RESUMO
OBJECTIVE: Gestational diabetes mellitus (GDM) is a transient form of diabetes characterized by impaired insulin secretion and action during pregnancy. Population-based differences in prevalence exist which could be explained by phenotypic and genetic differences. The aim of this study was to examine these differences in pregnant women from Punjab, India and Scandinavia. METHODS: Eighty-five GDM/T2D loci in European and/or Indian populations from previous studies were assessed for association with GDM based on Swedish GDM criteria in 4018 Punjabi Indian and 507 Swedish pregnant women. Selected loci were replicated in Scandinavian cohorts, Radiel (N = 398, Finnish) and STORK/STORK-G (N = 780, Norwegian). RESULTS: Punjabi Indian women had higher GDM prevalence, lower insulin secretion and better insulin sensitivity than Swedish women. There were significant frequency differences of GDM/T2D risk alleles between both populations. rs7178572 at HMG20A, previously associated with GDM in South Indian and European women, was replicated in North Indian women. The T2D risk SNP rs11605924 in the CRY2 gene was associated with increased GDM risk in Scandinavian but decreased GDM risk in Punjabi Indian women. No other overlap was seen between GDM loci in both populations. CONCLUSIONS: Gestational diabetes mellitus is more common in Indian than Swedish women, which partially can be attributed to differences in insulin secretion and action. There was marked heterogeneity in the GDM phenotypes between the populations which could only partially be explained by genetic differences.
Assuntos
Criptocromos/genética , Diabetes Gestacional/epidemiologia , Diabetes Gestacional/genética , Proteínas de Grupo de Alta Mobilidade/genética , Adulto , Alelos , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Índia/epidemiologia , Resistência à Insulina , Fenótipo , Polimorfismo de Nucleotídeo Único , Gravidez , Prevalência , Países Escandinavos e Nórdicos/epidemiologiaRESUMO
AIMS: To test whether the TCF7L2 gene was associated with gestational diabetes, whether the association between TCF7L2 and gestational diabetes was independent of HLA-DQB1*0602 and islet cell autoantibodies, as well as maternal age, number of pregnancies, family history of diabetes and the HLA-DQB1 genotypes, and to test whether the distribution of HLA-DQB1 alleles was affected by country of birth. METHODS: We genotyped the rs7903146, rs12255372 and rs7901695 single nucleotide polymorphisms of the TCF7L2 gene in 826 mothers with gestational diabetes and in 1185 healthy control subjects in the Diabetes Prediction in Skåne Study. The mothers were also typed for HLA-DQB1 genotypes and tested for islet cell autoantibodies against GAD65, insulinoma-associated antigen-2 and insulin. RESULTS: The heterozygous genotypes CT, GT and TC of the rs7903146 (T is risk for Type 2 diabetes), rs12255372 (T is risk for Type 2 diabetes) and rs7901695 (C is risk for Type 2 diabetes), respectively, as well as the homozygous genotypes TT, TT and CC of the rs7903146, rs12255372 and rs7901695, respectively, were strongly associated with gestational diabetes (P < 0.0001). These associations remained statistically significant after adjusting for maternal age, number of pregnancies, family history of diabetes and HLA-DQ genotypes and were independent of the presence of islet cell autoantibodies. No interaction was observed between TCF7L2 and HLA-DQB1*0602, which was shown to be negatively associated with gestational diabetes in mothers born in Sweden (P = 0.010). CONCLUSIONS: The TCF7L2 was associated with susceptibility for gestational diabetes independently of the presence of HLA-DQB1*0602 and islet cell autoantibodies and other factors such as maternal age, number of pregnancies, family history of diabetes and other HLA-DQ genotypes. The HLA-DQB1*0602 was negatively associated with gestational diabetes in mothers born in Sweden.
