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1.
BMC Endocr Disord ; 20(1): 155, 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33066762

RESUMO

BACKGROUND: Detailed description of hyperglycemia management in diabetic patients infected with SARS-CoV-2 remain limited, although patients with diabetes show higher complication and mortality rate than patients without diabetes. Transient non-severe increased insulin requirement in patients hospitalized for medical conditions such as sepsis or myocardial infarction is a well-known phenomenon. However, extremely high-dose insulin requirement remains a very rarely reported entity. Here, we report the case of an extreme and transitory insulin requirement episode in a type 2 diabetic patient presenting an acute respiratory distress syndrome caused by SARS-CoV-2. CASE PRESENTATION: A 57-year-old man resident in Geneva, Switzerland, previously known for type 2 diabetes for 3 years was admitted for an aggravation of his dyspnea. His type 2 diabetes was treated only with metformin and his latest Hb1Ac was 6.1%. Chest CT SCAN showed a bilateral multilobar ground-glass opacification. Twenty-four hours after his admission he presented a worsening of dyspnea and severe hypoxemia requiring a transfer to the intensive care unit rapidly followed by oro-tracheal intubation for mechanical ventilation support. A bronchoalveolar lavage was performed and test of SARS-CoV-2 by RT-qPCR assay was positive. At day 3, he presented a rapidly progressive insulin requirement at a rate of up to 50 units/hour intravenous insulin aspart. Despite the high insulin doses, he maintained an elevated plasma glucose level at 270 mg/dL on average. His extremely high-dose insulin requirement "resolved" at day 9, and the insulin infusion rate was rapidly reduced. CONCLUSIONS: This case may reflect a specific and profound impact of SARS-CoV-2 on metabolic homeostasis, in particular in diabetic patients that appear more prone to complications of COVID-19 infection. Yet, the mechanisms behind this remain to be elucidated. The optimal management of hyperglycemia of diabetic patients infected with SARS-CoV-2 has yet not be defined, however insulin remain the mainstay of treatment approach. Report of extreme dysregulation of chronic conditions such as diabetes in patients with COVID-19 may help clinicians to better take care of patients during the pandemic of SARS-CoV-2. To the best of our knowledge this is the first description of extremely high-dose insulin requirement in patient with COVID-19.


Assuntos
Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Pneumonia Viral/complicações , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/virologia , Relação Dose-Resposta a Droga , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/transmissão , Pneumonia Viral/virologia , Prognóstico
2.
Lancet Diabetes Endocrinol ; 8(10): 834-844, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32946820

RESUMO

BACKGROUND: Although metformin is increasingly being used in women with type 2 diabetes during pregnancy, little data exist on the benefits and harms of metformin use on pregnancy outcomes in these women. We aimed to investigate the effects of the addition of metformin to a standard regimen of insulin on neonatal morbidity and mortality in pregnant women with type 2 diabetes. METHODS: In this prospective, multicentre, international, randomised, parallel, double-masked, placebo-controlled trial, women with type 2 diabetes during pregnancy were randomly assigned from 25 centres in Canada and four in Australia to receive either metformin 1000 mg twice daily or placebo, added to insulin. Randomisation was done via a web-based computerised randomisation service and stratified by centre and pre-pregnancy BMI (<30 kg/m2 or ≥30 kg/m2) in a ratio of 1:1 using random block sizes of 4 and 6. Women were eligible if they had type 2 diabetes, were on insulin, had a singleton viable pregnancy, and were between 6 and 22 weeks plus 6 days' gestation. Participants were asked to check their fasting blood glucose level before the first meal of the day, before the last meal of the day, and 2 h after each meal. Insulin doses were adjusted aiming for identical glucose targets (fasting glucose <5·3 mmol/L [95 mg/dL], 2-h postprandial glucose <6·7 mmol/L [120 mg/dL]). Study visits were done monthly and patients were seen every 1-4 weeks as was needed for standard clinical care. At study visits blood pressure and bodyweight were measured; patients were asked about tolerance to their pills, any hospitalisations, insulin doses, and severe hypoglycaemia events; and glucometer readings were downloaded to the central coordinating centre. Participants, caregivers, and outcome assessors were masked to the intervention. The primary outcome was a composite of fetal and neonatal outcomes, for which we calculated the relative risk and 95% CI between groups, stratifying by site and BMI using a log-binomial regression model with an intention-to-treat analysis. Secondary outcomes included several relevant maternal and neonatal outcomes. The trial was registered with ClinicalTrials.gov, NCT01353391. FINDINGS: Between May 25, 2011, and Oct 11, 2018, we randomly assigned 502 women, 253 (50%) to metformin and 249 (50%) to placebo. Complete data were available for 233 (92%) participants in the metformin group and 240 (96%) in the placebo group for the primary outcome. We found no significant difference in the primary composite neonatal outcome between the two groups (40% vs 40%; p=0·86; relative risk [RR] 1·02 [0·83 to 1·26]). Compared with women in the placebo group, metformin-treated women achieved better glycaemic control (HbA1c at 34 weeks' gestation 41·0 mmol/mol [SD 8·5] vs 43·2 mmol/mol [-10]; 5·90% vs 6·10%; p=0·015; mean glucose 6·05 [0·93] vs 6·27 [0·90]; difference -0·2 [-0·4 to 0·0]), required less insulin (1·1 units per kg per day vs 1·5 units per kg per day; difference -0·4 [95% CI -0·5 to -0·2]; p<0·0001), gained less weight (7·2 kg vs 9·0 kg; difference -1·8 [-2·7 to -0·9]; p<0·0001) and had fewer caesarean births (125 [53%] of 234 in the metformin group vs 148 [63%] of 236 in the placebo group; relative risk [RR] 0·85 [95% CI 0·73 to 0·99]; p=0·031). We found no significant difference between the groups in hypertensive disorders (55 [23%] in the metformin group vs 56 [23%] in the placebo group; p=0·93; RR 0·99 [0·72 to 1·35]). Compared with those in the placebo group, metformin-exposed infants weighed less (mean birthweight 3156 g [SD 742] vs 3375 g [742]; difference -218 [-353 to -82]; p=0·002), fewer were above the 97th centile for birthweight (20 [9%] in the metformin group vs 34 [15%] in the placebo group; RR 0·58 [0·34 to 0·97]; p=0·041), fewer weighed 4000 g or more at birth (28 [12%] in the metformin group vs 44 [19%] in the placebo group; RR 0·65 [0·43 to 0·99]; p=0·046), and metformin-exposed infants had reduced adiposity measures (mean sum of skinfolds 16·0 mm [SD 5·0] vs 17·4 [6·2] mm; difference -1·41 [-2·6 to -0·2]; p=0·024; mean neonatal fat mass 13·2 [SD 6·2] vs 14·6 [5·0]; p=0·017). 30 (13%) infants in the metformin group and 15 (7%) in the placebo group were small for gestational age (RR 1·96 [1·10 to 3·64]; p=0·026). We found no significant difference in the cord c-peptide between groups (673 pmol/L [435] in the metformin group vs 758 pmol/L [595] in the placebo group; p=0·10; ratio of means 0·88 [0·72 to 1·02]). The most common adverse event reported was gastrointestinal (38 events in the metformin group and 38 events in the placebo group). INTERPRETATION: We found several maternal glycaemic and neonatal adiposity benefits in the metformin group. Along with reduced maternal weight gain and insulin dosage and improved glycaemic control, the lower adiposity and infant size measurements resulted in fewer large infants but a higher proportion of small-for-gestational-age infants. Understanding the implications of these effects on infants will be important to properly advise patients who are contemplating the use of metformin during pregnancy. FUNDING: Canadian Institutes of Health Research, Lunenfeld-Tanenbaum Research Institute, University of Toronto.


