorizing principles that consider cells as individual entities and classify them into complex taxonomies. RESULTS: We devise a conceptually different computational framework based on a holistic view, where single-cell datasets are used to infer global, large-scale regulatory networks. We develop correlation metrics that are specifically tailored to single-cell data, and then generate, validate, and interpret single-cell-derived regulatory networks from organs and perturbed systems, such as diabetes and Alzheimer's disease. Using tools from graph theory, we compute an unbiased quantification of a gene's biological relevance and accurately pinpoint key players in organ function and drivers of diseases. CONCLUSIONS: Our approach detects multiple latent regulatory changes that are invisible to single-cell workflows based on clustering or differential expression analysis, significantly broadening the biological insights that can be obtained with this leading technology.


Assuntos
Redes Reguladoras de Genes , Genômica/métodos , Transcriptoma , Doença de Alzheimer/genética , Animais , Diabetes Mellitus Tipo 2/genética , Estudos de Viabilidade , Genes Essenciais , Humanos , Camundongos Transgênicos , Análise de Célula Única
18.
Gene ; 706: 43-51, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31039436

RESUMO

Proteins differential expression in type 2 diabetes mellitus (T2DM) can be due to etiological factors or pathological changes, such proteins can be utilized as biomarkers. Identification of a marker protein out of thousands became a feasible task during the proteomics era by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). In this study, blood samples were obtained from 80 Bahraini subjects with and without T2DM, a subset was used for proteomic analysis by LC-MS/MS, while all samples were used for ELISA analysis of 3 proteins, TATA-box binding protein-associated factor RNA polymerase-1-C (TAF1C), ceruloplasmin (CERP) and fibronectin (FN). The former 2 proteins were selected from the T2DM-protein-panel identified by LC-MS/MS, and the latter was analyzed for validation of the setting. The main findings of the proteomic analysis are i. Identifications of 62 differentially expressed proteins in T2DM, ii. Upregulation of 71% of the identified proteins. While the ELISA analysis showed that; both TAF1C and FN were significantly increased in T2DM (P0.015 and P0.001, respectively), while CERP was not (P0.088). Logistic regression analysis: i. confirmed the above associations after correction for covariates, ii. Revealed an interaction between age and gender that affect the association of the proteins with T2DM. In conclusion, knowing that TAF1C is a prerequisite in ribosomal biogenesis, our ELISA results are suggestive of increased protein synthesis in T2DM, explaining the observed upregulation of the proteins identified by LC-MSMS. The association between T2DM and TAF1C is a novel finding that might open a new avenue in DM research.


Assuntos
Diabetes Mellitus Tipo 2/genética , Proteômica/métodos , Fatores Associados à Proteína de Ligação a TATA/genética , Fator de Transcrição TFIID/genética , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/fisiologia , Adulto , Biomarcadores , Cromatografia Líquida/métodos , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Humanos , Masculino , Espectrometria de Massas/métodos , Pessoa de Meia-Idade , Peptídeos , TATA Box/genética , TATA Box/fisiologia , Fatores Associados à Proteína de Ligação a TATA/fisiologia , Fator de Transcrição TFIID/fisiologia
19.
Braz Oral Res ; 33: e034, 2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31038568

RESUMO

Specific variants in genes that encode adipokines and their mRNA and protein expression were previously studied in type 2 diabetes mellitus (T2DM) and obesity, and similar studies have been performed for chronic periodontitis (CP). The aim of this case-control study was to investigate the possible impacts of adiponectin (ADIPOQ), leptin (LEP) and its receptor (LEPR), and resistin (RETN) on the etiopathogenesis of CP. Examinations were performed on 118 non-periodontitis healthy subjects (healthy controls, HC), 205 healthy individuals with CP (H + CP) and 86 type 2 diabetes patients with CP (T2DM + CP). Variants within the ADIPOQ (rs2241766, rs1501299), LEP (rs13228377, rs2167270), LEP receptor (rs1805096), and RETN (rs1862513) genes were determined by qPCR. In addition, the plasma levels of ADIPOQ, LEP, and RETN were analysed by ELISA for 80 individuals. The genotype frequencies of the SNP ADIPOQ +45G/T (rs2241766) differed between the HC and H + CP groups (p=0.03, pcorr>0.05), and carriers of the TT genotype had a lower risk of developing CP compared to carriers of the GG or TG genotypes (p<0.01, pcorr>0.05). However, there were no significant differences in the plasma levels of ADIPOQ, LEP or RETN between the study groups (p > 0.05). Plasma levels of the adipokines were also independent of the gene profiles (p > 0.05). Adipokine plasma levels did not change in patients with H + CP/T2DM + CP compared to HC, but we did identify a specific polymorphism in the ADIPOQ gene that was associated with CP. Although the ADIPOQ +45G/T (rs2241766) gene variant may be a candidate biomarker for CP, further research is required in larger populations with different ethnic backgrounds before any final conclusions can be drawn about the role of this gene in CP.


Assuntos
Adipocinas/sangue , Adipocinas/genética , Periodontite Crônica/sangue , Diabetes Mellitus Tipo 2/sangue , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Análise de Variância , Biomarcadores/sangue , Estudos de Casos e Controles , Periodontite Crônica/genética , Diabetes Mellitus Tipo 2/genética , Feminino , Variação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Valores de Referência , Estatísticas não Paramétricas
20.
J Mol Histol ; 50(3): 239-251, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31049798

RESUMO

Reduced expression of endothelial nitric oxide synthase (eNOS) is a hallmark of endothelial dysfunction in diabetes, which predisposes diabetic patients to numerous cardiovascular complications including blunted angiogenesis. The Krüppel-like factor (KLF) five has been implicated as a central regulator of cardiovascular remodeling, but its role in endothelial cells (ECs) remains poorly understood. We show here that expression of endothelial KLF5 was significantly increased in the ECs from mouse diabetes mellitus type 2 (T2DM) model, when compared to non-diabetic or T1DM mouse. KLF5 up-regulation by insulin was dependent on activation of multiple pathways, including mammalian target of rapamycin, oxidative stress and Protein kinase C pathways. Hyperinsulinemia-induced KLF5 inhibited endothelial function and migration, and thereby compromised in vitro and in vivo angiogenesis. Mechanistically, KLF5 acted in concert with the MTA1 coregulator to negatively regulate NOS3 transcription, thereby leading to the diminished eNOS levels in ECs. Conversely, potentiation of cGMP content (the essential downstream effector of eNOS signaling) by pharmacological approaches successfully rescued the endothelial proliferation and in vitro tube formation, in the HUVECs overexpressing the exogenous KLF5. Collectively, the available data suggest that the augmentation of endothelial KLF5 expression by hyperinsulinemia may represent a novel mechanism for negatively regulating eNOS expression, and may thus help to explain for the T2DM-related endothelial dysfunction at the transcriptional level.


Assuntos
Hiperinsulinismo/genética , Fatores de Transcrição Kruppel-Like/genética , Neovascularização Patológica/genética , Óxido Nítrico Sintase Tipo III/genética , Animais , Movimento Celular/genética , Proliferação de Células/genética , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Expressão Gênica/genética , Células Endoteliais da Veia Umbilical Humana , Humanos , Hiperinsulinismo/patologia , Masculino , Camundongos , Estresse Oxidativo/genética , Proteína Quinase C/genética , Transdução de Sinais/genética
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