Assuntos
Autoanticorpos/genética , Diabetes Gestacional/genética , Predisposição Genética para Doença/genética , Antígenos HLA-DQ/genética , Ilhotas Pancreáticas , Glicoproteínas de Membrana/genética , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Adulto , Diabetes Gestacional/imunologia , Feminino , Genótipo , Antígenos HLA-DQ/imunologia , Cadeias beta de HLA-DQ , Humanos , Idade Materna , Glicoproteínas de Membrana/imunologia , Paridade , Polimorfismo de Nucleotídeo Único/genética , Gravidez , SuéciaRESUMO
AIMS/HYPOTHESIS: We studied the incidence of postpartum diabetes after gestational diabetes mellitus and investigated biochemical and clinical predictors of postpartum diabetes. METHODS: We monitored 174 women with gestational diabetes by performing oral glucose tolerance tests during pregnancy as well as 1, 2 and 5 years postpartum. Women who developed impaired fasting glucose, impaired glucose tolerance or diabetes were compared with women who remained normoglycaemic at 5 years. Insulinogenic index, disposition index and HOMA-beta cell index were used to assess beta cell function; insulin resistance was estimated by HOMA index of insulin resistance. RESULTS: At 5 years postpartum, 30% of the women had developed diabetes and 51% some form of abnormal glucose tolerance. Women who developed diabetes had higher fasting glucose and HbA(1c) during pregnancy than those who remained normoglycaemic. They also had lower HOMA-beta cell index, insulinogenic index and disposition index than the normoglycaemic women. HbA(1c) and fasting glucose during pregnancy as well as the number of previous pregnancies and family history of diabetes were independent predictors of postpartum diabetes. HbA(1c) > or =4.7% (Swedish Mono S) or > or =5.7% (National Glycohemoglobin Standardization Program) and fasting blood glucose > or =5.2 mmol/l were associated with a four- to sixfold increased risk. CONCLUSIONS/INTERPRETATION: Among women with gestational diabetes mellitus, those at risk of future diabetes can be identified by HbA(1c) and fasting glucose values in the upper normal range during pregnancy. A family history of diabetes and previous pregnancies further increase this risk.
Assuntos
Diabetes Mellitus/diagnóstico , Diabetes Gestacional/fisiopatologia , Adulto , Glicemia/metabolismo , Índice de Massa Corporal , Diabetes Mellitus/epidemiologia , Diabetes Gestacional/diagnóstico , Feminino , Teste de Tolerância a Glucose , Hemoglobinas Glicadas/metabolismo , Humanos , Gravidez , Complicações na Gravidez , Risco , Suécia , Fatores de Tempo , Resultado do TratamentoRESUMO
AIMS/HYPOTHESIS: We tested whether gestational diabetes mellitus (GDM) is associated with HLA-DQ genotypes. METHODS: A total of 764 mothers with non-autoimmune (GAD65, insulinoma-associated protein 2 [IA-2] and insulin autoantibody-negative) GDM were ascertained between September 2000 and August 2004 in the population-based Diabetes Prediction in Skåne (DiPiS) study. HLA-DQB1 genotypes were determined in these mothers and in 1191 randomly selected non-diabetic control mothers also negative for islet autoantibodies. The data were analysed in relation to maternal age, country of birth, number of pregnancies/siblings and pregnancy weight gain. RESULTS: The frequency of type 1 diabetes high-risk HLA-DQ alleles (DQB1*0201, DQB1*0302) did not differ between GDM mothers and controls. In contrast, the low-risk DQB1*0602 allele was less prevalent (OR 0.64, 95% CI = 0.51-0.80, p = 0.0006) in GDM than in control mothers. The difference in DQB1*0602 frequency between GDM mothers and controls remained after multiple logistic regression analysis correcting for maternal age, country of birth, number of pregnancies/siblings and weight gain during pregnancy (OR 0.67, 95% CI 0.51-0.88, p = 0.009). CONCLUSIONS/INTERPRETATION: The negative association between mothers who have non-autoimmune GDM and HLA-DQ*0602 suggest that this allele may protect not only from type 1 diabetes but also from GDM.