Assuntos
Biomarcadores/análise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Adolescente , Adulto , Glicemia/análise , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Método Duplo-Cego , Feminino , Seguimentos , Hemoglobina A Glicada/análise , Humanos , Agências Internacionais , Pessoa de Meia-Idade , Gravidez , Resultado da Gravidez , Estudos Prospectivos , Adulto Jovem
3.
Nat Commun ; 11(1): 4458, 2020 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-32895383

RESUMO

In rodent models of type 2 diabetes (T2D), sustained remission of hyperglycemia can be induced by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1), and the mediobasal hypothalamus (MBH) was recently implicated as the brain area responsible for this effect. To better understand the cellular response to FGF1 in the MBH, we sequenced >79,000 single-cell transcriptomes from the hypothalamus of diabetic Lepob/ob mice obtained on Days 1 and 5 after icv injection of either FGF1 or vehicle. A wide range of transcriptional responses to FGF1 was observed across diverse hypothalamic cell types, with glial cell types responding much more robustly than neurons at both time points. Tanycytes and ependymal cells were the most FGF1-responsive cell type at Day 1, but astrocytes and oligodendrocyte lineage cells subsequently became more responsive. Based on histochemical and ultrastructural evidence of enhanced cell-cell interactions between astrocytes and Agrp neurons (key components of the melanocortin system), we performed a series of studies showing that intact melanocortin signaling is required for the sustained antidiabetic action of FGF1. These data collectively suggest that hypothalamic glial cells are leading targets for the effects of FGF1 and that sustained diabetes remission is dependent on intact melanocortin signaling.


Assuntos
Diabetes Mellitus Experimental/dietoterapia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fator 1 de Crescimento de Fibroblastos/administração & dosagem , Hipoglicemiantes/administração & dosagem , Hipotálamo/efeitos dos fármacos , Proteínas Recombinantes/administração & dosagem , Proteína Relacionada com Agouti/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Glicemia/análise , Comunicação Celular , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/patologia , Dieta Hiperlipídica/efeitos adversos , Sacarose na Dieta/administração & dosagem , Sacarose na Dieta/efeitos adversos , Humanos , Hipotálamo/citologia , Hipotálamo/patologia , Injeções Intraventriculares , Leptina/genética , Masculino , Melanocortinas/metabolismo , Hormônios Estimuladores de Melanócitos/administração & dosagem , Camundongos , Camundongos Knockout , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , RNA-Seq , Receptor Tipo 4 de Melanocortina/genética , Receptores de Melanocortina/antagonistas & inibidores , Receptores de Melanocortina/metabolismo , Indução de Remissão/métodos , Transdução de Sinais/efeitos dos fármacos , Análise de Célula Única , Técnicas Estereotáxicas , Transcriptoma/efeitos dos fármacos
4.
Front Immunol ; 11: 1582, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32793223

RESUMO

Metabolic abnormalities such as dyslipidemia, hyperinsulinemia, or insulin resistance and obesity play key roles in the induction and progression of type 2 diabetes mellitus (T2DM). The field of immunometabolism implies a bidirectional link between the immune system and metabolism, in which inflammation plays an essential role in the promotion of metabolic abnormalities (e.g., obesity and T2DM), and metabolic factors, in turn, regulate immune cell functions. Obesity as the main inducer of a systemic low-level inflammation is a main susceptibility factor for T2DM. Obesity-related immune cell infiltration, inflammation, and increased oxidative stress promote metabolic impairments in the insulin-sensitive tissues and finally, insulin resistance, organ failure, and premature aging occur. Hyperglycemia and the subsequent inflammation are the main causes of micro- and macroangiopathies in the circulatory system. They also promote the gut microbiota dysbiosis, increased intestinal permeability, and fatty liver disease. The impaired immune system together with metabolic imbalance also increases the susceptibility of patients to several pathogenic agents such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Thus, the need for a proper immunization protocol among such patients is granted. The focus of the current review is to explore metabolic and immunological abnormalities affecting several organs of T2DM patients and explain the mechanisms, whereby diabetic patients become more susceptible to infectious diseases.


Assuntos
Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/patologia , Hiperglicemia/imunologia , Síndrome Metabólica/imunologia , Obesidade/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Suscetibilidade a Doenças/imunologia , Disbiose/imunologia , Microbioma Gastrointestinal , Humanos , Sistema Imunitário/metabolismo , Inflamação/imunologia , Estresse Oxidativo/imunologia , Pandemias , Pneumonia Viral/imunologia
5.
Gene ; 763: 145058, 2020 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-32798635

RESUMO

BACKGROUND: The nuclear receptors Rev-erb alpha and Rev-erb beta are transcription factors that regulate the function of genes in glucose and lipid metabolism, and they also form a link between circadian rhythm and metabolism. We evaluated the variations in Rev-erb alpha and Rev-erb beta genes together with biochemical parameters as risk factors in type 2 diabetic (T2DM) patients. METHODS: Molecular analyses of Rev-erb alpha and Rev-erb beta genes were performed on genomic DNA by using next-generation sequencing in 42 T2DM patients (21 obese and 21 non-obese) and 66 healthy controls. RESULTS: We found 26 rare mutations in the study groups, including 13 missense mutations, 9 silent mutations, 3 5'UTR variations, and a 3'UTR variation, of which 9 were novel variations (5 missense and 3 silent and 1 5'UTR). Six common variations were also found in the Rev-erb genes; Rev-erb beta Chr3:24003765 A > G, Rev-erb beta rs924403442 (Chr3:24006717) G > T, Rev-erb alpha Chr17:38253751 T > C, Rev-erb alpha rs72836608 C > A, Rev-erb alpha rs2314339 C > T and Rev-erb alpha rs2102928 C > T. Of these, Rev-erb beta Chr3:24003765 A > G was a novel missense mutation (p.Q197R), while others were identified as intronic variants. T2DM patients with Rev-erb beta rs924403442 T allele had lower body surface area (BSA) than noncarriers (GG genotype) (p = 0.039). Rev-erb alpha rs72836608 A allele and Rev-erb alpha rs2314339 CC genotype were associated with decreased serum HDL-cholesterol levels in T2DM patients (p = 0.025 and p = 0.027, respectively). In our study, different effects of Rev-erbs polymorphisms were found according to gender and presence of obesity. Rev-erb alpha rs72836608 (C > A) and rs2314339 (C > T) and Rev-erb alpha rs2102928 (C > T) were associated with low HDL-C levels in male T2DM patients. In female patients, Rev-erb alpha rs2102928 (C > T) was associated with high microalbuminuria and Rev-erb beta rs9244403442 G > T was associated with low HDL and high BSA values. In addition, Rev-erb alpha Chr17: 38,253,751 (T > C), rs72836608 (C > A), and rs2314339 (C > T) and Rev-erb beta Chr3:24003765 (A > G) were associated with increased serum GGT levels in obese T2DM patients. In non-obese patients, Rev-erbs SNPs had no effect on serum GGT levels. CONCLUSION: Our findings indicate that variations in the Rev-erb alpha and Rev-erb beta genes can affect metabolic changes in T2DM and these effects may vary depending on gender and obesity.


Assuntos
Diabetes Mellitus Tipo 2/genética , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Polimorfismo de Nucleotídeo Único , Receptores Citoplasmáticos e Nucleares/genética , Proteínas Repressoras/genética , Diabetes Mellitus Tipo 2/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
6.
PLoS One ; 15(8): e0237667, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32833960

RESUMO

BACKGROUND AND AIMS: This is the first time that obesity and diabetes mellitus (DM) as protein conformational diseases (PCD) are reported in children and they are typically diagnosed too late, when ß-cell damage is evident. Here we wanted to investigate the level of naturally-ocurring or real (not synthetic) oligomeric aggregates of the human islet amyloid polypeptide (hIAPP) that we called RIAO in sera of pediatric patients with obesity and diabetes. We aimed to reduce the gap between basic biomedical research, clinical practice-health decision making and to explore whether RIAO work as a potential biomarker of early ß-cell damage. MATERIALS AND METHODS: We performed a multicentric collaborative, cross-sectional, analytical, ambispective and blinded study; the RIAO from pretreated samples (PTS) of sera of 146 pediatric patients with obesity or DM and 16 healthy children, were isolated, measured by sound indirect ELISA with novel anti-hIAPP cytotoxic oligomers polyclonal antibody (MEX1). We carried out morphological and functional studied and cluster-clinical data driven analysis. RESULTS: We demonstrated by western blot, Transmission Electron Microscopy and cell viability experiments that RIAO circulate in the blood and can be measured by ELISA; are elevated in serum of childhood obesity and diabetes; are neurotoxics and works as biomarkers of early ß-cell failure. We explored the range of evidence-based medicine clusters that included the RIAO level, which allowed us to classify and stratify the obesity patients with high cardiometabolic risk. CONCLUSIONS: RIAO level increases as the number of complications rises; RIAOs > 3.35 µg/ml is a predictor of changes in the current indicators of ß-cell damage. We proposed a novel physio-pathological pathway and shows that PCD affect not only elderly patients but also children. Here we reduced the gap between basic biomedical research, clinical practice and health decision making.