Assuntos
Diabetes Mellitus Tipo 1/genética , Diabetes Gestacional/genética , Antígenos HLA-DQ/genética , Glicoproteínas de Membrana/genética , Alelos , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Gestacional/epidemiologia , Feminino , Predisposição Genética para Doença/epidemiologia , Genótipo , Cadeias beta de HLA-DQ , Humanos , Gravidez , Fatores de RiscoRESUMO
BACKGROUND: There is compelling evidence showing that achieving good glycaemic control reduces the risk of microvascular complications in people with type 1 and type 2 diabetes. Likewise, there is clear evidence to show that achieving good glycaemic control reduces the risk of macrovascular complications in type 1 diabetes. The UKPDS 10-year follow up suggests that good glycaemic control also reduces the risk of macrovascular complications in type 2 diabetes. Despite this, recent results from ACCORD, ADVANCE and VADT present conflicting results and data from the ACCORD trial appear to suggest that very low HbA(1c) targets (<6.0%) may, in fact, be dangerous in certain patient populations. AIM: To review recent results from ACCORD, ADVANCE and VADT and provide clear guidance on the clinical significance of the new data and their implications for the practising physician treating patients with type 2 diabetes. METHODS: A Pubmed search was used to identify major randomised clinical trials examining the association between glycaemic control and diabetes-associated complications. The data was reviewed and discussed by the GTF through a consensus meeting. The recommendations for clinical practice in this statement are the conclusions of these analyses and discussions. RESULTS: Evidence from ACCORD, ADVANCE, VADT and UKPDS suggests that certain patient populations, such as those with moderate diabetes duration and/or no pre-existing CVD, may benefit from intensive blood glucose control. These trials highlight the benefit of a multifactorial treatment approach to diabetes. However, ACCORD results indicate that aggressive HbA(1c) targets (<6.0%) may not be beneficial in patients with existing CVD and a longer duration of diabetes. CONCLUSIONS: Glycaemic control remains a very important component of treatment for type 2 diabetes and contrasting results from the ACCORD, ADVANCE and VADT should not discourage physicians from controlling blood glucose levels.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucose/uso terapêutico , Hipoglicemiantes/uso terapêutico , Glicemia/metabolismo , Angiopatias Diabéticas/prevenção & controle , Humanos , Hiperglicemia/prevenção & controle , Hipoglicemia/prevenção & controleRESUMO
AIM: To compare effects of early insulin vs. glibenclamide treatment on beta-cell function, metabolic control and quality of life (QL) in recently diagnosed patients with type 2 diabetes. METHODS: Forty-nine patients with type 2 diabetes diagnosed 0-2 years before inclusion were randomized to two daily injections of premixed 30% soluble and 70% NPH insulin or glibenclamide at six diabetic clinics in Sweden. C-peptide-glucagon tests were performed yearly after 3 days of withdrawal of treatment. RESULTS: Thirty-four patients completed 4 years of study. Daily dose of insulin was increased from 20.4 +/- 1.8 U at year 1 to 26.1 +/- 2.9 U at year 4 (p = 0.005). Glibenclamide dosage increased from 2.7 +/- 0.4 mg at year 1 to 4.5 +/- 0.8 mg at year 4 (p = 0.02). Weight increased more in insulin than in glibenclamide treated (+4.4 +/- 0.8 vs. +0.3 +/- 1.0 kg, p < 0.005). Following short-term withdrawal of treatment, the C-peptide responses to glucagon were significantly higher in the insulin vs. glibenclamide group at years 1 (p < 0.01) and 2 (p < 0.02). HbA1c improved identical during the first year but thereafter deteriorated in the glibenclamide group (p < 0.005 for difference at year 4). Ratios of proinsulin to insulin were higher during treatment in glibenclamide- vs. insulin-treated patients after year 2. QL after 4 years as measured by the MOS 36-item Short-Form Health Survey (SF-36) form was not significantly altered. CONCLUSIONS: In a 4-year perspective, beta-cell function deteriorated in both groups. However, deterioration occurred faster in the glibenclamide group, indicating that alleviating demands on secretion by insulin treatment is beneficial.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Glibureto/uso terapêutico , Hipoglicemiantes/uso terapêutico , Insulina de Ação Prolongada/uso terapêutico , Adulto , Idoso , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Peptídeo C/sangue , Diabetes Mellitus Tipo 2/sangue , Esquema de Medicação , Jejum/sangue , Feminino , Seguimentos , Glucagon , Glibureto/administração & dosagem , Hemoglobinas Glicadas/metabolismo , Indicadores Básicos de Saúde , Humanos , Hipoglicemiantes/administração & dosagem , Insulina/sangue , Insulina de Ação Prolongada/administração & dosagem , Células Secretoras de Insulina , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Proinsulina/sangue , Qualidade de VidaRESUMO
OBJECTIVE: To determine the impact of improved glycemic control on the development and progression of retinopathy after the institution of insulin therapy in patients with type 2 diabetes and to assess the relation to IGF-1 and hemostatic variables. RESEARCH DESIGN AND METHODS: In a prospective observational study, 45 type 2 diabetic patients were examined at baseline and 1, 3, 6, 12, and 24 months after change to insulin therapy. Retinopathy was graded on fundus photographs using the Wisconsin scale; HbA1c, IGF-1, and hemostatic variables were measured. RESULTS: During the observation period of 2 years, 23 patients progressed in the retinopathy scale; 8 progressed > or = 3 levels. After 2 years of insulin treatment, HbA1c and IGF-1 were significantly lower than at baseline, whereas the hemostatic variables had not changed significantly. Progression of retinopathy > or = 3 levels was related to the degree of HbA1c reduction, the duration of diabetes, a higher prothrombin fragment 1 + 2 levels (F1 + 2), but not to other hemostatic variables or IGF-1. The relative risk for progression > or = 3 levels was 2.6 when HbA1c had been reduced > or = 3 percent units (95% CI 1.1-6.1). CONCLUSIONS: The magnitude of improvement of HbA1c by the institution of insulin treatment over a 2-year period may be associated with progression of retinopathy in patients with type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 2/fisiopatologia , Retinopatia Diabética/fisiopatologia , Hemostasia , Fator de Crescimento Insulin-Like I/análise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Retinopatia Diabética/tratamento farmacológico , Progressão da Doença , Feminino , Angiofluoresceinografia , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
An elevated level of serum aspartate aminotransferase (ASAT) activity in a subjectively healthy woman was shown to be due to circulating ASAT:IgG complexes. The complexes were demonstrated by taking advantage of the specific interaction between protein A and IgG. Thus, greater than 90% of the patient's ASAT activity in serum could be bound to protein A-Sepharose demonstrating that nearly all the patient's serum ASAT was complexed to IgG. The ASAT-binding capacity of patient serum was calculated as approximately 850 micrograms ASAT/l which corresponds to about 0.01% of patient's IgG.