Assuntos
Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/patologia , Células Secretoras de Insulina/patologia , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Obesidade/patologia , Estrutura Quaternária de Proteína , Adolescente , Animais , Linhagem Celular , Sobrevivência Celular , Células Cultivadas , Criança , Pré-Escolar , Estudos Transversais , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Humanos , Polipeptídeo Amiloide das Ilhotas Pancreáticas/sangue , Polipeptídeo Amiloide das Ilhotas Pancreáticas/toxicidade , Polipeptídeo Amiloide das Ilhotas Pancreáticas/ultraestrutura , Microscopia Eletrônica de Transmissão , Neurônios/efeitos dos fármacos , Obesidade/sangue , Obesidade/complicações , Projetos Piloto , Cultura Primária de Células , Multimerização Proteica , Ratos , Testes de Toxicidade Aguda
7.
Life Sci ; 258: 118243, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32791154

RESUMO

AIMS: Although autophagy impairment is a well-established cause of muscle atrophy and P300 has recently been identified as an important regulator of autophagy, the effects of P300 on autophagy and muscle atrophy in type 2 diabetes (T2D) remain unexplored. We aimed at characterizing the role of P300 in diabetic muscle and its underlying mechanism. MAIN METHODS: Protein levels of phosphorylated P300, total P300, acetylated histone H3, LC3, p62 and myosin heavy chain, and mRNA levels of Atrogin-1 and MuRF1 were analyzed in palmitic acid (PA)-treated myotubes and db/db mice. Autophagic flux was assessed using transmission electron microscopy, immunofluorescence and mRFP-GFP-LC3 lentivirus transfection in cells. Muscle weight, blood glucose and grip strength were measured in mice. Hematoxylin and eosin (H&E) staining was performed to determine changes in muscle fiber size. To investigate the effects of P300 on autophagy and myofiber remodeling, a P300 specific inhibitor, c646, was utilized. 3-Methyladenine (3-MA) was utilized to inhibit autophagosomes formation, and chloroquine (CQ) was used to block autophagic flux. KEY FINDINGS: Phosphorylation of P300 in response to PA enhanced its activity and subsequently suppressed autophagic flux, leading to atrophy-related morphological and molecular changes in myotubes. Inhibition of P300 reestablished autophagic flux and ameliorated PA-induced myotubes atrophy. However, this effect was largely abolished by co-treatment with the autophagy inhibitor CQ. In vivo results demonstrated that inhibition of P300 partially rescued muscle wasting in db/db mice, accompanied with autophagy reactivation. SIGNIFICANCE: The findings revealed that T2D-induced overactivation of P300 contributes to muscle atrophy by blocking autophagic flux.


Assuntos
Autofagia/fisiologia , Diabetes Mellitus Tipo 2/metabolismo , Proteína p300 Associada a E1A/metabolismo , Atrofia Muscular/metabolismo , Animais , Linhagem Celular , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Proteína p300 Associada a E1A/genética , Força da Mão/fisiologia , Masculino , Camundongos , Camundongos Transgênicos , Atrofia Muscular/genética , Atrofia Muscular/patologia , Mioblastos/metabolismo , Mioblastos/patologia
8.
Niger J Clin Pract ; 23(7): 970-974, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620727

RESUMO

Background: Diabetes mellitus is one of the most common metabolic disorders with a rising prevalence. It cuts across all ages and socioeconomic status. Various skin lesions are frequently observed in diabetic patients. Aims: This study was carried out to determine the prevalence, pattern, and determinants of skin diseases in diabetic patients at the Barau Dikko Teaching Hospital, Kaduna, North West Nigeria. Materials and Methods: One hundred consecutive diabetic patients attending the clinic were included in the study. Results: Many of the patients had more than one skin condition at a time. The most prevalent skin diseases were idiopathic guttate hypomelanosis which was seen in 61% of patients, infections from fungal, bacterial, and viral causes occurred in 30% of patients, other skin disorders were diabetic dermopathy seen in 17% of patients, palmoplantar hyperpigmentation was seen in 13% of patients, while pruritus occurred in 12% of patients and xerosis was seen in 10% of patients. Conclusion: Skin disorders are common among diabetic patients at Barau Dikko Teaching Hospital, Kaduna, North West Nigeria.


Assuntos
Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Dermatopatias/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Instituições de Assistência Ambulatorial , Estudos Transversais , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/patologia , Feminino , Hospitais de Ensino , Humanos , Masculino , Pessoa de Meia-Idade , Nigéria/epidemiologia , Prevalência , Prurido/epidemiologia , Pele/patologia , Adulto Jovem
9.
PLoS One ; 15(7): e0236453, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32726329

RESUMO

OBJECTIVES: To assess the potential value of some miRNAs as diagnostic biomarkers for mild cognitive impairment (MCI) among patients with type2 diabetes mellitus (T2DM) and to identify other risk factors for MCI among them. METHODS: This study enrolled 163 adults with T2DM using face to face interview. Cognitive function with its domains was assessed using Adenbrooke's Cognitive Examination III (ACE III). Lipid profile, glycated hemoglobin, and miR-128, miR-132, miR- 874, miR-134, miR-323, and miR-382 expressions, using quantitative real-time PCR, were assessed. RESULTS: MCI was detected among 59/163 (36.2%) patients with T2DM. Plasma expression of miR-132 was significantly higher in T2DM patients with MCI compared to those without MCI and to normal cognitive healthy individuals (median = 2, 1.1 and 1.2 respectively, P < 0.05. Logistic regression analysis showed that higher miR-132 expression with adjusted odds ratio (AOR): 1.2 (95% CI 1.0-1.3), female gender (AOR:2.1; 95%CI 1.0-4.3), education below postgraduate (secondary and university education with AOR: 9.5 & 19.4 respectively) were the significant predicting factors for MCI among T2DM patients. Using ROC curve, miR-132 was the only assayed miRNA that significantly differentiates T2DM patients with MCI from those with normal cognition with 72.3% sensitivity, 56.2% specificity, and 63.8% accuracy (P < 0.05). Other studied miRNAs showed lower sensitivity and specificity for detecting MCI among studied T2DM participants. CONCLUSION: MCI affects nearly one-third of adult patients with T2DM. A significantly over expression of miR-132 was detected among T2DM with MCI compared to those with normal cognition.


Assuntos
Biomarcadores/sangue , Disfunção Cognitiva/sangue , Diabetes Mellitus Tipo 2/sangue , MicroRNAs/sangue , Adulto , Cognição/fisiologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Feminino , Hemoglobina A Glicada/genética , Humanos , Lipídeos/sangue , Masculino , MicroRNAs/classificação , MicroRNAs/genética , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fatores de Risco
10.
PLoS Genet ; 16(7): e1008903, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32678846

RESUMO

Genome wide association studies (GWAS) of human diseases have generally identified many loci associated with risk with relatively small effect sizes. The omnigenic model attempts to explain this observation by suggesting that diseases can be thought of as networks, where genes with direct involvement in disease-relevant biological pathways are named 'core genes', while peripheral genes influence disease risk via their interactions or regulatory effects on core genes. Here, we demonstrate a method for identifying candidate core genes solely from genes in or near disease-associated SNPs (GWAS hits) in conjunction with protein-protein interaction network data. Applied to 1,381 GWAS studies from 5 ancestries, we identify a total of 1,865 candidate core genes in 343 GWAS studies. Our analysis identifies several well-known disease-related genes that are not identified by GWAS, including BRCA1 in Breast Cancer, Amyloid Precursor Protein (APP) in Alzheimer's Disease, INS in A1C measurement and Type 2 Diabetes, and PCSK9 in LDL cholesterol, amongst others. Notably candidate core genes are preferentially enriched for disease relevance over GWAS hits and are enriched for both Clinvar pathogenic variants and known drug targets-consistent with the predictions of the omnigenic model. We subsequently use parent term annotations provided by the GWAS catalog, to merge related GWAS studies and identify candidate core genes in over-arching disease processes such as cancer-where we identify 109 candidate core genes.


Assuntos
Doença de Alzheimer/genética , Neoplasias da Mama/genética , Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla , Mapas de Interação de Proteínas/genética , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Proteína BRCA1/genética , Neoplasias da Mama/patologia , Diabetes Mellitus Tipo 2/patologia , Feminino , Humanos , Insulina/genética , Polimorfismo de Nucleotídeo Único/genética , Pró-Proteína Convertase 9/genética , Fatores de Risco
11.
PLoS One ; 15(7): e0235640, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32730268

RESUMO

BACKGROUND: Fluid overload is common in patients with diabetes and chronic kidney disease (DM and CKD; DMCKD) and can lead to structural and functional cardiac abnormalities including left ventricular hypertrophy (LVH) and left ventricular diastolic dysfunction (LVDD). Fluid overload represents a crucial step in the pathophysiological pathways to chronic heart failure in patients with end-stage renal disease. We evaluated the impact of fluid overload on cardiac alterations in patients with diabetes and non-dialysis-dependent CKD stage 5 (DMCKD5-ND) without intrinsic heart disease. METHODS: Bioimpedance spectroscopy, echocardiography, and N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) measurement were performed in 135 consecutive patients on the same day. Patients were divided into groups by tertiles of overhydration/extracellular water (OH/ECW) per bioimpedance spectroscopy. RESULTS: Fluid balance markers including OH/ECW and NT-proBNP were significantly higher in the LVDD+LVH group. OH/ECW and its exacerbation were positively associated with the ratio between early mitral inflow and annular early diastolic velocities (E/e' ratio) and left ventricular mass index (LVMI). The prevalence of LVH progressively increased across increasing tertiles of OH/ECW. In multiple regression analyses, OH/ECW as a continuous and categorical variable was independently associated with the E/e' ratio and LVMI after adjustment for multiple confounding factors. CONCLUSIONS: Fluid overload was independently associated with LVDD and LVH in patients with DMCKD5-ND. Our study suggests that structural and functional cardiac abnormalities and volume status should be evaluated simultaneously in patients with early-stage DMCKD rather than only DMCKD5-ND, in addition to intensive blood pressure and glycemic control, regardless of evident cardiovascular disease.


Assuntos
Diabetes Mellitus Tipo 2/patologia , Hidratação , Falência Renal Crônica/patologia , Idoso , Espectroscopia Dielétrica , Ecocardiografia , Feminino , Taxa de Filtração Glomerular , Humanos , Hipertrofia Ventricular Esquerda/epidemiologia , Hipertrofia Ventricular Esquerda/patologia , Falência Renal Crônica/terapia , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Prevalência , Diálise Renal , Índice de Gravidade de Doença , Disfunção Ventricular Esquerda/patologia
12.
PLoS One ; 15(7): e0235335, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32628695

RESUMO

Diabetes is associated with a dramatic mortality rate due to its vascular complications. Chronic hyperglycemia in diabetes leads to enhanced glycation of erythrocytes and oxidative stress. Even though erythrocytes play a determining role in vascular complications, very little is known about how erythrocyte structure and functionality can be affected by glycation. Our objective was to decipher the impact of glycation on erythrocyte structure, oxidative stress parameters and capacity to interact with cultured human endothelial cells. In vitro glycated erythrocytes were prepared following incubation in the presence of different concentrations of glucose. To get insight into the in vivo relevance of our results, we compared these data to those obtained using red blood cells purified from diabetics or non-diabetics. We measured erythrocyte deformability, susceptibility to hemolysis, reactive oxygen species production and oxidative damage accumulation. Altered structures, redox status and oxidative modifications were increased in glycated erythrocytes. These modifications were associated with reduced antioxidant defence mediated by enzymatic activity. Enhanced erythrocyte phagocytosis by endothelial cells was observed when cultured with glycated erythrocytes, which was associated with increased levels of phosphatidylserine-likely as a result of an eryptosis phenomenon triggered by the hyperglycemic treatment. Most types of oxidative damage identified in in vitro glycated erythrocytes were also observed in red blood cells isolated from diabetics. These results bring new insights into the impact of glycation on erythrocyte structure, oxidative damage and their capacity to interact with endothelial cells, with a possible relevance to diabetes.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Eritrócitos/patologia , Produtos Finais de Glicação Avançada/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Glicemia/metabolismo , Linhagem Celular , Técnicas de Cocultura , Diabetes Mellitus Tipo 2/patologia , Células Endoteliais , Eriptose , Deformação Eritrocítica , Eritrócitos/metabolismo , Hemoglobina A Glicada/análise , Voluntários Saudáveis , Hemólise , Humanos , Estresse Oxidativo , Cultura Primária de Células
13.
PLoS One ; 15(7): e0236603, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32706828