Assuntos
Aspartato Aminotransferases/sangue , Imunoglobulina G/metabolismo , Adulto , Feminino , Humanos , Ligação Proteica , Sefarose , Proteína Estafilocócica ARESUMO
Long-term effects on insulin sensitivity and leucocyte sodium transport were studied in 42 glucose-intolerant hypertensives on beta-blockers, randomly assigned to continuous beta-blockade (beta group) or a switch to captopril treatment (mean daily dose 69.1 mg) (ACE group). In the ACE group, despite a tendency towards improvement, glucose uptake during the euglycaemic insulin clamp procedure did not change significantly from the baseline value of 4.0(0.5-12.9) mg/kg/min, values at 6 and 12 months being 4.8(1.3-14.7) and 4.4(1.5-9.8) mg/kg/min, respectively: the corresponding values for the beta group were 4.2(1.1-15.3), 3.6(1.2-8.9) and 4.0(1.5-12.0) mg/kg/min. The 22Na efflux rate constant, both baseline and follow-up values, was similar in both groups, and unrelated to insulin sensitivity. Owing to the surprisingly great variation in peripheral glucose uptake, the subgroup with values below the median for the population as a whole (4.9 mg/kg/min) was evaluated separately: those switched to captopril treatment manifested a 60% improvement in glucose disposal at 6 months and persisting at 12 months, the respective values being 2.1(0.5-4.8) (baseline), 3.5(1.3-6.3) and 3.4(1.5-6.1) mg/kg/min, (P = 0.012). The body mass index (BMI) was not significantly affected. Values for BMI, peripheral insulin and triglycerides were higher in the subgroup with glucose disposal below the median than in the subgroup with values above the median. Correlation between BMI and glucose uptake was highly significant (r = -0.75, P = 0.0001). The present findings suggest that captopril may be a better alternative than beta-blockers for treating the highly insulin-resistant, glucose-intolerant patients, predominantly to be found among the overweight.
Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Captopril/uso terapêutico , Glucose/farmacologia , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Resistência à Insulina/fisiologia , Sódio/farmacocinética , Adulto , Idoso , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/fisiologia , Índice de Massa Corporal , Relação Dose-Resposta a Droga , Feminino , Teste de Tolerância a Glucose , Humanos , Hipertensão/sangue , Insulina/sangue , Insulina/farmacologia , Masculino , Pessoa de Meia-Idade , ATPase Trocadora de Sódio-Potássio/fisiologia , Estatística como Assunto , Fatores de Tempo , Triglicerídeos/sangueRESUMO
Blood pressure (BP) and serum urate concentrations were measured in 22 normoglycaemic, non-obese, middle-aged men with a strong family history of Type 2 diabetes and in 51 controls, taking confounding variables such as sex, age, body weight and life style habits into account. The subjects with a positive family history of diabetes, who were also characterized by impaired physical fitness and insulin secretion, had significantly elevated BP in comparison with the controls, most pronounced for diastolic BP. Serum urate concentration tended to be somewhat higher in the positive family history group than in controls, although not significantly. Blood pressure was positively correlated to plasma insulin concentrations, while negatively correlated to physical fitness, assessed by submaximal exercise tests. The data support the hypotheses that some of the metabolic disturbances and atherosclerosis risk factors associated with Type 2 diabetes mellitus may precede the disturbance of glucose tolerance and that advice on life style habits may be of benefit to certain individuals at risk.