RESUMO

BACKGROUND AND OBJECTIVE: Dipeptidyl peptidase-4 (DPP-4) inhibitors have been suggested to have pancreatic beta-cell preserving effect according to studies using homeostatic model of assessment for beta-cell function (HOMA-ß). However, whether HOMA-ß is a suitable biomarker for comparisons between hypoglycemic drugs with different mechanisms of action remains unclear. Therefore, we conducted a meta-analysis to compare the effects of DPP-4 inhibitors and other classes of hypoglycemic drugs on HOMA-ß and proinsulin-to-insulin ratio (PIR). METHODS: We searched MEDLINE, CENTRAL, and Ichushi-web for the period of 1966 to May 2020. We collected randomized, controlled clinical trials in patients with type 2 diabetes mellitus comparing DPP-4 inhibitors and other classes of hypoglycemic agents [α-glucosidase inhibitors (α-GIs), glucagon-like peptide-1 (GLP-1) analogues, metformin, sodium-glucose cotransporter 2 (SGLT2) inhibitors, sulfonylureas, or thiazolidinediones]. Weighted mean differences and 95% confidence intervals of changes in HOMA-ß or PIR during study periods were calculated for pairwise comparisons. RESULTS: Thirty-seven and 21 relevant trials were retrieved for comparisons of HOMA-ß and PIR, respectively. HOMA-ß and PIR consistently showed superiority of DPP-4 inhibitors compared with α-GIs. Both biomarkers consistently supported inferiority of DPP-4 inhibitors compared with GLP-1 analogues. However, PIR showed inferiority of DPP-4 inhibitors compared with metformin, and superiority compared with SGLT2 inhibitors, whereas HOMA-ß showed no significant differences between DPP-4 inhibitors and the two other agents. CONCLUSION: DPP-4 inhibitors appear to be superior to α-GIs but inferior to GLP-1 analogues in preservation of beta-cell function assessed by either HOMA-ß or PIR. DPP-4 inhibitors seem to be superior to SGLT2 inhibitors but inferior to metformin on islet function assessed only by PIR. Because HOMA-ß and PIR may indicate different aspects of beta-cell function, results of beta-cell function preserving effects of hypoglycemic agents should be interpreted with caution.


Assuntos
Biomarcadores/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Hipoglicemiantes/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/patologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/metabolismo , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Metformina/farmacologia , Metformina/uso terapêutico , Proinsulina/metabolismo , Compostos de Sulfonilureia/farmacologia , Compostos de Sulfonilureia/uso terapêutico , Tiazolidinedionas/farmacologia , Tiazolidinedionas/uso terapêutico
14.
Diab Vasc Dis Res ; 17(4): 1479164120945675, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32722929

RESUMO

Activation of the prostaglandin E2 receptor EP4 alters polarization of adipose tissue macrophages towards the anti-inflammatory M2 phenotype to suppress chronic inflammation. However, the role of EP4 signalling in pancreatic macrophages that affect insulin secretion is unclear. We examined the role of EP4 signalling in islet inflammation in vitro and in vivo. Obese diabetic db/db mice were treated with an EP4-selective agonist or vehicle for 4 weeks. Islet morphology did not significantly differ and glucose-stimulated insulin secretion was increased, whereas the pancreatic M1/M2 ratio was decreased in the EP4 agonist-treated group compared to the vehicle group. Because EP4 activation in MIN6 cells did not affect insulin secretion, we used a MIN6/macrophage co-culture system to evaluate the role of EP4 signalling in islet inflammation and subsequent inhibition of insulin release. Co-culture with M1-polarized macrophages markedly suppressed insulin expression in MIN6 cells; however, modulation of M1 polarization by the EP4 agonist significantly reversed the negative impact of co-cultivation on insulin production. The enhanced expression levels of pro-inflammatory cytokines in co-cultured MIN6 cells were markedly inhibited by EP4 agonist treatment of M1 macrophages. Thus, EP4 activation may suppress islet inflammation and protect ß-cell function by altering inflammatory macrophages in the diabetic pancreas.


Assuntos
Plasticidade Celular , Diabetes Mellitus Tipo 2/metabolismo , Inflamação/metabolismo , Células Secretoras de Insulina/metabolismo , Macrófagos Peritoneais/metabolismo , Obesidade/metabolismo , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Animais , Linhagem Celular Tumoral , Técnicas de Cocultura , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/patologia , Modelos Animais de Doenças , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Insulina/metabolismo , Células Secretoras de Insulina/patologia , Ativação de Macrófagos , Macrófagos Peritoneais/patologia , Camundongos , Obesidade/patologia , Fenótipo , Via Secretória , Transdução de Sinais
15.
Ann Biol Clin (Paris) ; 78(3): 243-252, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32540813

RESUMO

Adiponectin is a major adipokine involved in energy homeostasis that exerts insulin-sensitizing properties. The level of adiponectin is reduced in situations of insulin resistance and is negatively associated with several pathophysiological situations including abdominal obesity, metabolic syndrome, steatosis and non-alcoholic steatohepatitis, type 2 diabetes, some cancers and cognitive diseases. These aspects are discussed in this review.