Assuntos
Diabetes Mellitus Tipo 2/genética , Hipertensão/genética , Humanos , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Aptidão Física , Fumar , Ácido Úrico/sangueRESUMO
The impact of type 2 diabetes heredity on nutrient intake was studied, by means of dietary histories, in 51 normoglycaemic, non-obese men, aged 54-59 years; 29 with familial aggregation of type 2 diabetes, and 22 with no such family history. The average daily intake of energy, macronutrients and minerals was almost identical in the two groups. Mean energy intake was approximately 2400 kcal/d, about 15 per cent of the energy deriving from protein, 35 per cent from fat, 45 per cent from carbohydrate and 5 per cent from alcohol. The average daily intake or dietary fibre was approximately 17 g, or 7 g/1000 kcal. Mean daily sodium and potassium intake, estimated from food sources, was about 3000 and 4000 mg, respectively. The findings provide no support for the existence of any relationship between type 2 diabetes heredity and dietary habits or nutrient intake.
Assuntos
Diabetes Mellitus Tipo 2/genética , Dieta para Diabéticos , Comportamento Alimentar/fisiologia , Diabetes Mellitus Tipo 2/metabolismo , Fibras na Dieta/metabolismo , Ingestão de Energia , Metabolismo Energético , Teste de Tolerância a Glucose , Humanos , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Obesidade/metabolismo , Sódio na Dieta/metabolismoRESUMO
AIMS: To examine whether genetic variants that predispose individuals to type 2 diabetes (T2D) could predict the development of diabetes after gestational diabetes mellitus (GDM). METHODS: 13 SNPs (FTO rs8050136, CDKAL1 rs7754840 and rs7756992, CDKN2A/2B rs10811661, HHEX rs1111875, IGF2BP2 rs1470579 and rs4402960, SLC30A8 rs13266634, TCF7L2 rs7903146, PPARG rs1801282, GCK rs1799884, HNF1A rs1169288, and KCNJ11 rs5219) were genotyped in 793 women with GDM after a median follow-up of 57 months. RESULTS: After adjustment for age and ethnicity, the TCF7L2 rs7903146 and the FTO rs8050136 variants significantly predicted postpartum diabetes; hazard ratio (95% confidence interval 1.29 (1.01-1.66) and 1.36 (1.06-1.74), respectively (additive model) versus 1.45 (1.01-2.08) and 1.56 (1.06-2.29) (dominant model)). Adjusting for BMI attenuated the effect of the FTO variant, suggesting that the effect was mediated through its effect on BMI. Combining all risk alleles to a weighted risk score was significantly associated with the risk of postpartum diabetes (hazard ratio 1.11, 95% confidence interval 1.05-1.18, p=0.00016 after adjustment for age and ethnicity). CONCLUSIONS: The TCF7L2 rs7903146 and FTO rs8050136 polymorphisms, and particularly a weighted risk score of T2D risk alleles, predict diabetes after GDM. Further studies in other populations are needed to confirm our results.
Assuntos
Diabetes Mellitus Tipo 2/genética , Diabetes Gestacional/genética , Testes Genéticos , Transtornos Puerperais/genética , Adulto , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/etiologia , Diabetes Gestacional/diagnóstico , Diabetes Gestacional/epidemiologia , Feminino , Predisposição Genética para Doença , Genótipo , Teste de Tolerância a Glucose , Humanos , Polimorfismo de Nucleotídeo Único/fisiologia , Período Pós-Parto , Gravidez , Proteínas/genética , Transtornos Puerperais/diagnóstico , Transtornos Puerperais/epidemiologia , Transtornos Puerperais/etiologia , Fatores de Risco , Proteína 2 Semelhante ao Fator 7 de Transcrição/genéticaAssuntos
Albuminúria/fisiopatologia , Doenças do Sistema Nervoso Autônomo/epidemiologia , Neuropatias Diabéticas/fisiopatologia , Hiperinsulinismo/fisiopatologia , Obesidade/fisiopatologia , Inibidor 1 de Ativador de Plasminogênio/sangue , Adulto , Albuminúria/etiologia , Doenças do Sistema Nervoso Autônomo/etiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Neuropatias Diabéticas/epidemiologia , Neuropatias Diabéticas/etiologia , Humanos , Hiperinsulinismo/etiologia , Pessoa de Meia-Idade , Prevalência , Suécia/epidemiologiaRESUMO
BACKGROUND: Good glycaemic control is crucial in reducing the risk of diabetes-related complications. Despite the availability of evidence-based treatment guidelines, glycaemic control appears to remain suboptimal in most countries. OBJECTIVES: In this commentary we outline the extent to which diabetes guideline targets on HbA(1c) are being met in clinical practice and--where targets are being missed--to identify potential reasons for this shortfall. Furthermore, we discuss possible actions that may improve glycaemic control. METHODS: A literature search of MEDLINE using 20 core terms was conducted to help assess the state of glycaemic control in patients with type 2 diabetes worldwide. RESULTS: Despite clinical guidelines, evidence suggests that glycaemic control is suboptimal in most parts of the world, with average HbA(1c) values varying from 7.0% to 12.6% and thus above virtually all HbA(1c) recommendations. The potential reasons for this shortfall are numerous. However, lack of diabetes education and awareness of HbA(1c) appear to be particularly important. A number of education initiatives from around the world have been shown to improve HbA(1c) levels significantly and thus improve standards of care. CONCLUSIONS: Poor glycaemic control in patients with type 2 diabetes appears to be a worldwide problem. As the global rise in diabetes (and its complications) seems destined to affect many less affluent countries, it is essential that appropriate steps are taken to address the barriers to good glycaemic control and ultimately improve outcomes for all people with type 2 diabetes.
Assuntos
Glicemia/análise , Diabetes Mellitus Tipo 2/sangue , Hemoglobinas Glicadas/análise , Guias como Assunto , Humanos , Cooperação do PacienteRESUMO
AIMS/HYPOTHESIS: Genetic and epidemiological studies suggest an association between gestational diabetes mellitus and type 2 diabetes. Both are polygenic multifactorial disorders characterised by beta cell dysfunction and insulin resistance. Our aim was to investigate whether common genetic variants that have previously been associated with type 2 diabetes or related phenotypes would also confer risk for gestational diabetes mellitus. MATERIALS AND METHODS: In 1,881 unrelated pregnant Scandinavian women (649 women with gestational diabetes mellitus, 1,232 non-diabetic control subjects) we genotyped the transcription factor 7-like 2 (TCF7L2 rs7903146), adiponectin (ADIPOQ +276G > T), peroxisome-proliferator activated receptor, gamma 2 (PPARG Pro12Ala), PPARG-coactivator, 1 alpha (PPARGC1A Gly482Ser), forkhead box C2 (FOXC2 -512C > T) and beta3-adrenergic receptor (ADRB3 Trp64Arg) polymorphisms using TaqMan allelic discrimination assay or RFLP. RESULTS: The CC, CT and TT genotype frequencies of the TCF7L2 rs7903146 variant differed significantly between women with gestational diabetes mellitus and control women (46.3, 43.6 and 10.1% vs 58.5, 35.3 and 6.2%, p = 3.7 x 10(-6), corrected p value [Pc] for multiple testing Pc = 2.2 x 10(-5)). The T-allele was associated with an increased risk of gestational diabetes mellitus (odds ratio 1.49 [95% CI 1.28-1.75], p = 4.9 x 10(-7) [Pc = 2.8 x 10(-6)]). Compared with wild-type CC-genotype carriers, heterozygous (CT-genotype) and homozygous (TT-genotype) carriers had a 1.6-fold (95% CI 1.26-1.93, p = 3.7 x 10(-5) [Pc = 0.0002]) and a 2.1-fold (95% CI 1.41-2.99, p = 0.0001 [Pc = 0.0008]) increased risk of gestational diabetes mellitus, respectively. The other polymorphisms studied were not significantly associated with gestational diabetes mellitus (ADIPOQ +276G > T: 1.17 [1.01-1.36], p = 0.039 [Pc = 0.23]; PPARG Pro12Ala: 1.06 [0.87-1.29], p = 0.53; PPARGC1A Gly482Ser: 0.96 [0.83-1.10], p = 0.54; FOXC2 -512C > T: 1.01 [0.87-1.16], p = 0.94; and ADRB3 Trp64Arg: 1.22 [0.95-1.56], p = 0.12). CONCLUSIONS/INTERPRETATION: The TCF7L2 rs7903146 variant is associated with an increased risk of gestational diabetes mellitus in Scandinavian women.