Assuntos
Adiponectina/fisiologia , Animais , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/patologia , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Humanos , Insulina/metabolismo , Resistência à Insulina/fisiologia , Síndrome Metabólica/etiologia , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Neoplasias/etiologia , Neoplasias/metabolismo , Neoplasias/patologia , Obesidade/metabolismo , Obesidade/patologia , Obesidade/fisiopatologia
16.
Nat Commun ; 11(1): 2695, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32483258

RESUMO

Obesity and type 2 diabetes (T2D) are metabolic disorders influenced by lifestyle and genetic factors that are characterized by insulin resistance in skeletal muscle, a prominent site of glucose disposal. Numerous genetic variants have been associated with obesity and T2D, of which the majority are located in non-coding DNA regions. This suggests that most variants mediate their effect by altering the activity of gene-regulatory elements, including enhancers. Here, we map skeletal muscle genomic enhancer elements that are dynamically regulated after exposure to the free fatty acid palmitate or the inflammatory cytokine TNFα. By overlapping enhancer positions with the location of disease-associated genetic variants, and resolving long-range chromatin interactions between enhancers and gene promoters, we identify target genes involved in metabolic dysfunction in skeletal muscle. The majority of these genes also associate with altered whole-body metabolic phenotypes in the murine BXD genetic reference population. Thus, our combined genomic investigations identified genes that are involved in skeletal muscle metabolism.


Assuntos
Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Elementos Facilitadores Genéticos , Resistência à Insulina/genética , Músculo Esquelético/metabolismo , Obesidade/genética , Obesidade/metabolismo , Animais , Linhagem Celular , Cromatina/genética , Cromatina/metabolismo , Diabetes Mellitus Tipo 2/patologia , Feminino , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Masculino , Camundongos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Obesidade/patologia , Ácido Palmítico/farmacologia , Fatores de Iniciação de Peptídeos/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Fator de Necrose Tumoral alfa/farmacologia
17.
PLoS One ; 15(6): e0234132, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32502168

RESUMO

Diabetic animal models have made significant contributions to understanding the etiology of diabetes and to the development of new medications. Our research group recently developed a novel diabetic mouse strain, the insulin hyposecretion (ihs)mouse. The strain involves neither obesity nor insulitis but exhibits notable pancreatic ß-cell dysfunction, distinguishing it from other well-characterized animal models. In ihs mice, severe impairment of insulin secretion from pancreas has been elicited by glucose or potassium chloride stimulation. To clarify the genetic basis of impaired insulin secretion, beginning with identifying the causative gene, genetic linkage analysis was performed using [(C57BL/6 × ihs) F1 × ihs] backcross progeny. Genetic linkage analysis and quantitative trait loci analysis for blood glucose after oral glucose loading indicated that a recessively acting locus responsible for impaired glucose tolerance was mapped to a 14.9-Mb region of chromosome 18 between D18Mit233 and D18Mit235 (the ihs locus). To confirm the gene responsible for the ihs locus, a congenic strain harboring the ihs locus on the C57BL/6 genetic background was developed. Phenotypic analysis of B6.ihs-(D18Mit233-D18Mit235) mice showed significant glucose tolerance impairment and markedly lower plasma insulin levels during an oral glucose tolerance test. Whole-genome sequencing and Sanger sequencing analyses on the ihs genome detected two ihs-specific variants changing amino acids within the ihs locus; both variants in Slc25a46 and Tcerg1 were predicted to disrupt the protein function. Based on information regarding gene functions involving diabetes mellitus and insulin secretion, reverse-transcription quantitative polymerase chain reaction analysis revealed that the relative abundance of Reep2 and Sil1 transcripts from ihs islets was significantly decreased whereas that of Syt4 transcripts were significantly increased compared with those of control C57BL/6 mice. Thus, Slc25a46, Tcerg1, Syt4, Reep2 and Sil1 are potential candidate genes for the ihs locus. This will be the focus of future studies in both mice and humans.


Assuntos
Diabetes Mellitus Tipo 2/genética , Loci Gênicos , Animais , Glicemia/análise , Diabetes Mellitus Tipo 2/patologia , Modelos Animais de Doenças , Ligação Genética , Teste de Tolerância a Glucose , Secreção de Insulina , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , Proteínas de Transporte de Fosfato/genética , Proteínas de Transporte de Fosfato/metabolismo , Sinaptotagminas/genética , Sinaptotagminas/metabolismo , Fatores de Elongação da Transcrição/genética , Fatores de Elongação da Transcrição/metabolismo
18.
Lancet Diabetes Endocrinol ; 8(7): 616-627, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32559477

RESUMO

An increase in fat mass is considered to be an important risk factor for the worldwide increase in type 2 diabetes and cardiovascular disease. However, for a given fat mass, there is a large variability in the risk prediction of these cardiometabolic diseases. For example, some lean people unexpectedly have a risk of type 2 diabetes and cardiovascular disease that is similar to the increased risk that is observed in most people who have obesity. What both of these phenotypes have in common is a very characteristic fat distribution. As a result, much focus has been given on the strong predictive power of increased visceral fat mass. However, an analysis of the causes of type 2 diabetes and cardiovascular disease, as well as comparisons to rare diseases such as lipodystrophy and studying genetically determined fat distribution in the general population, suggest that an impaired ability to expand subcutaneous fat in the lower part of the body is also important for predicting the incidence of these cardiometabolic diseases. This Review, first, addresses the identification of distinct fat distribution phenotypes and their risk of cardiometabolic diseases by discussing findings from published studies that have applied precise quantification of different fat depots. Second, this Review provides support for the theory that a lower amount of lower-body fat mass is equally important to a high amount of visceral fat mass as a determinant of cardiometabolic diseases. Third, this Review discusses the genetic and lifestyle-related causes of metabolically healthy and unhealthy fat distribution. Finally, this Review summarises and appraises the effectiveness of lifestyle-related interventions and pharmacological interventions for reducing visceral adiposity and maintaining lower-body fat mass to prevent and treat cardiometabolic diseases.