Assuntos
Diabetes Gestacional/genética , Variação Genética , Polimorfismo Genético , Fatores de Transcrição TCF/genética , Adiponectina/genética , Substituição de Aminoácidos , Diabetes Gestacional/epidemiologia , Feminino , Frequência do Gene , Genótipo , Humanos , PPAR gama/genética , Polimorfismo de Fragmento de Restrição , Polimorfismo de Nucleotídeo Único , Gravidez , Valores de Referência , Medição de Risco , Países Escandinavos e Nórdicos/epidemiologia , Proteína 2 Semelhante ao Fator 7 de TranscriçãoRESUMO
AIMS/HYPOTHESIS: Impaired beta cell function is the hallmark of gestational diabetes mellitus (GDM) and MODY. In addition, women with MODY gene mutations often present with GDM, but it is not known whether common variants in MODY genes contribute to GDM. SUBJECTS AND METHODS: We genotyped five common variants in the glucokinase (GCK, commonly known as MODY2), hepatocyte nuclear factor 1-alpha (HNF1A, commonly known as MODY3) and 4-alpha (HNF4A commonly known as MODY1) genes in 1,880 Scandinavian women (648 women with GDM and 1,232 pregnant non-diabetic control women). RESULTS: The A allele of the GCK -30G-->A polymorphism was more common in GDM women than in control subjects (odds ratio [OR] 1.28 [95% CI 1.06-1.53], p=0.008, corrected p value, p=0.035). Under a recessive model [AA vs GA+GG], the OR increased further to 2.12 (95% CI 1.21-3.72, p=0.009). The frequency of the L allele of the HNF1A I27L polymorphism was slightly higher in GDM than in controls (1.16 [95% CI 1.001-1.34], p=0.048, corrected p value, p=0.17). However, the OR increased under a dominant model (LL+IL vs II; 1.31 [95% CI 1.08-1.60], p=0.007). The rs2144908, rs2425637 and rs1885088 variants, which are located downstream of the primary beta cell promoter (P2) of HNF4A, were not associated with GDM. CONCLUSIONS/INTERPRETATION: The -30G-->A polymorphism of the beta-cell-specific promoter of GCK and the I27L polymorphism of HNF1A seem to increase the risk of GDM in Scandinavian women.
Assuntos
Diabetes Gestacional/genética , Predisposição Genética para Doença , Glucoquinase/genética , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/genética , Polimorfismo de Nucleotídeo Único , Adulto , Diabetes Mellitus Tipo 2/genética , Feminino , Frequência do Gene , Humanos , Desequilíbrio de Ligação , Gravidez , SuéciaRESUMO
AIMS/HYPOTHESIS: Gestational diabetes mellitus (GDM) and type 2 diabetes share a common pathophysiological background, including beta cell dysfunction and insulin resistance. In addition, women with GDM are at increased risk of developing type 2 diabetes later in life. Our aim was to investigate whether, like type 2 diabetes, GDM has a genetic predisposition by studying five common polymorphisms in four candidate genes that have previously been associated with type 2 diabetes. MATERIALS AND METHODS: We studied 1,777 unrelated Scandinavian women (588 with GDM and 1,189 pregnant non-diabetic controls) for polymorphisms in the genes encoding potassium inwardly rectifying channel subfamily J, member 11 (KCNJ11 E23K), insulin receptor substrate 1 (IRS1 G972R), uncoupling protein 2 (UCP2 -866G-->A) and calpain 10 (CAPN10 SNP43 and SNP44). RESULTS: The EE, EK and KK genotype frequencies of the KCNJ11 E23K polymorphism differed significantly between GDM and control women (31.5, 52.7 and 15.8% vs 37.3, 48.8 and 13.9%, respectively; p=0.050). In addition, the frequency of the K allele was increased in women with GDM (odds ratio [OR]=1.17, 95% CI 1.02-1.35; p=0.027), and this effect was greater under a dominant model (KK/EK vs EE) (OR=1.3, 95% CI 1.05-1.60; p=0.016). Analysis of the IRS1 G972R polymorphism showed that RR homozygosity was found exclusively in women with GDM (91.0, 8.3 and 0.7% vs 90.7, 9.3 and 0.0% for GG, GR and RR genotypes, respectively; p=0.014). The genotype and allele frequencies of the other polymorphisms studied were not statistically different between the GDM and control women. CONCLUSIONS/INTERPRETATION: The E23K polymorphism of KCNJ11 seems to predispose to GDM in Scandinavian women.
Assuntos
Diabetes Mellitus Tipo 2/genética , Diabetes Gestacional/genética , Predisposição Genética para Doença , Polimorfismo Genético , Canais de Potássio Corretores do Fluxo de Internalização/genética , Adulto , Alelos , Calpaína/genética , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Diabetes Gestacional/epidemiologia , Diabetes Gestacional/fisiopatologia , Feminino , Frequência do Gene , Genótipo , Humanos , Proteínas Substratos do Receptor de Insulina , Resistência à Insulina/genética , Resistência à Insulina/fisiologia , Células Secretoras de Insulina/fisiologia , Canais Iônicos , Proteínas de Membrana Transportadoras/genética , Proteínas Mitocondriais/genética , Razão de Chances , Fosfoproteínas/genética , Canais de Potássio Corretores do Fluxo de Internalização/fisiologia , Gravidez , Risco , Suécia/epidemiologia , Proteína Desacopladora 2RESUMO
The number of specific (3H)ouabain binding sites and dissociation constants (Kd) were determined by Scatchard analysis of values for leucocytes from patients with B-cell chronic lymphocytic leukaemia (CLL), chronic myeloid leukaemia (CML), acute blastic leukaemia (AL) and healthy subjects. CLL lymphocytes and normal B-cells bound significantly less (3H)ouabain than did normal T-lymphocytes. CML granulocytes showed the same binding characteristics as normal granulocytes, while blast cells from AL patients bound significantly more (3H)ouabain than did normal granulocytes or B-cells. The increased binding capacity in blast cells might, at least partly, reflect their larger cell size. A decrease in Kd values was only found in CLL lymphocytes, as compared with normal B-cells. Intralymphocytic sodium content in CLL lymphocytes was significantly increased, as compared with that in T-cell-enriched normal lymphocytes. (3H)ouabain binding did not show any relationship to different prognostic variables in CLL. The present data mainly argue against altered Na+/K+-ATPase enzyme activity as an indicator of malignancy.
Assuntos
Leucemia/metabolismo , Ouabaína/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Doença Aguda , Linfócitos B/metabolismo , Feminino , Granulócitos/metabolismo , Humanos , Leucemia Linfoide/metabolismo , Leucemia Mieloide/metabolismo , Masculino , Prognóstico , Sódio/metabolismo , Linfócitos T/metabolismoRESUMO
Randomized subgroups from a health screening population were reinvestigated with oral glucose tolerance tests (OGTT) with simultaneous insulin and C-peptide measurements and submaximal exercise tests. Twenty-two normoglycaemic non-obese males with a strong family history of Type 2 diabetes were compared to 51 controls. While glucose levels tended to be somewhat higher, there was a tendency towards lower insulin and C-peptide levels in the hereditary group compared to controls, especially during the early phase of the OGTT, as reflected in a significant difference in the 40 min insulin level and the 0-40 min increment. Estimated maximal oxygen uptake was significantly lower in the hereditary group as were the sum ratios of insulin and C-peptide to glucose in the early phase of the OGTT. Insulin to C-peptide ratios did not differ. The data support both a decreased physical fitness, indicating peripheral insulin insensitivity, and a decreased insulin secretion among normoglycaemic individuals with familial aggregation of Type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 2/genética , Insulina/metabolismo , Aptidão Física , Glicemia/análise , Peptídeo C/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Teste de Tolerância a Glucose , Humanos , Insulina/sangue , Secreção de Insulina , Cinética , Masculino , Valores de ReferênciaRESUMO
The in-vitro and in-vivo effects of cigarette smoke were studied in human peripheral blood lymphocytes by applying a method for the capping of beta 2-microglobulin- or phytohaemagglutinin (PHA)-stimulated lymphocyte transformation (measured as (3H)thymidine incorporation) involving the transglutaminase pseudosubstrate monodansylthiacadaverine (MDTC), whose presence resulted in significantly reduced capping and (3H)thymidine incorporation in a concentration-dependent manner. The addition of dimethyl sulphoxide-soluble particles from cigarette smoke to lymphocytes in vitro significantly reduced the capping ability and the PHA-induced (3H)thymidine incorporation. Whereas no significant change in MDTC-dependent capping inhibition was seen in lymphocytes from smokers after 10 d abstinence from smoking. there was a marked decrease in (3H)thymidine incorporation in lymphocytes from smokers after smoking three cigarettes following 10 h abstinence. The tentative conclusion is that exposure to cigarette smoke, or smoke extract, impairs MDTC-dependent capping inhibition and PHA-stimulated lymphocyte transformation by transglutaminase inhibition.