Assuntos
Tecido Adiposo/patologia , Distribuição da Gordura Corporal , Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/etiologia , Resistência à Insulina , Obesidade/complicações , Doenças Cardiovasculares/patologia , Diabetes Mellitus Tipo 2/patologia , Humanos , Fatores de Risco
19.
Lancet Diabetes Endocrinol ; 8(7): 606-615, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32559476

RESUMO

BACKGROUND: Cardiovascular outcome trials have shown cardiovascular benefit with sodium-glucose co-transporter-2 (SGLT2) inhibitors in patients with type 2 diabetes, whereas dipeptidyl peptidase-4 (DPP-4) inhibitors have not shown an effect. We aimed to address knowledge gaps regarding the comparative effectiveness of SGLT2 inhibitor use in clinical practice (with DPP-4 inhibitor use as an active comparator) across a range of cardiovascular risks and in diverse geographical settings. METHODS: In this comparative cohort study, we used data from clinical practice from 13 countries in the Asia-Pacific, Middle East, European, and North American regions to assess the risk of cardiovascular events and death in adult patients with type 2 diabetes newly initiated on SGLT2 inhibitors compared with those newly initiated on DPP-4 inhibitors. De-identified health records were used to select patients who were initiated on these drug classes between Dec 1, 2012, and May 1, 2016, with follow-up until Dec 31, 2014, to Nov 30, 2017 (full range; dates varied by country). Non-parsimonious propensity scores for SGLT2 inhibitor initiation were developed for each country and patients who were initiated on an SGLT2 inhibitor were matched with those who were initiated on a DPP-4 inhibitor in a 1:1 ratio. Outcomes assessed were hospitalisation for heart failure, all-cause death, myocardial infarction, and stroke. Hazard ratios (HRs) were estimated by country and then pooled in a weighted meta-analysis. FINDINGS: Following propensity score matching, 193 124 new users of SGLT2 inhibitors and 193 124 new users of DPP-4 inhibitors were included in the study population. Participants had a mean age of 58 years (SD 12·2), 170 335 (44·1%) of 386 248 were women, and 111 933 (30·1%) of 372 262 had established cardiovascular disease. Initiation of an SGLT2 inhibitor versus a DPP-4 inhibitor was associated with substantially lower risks of hospitalisation for heart failure (HR 0·69, 95% CI 0·61-0·77; p<0·0001), all-cause death (0·59, 0·52-0·67; p<0·0001), and the composite of hospitalisation for heart failure or all-cause death (0·64, 0·57-0·72; p<0·0001). Risks of myocardial infarction (HR 0·88, 0·80-0·98; p=0·020) and stroke (0·85 0·77-0·93; p=0·0004) were significantly but modestly lower with SGLT2 inhibitors versus DPP-4 inhibitors. INTERPRETATION: In this large, international, observational study, initiation of SGLT2 inhibitors versus DPP-4 inhibitors was associated with lower risks of heart failure, death, myocardial infarction, and stroke, providing further support for the cardiovascular benefits associated with use of SGLT2 inhibitors in patients with type 2 diabetes. FUNDING: AstraZeneca.


Assuntos
Biomarcadores/análise , Doenças Cardiovasculares/mortalidade , Diabetes Mellitus Tipo 2/mortalidade , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Glicemia/análise , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/diagnóstico , Estudos de Coortes , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/patologia , Feminino , Seguimentos , Humanos , Agências Internacionais , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Taxa de Sobrevida
20.
Gene ; 754: 144846, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32512158

RESUMO

OBJECTIVES: Obesity is a major risk factor in aetiology of type 2 diabetes mellitus (T2DM). Leptin (LEP) is an anti-obesity hormone which regulates food intake, energy expenditure and glucose metabolism. The genetic variants in leptin and leptin receptor gene (LEPR) may play major role in the pathogenesis of T2DM and obesity. The current study aimed to investigate the association of polymorphisms in LEP (rs7799039, -2548G/A and rs2167270, 19G/A) and LEPR (rs1137101, 668A/G) gene with type 2 diabetes in North Indian Punjabi population. METHODS: A total of 817 subjects were included for the present case-control study, consisting of 417 T2DM patients and 400 healthy controls. The anthropometric, physiometric and biochemical measurements were taken from all the subjects. The genotyping of LEP and LEPR gene variants were carried out by polymerase chain reaction based restriction fragment length polymorphism method (PCR-RFLP), followed by genotyping of 10% of the samples for each polymorphism by Sanger sequencing method for quality control measurement. RESULTS: The risk genotype frequencies were found to be significantly higher in T2DM cases than control subjects (rs7799039, p = 0.001; rs2167270, p = 0.019 and rs1137101, p = 0.003). Under recessive genetic model LEPrs7799039 and LEPRrs1137101 polymorphism conferred 3.4 and 2.1 fold risk towards the development of T2DM after adjustment of various covariates (OR = 3.44, 95%CI: 1.768-6.681, p = 0.001 and OR: 2.12, 95%CI: 1.256-3.569, p = 0.005, respectively). In the stratified analysis of LEP variant rs7799039 by age, gender, BMI and alcohol use, a significantly increased risk of T2DM was found in female, BMI ≥ 23 and never drinking subgroups. However, in the LEPR variant rs1137101, significantly increased risk of T2DM was observed in age <50, male, BMI ≥ 23 and never drinking subgroup. The A-G haplotype combination of rs7799039A and rs2167270G conferred significant 2 fold risk towards T2DM (OR = 2.35, 95%CI: 1.34-4.12, p = 0.002). In control group, the genetic variants rs7799039 and rs1137101 were significantly associated with levels of random blood sugar and low density lipoprotein cholesterol levels. CONCLUSION: The present study revealed the association of LEP rs7799039 and LEPR rs1137101 with type 2 diabetes mellitus, which suggest its predominant role in the estimation of type 2 diabetes mellitus in North Indian Punjabi population.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Diabetes Mellitus Tipo 2/epidemiologia , Predisposição Genética para Doença , Leptina/genética , Obesidade/fisiopatologia , Polimorfismo de Nucleotídeo Único , Receptores para Leptina/genética , Adulto , Idoso , Biomarcadores/análise , Glicemia/análise , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Feminino , Seguimentos , Genótipo , Humanos , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Prognóstico
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