RESUMO
AIMS/HYPOTHESIS: Voltage-gated calcium channels of the L-type have been shown to be essential for rodent pancreatic beta cell function, but data about their presence and regulation in humans are incomplete. We therefore sought to elucidate which L-type channel isoform is functionally important and its association with inherited diabetes-related phenotypes. METHODS: Beta cells of human islets from cadaver donors were enriched using FACS to study the expression of the genes encoding voltage-gated calcium channel (Cav)1.2 and Cav1.3 by absolute quantitative PCR in whole human and rat islets, as well as in clonal cells. Single-cell exocytosis was monitored as increases in cell capacitance after treatment with small interfering (si)RNA against CACNA1D (which encodes Cav1.3). Three single nucleotide polymorphisms (SNPs) were genotyped in 8,987 non-diabetic and 2,830 type 2 diabetic individuals from Finland and Sweden and analysed for associations with type 2 diabetes and insulin phenotypes. RESULTS: In FACS-enriched human beta cells, CACNA1D mRNA expression exceeded that of CACNA1C (which encodes Cav1.2) by approximately 60-fold and was decreased in islets from type 2 diabetes patients. The latter coincided with diminished secretion of insulin in vitro. CACNA1D siRNA reduced glucose-stimulated insulin release in INS-1 832/13 cells and exocytosis in human beta cells. Phenotype/genotype associations of three SNPs in the CACNA1D gene revealed an association between the C allele of the SNP rs312480 and reduced mRNA expression, as well as decreased insulin secretion in vivo, whereas both rs312486/G and rs9841978/G were associated with type 2 diabetes. CONCLUSION/INTERPRETATION: We conclude that the L-type calcium channel Cav1.3 is important in human glucose-induced insulin secretion, and common variants in CACNA1D might contribute to type 2 diabetes.
Assuntos
Canais de Cálcio Tipo L/genética , Canais de Cálcio Tipo L/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Adulto , Células Cultivadas , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de OligonucleotídeosRESUMO
AIMS/HYPOTHESIS: Type 2 diabetes is a chronic metabolic disorder associated with devastating microvascular complications. Genome-wide association studies have identified more than 60 genetic variants associated with type 2 diabetes and/or glucose and insulin traits, but their role in the progression of diabetes is not established. The aim of this study was to explore whether these variants were also associated with the development of nephropathy in patients with type 2 diabetes. METHODS: We studied 28 genetic variants in 2,229 patients with type 2 diabetes from the local Malmö Scania Diabetes Registry (SDR) published during 2007-2010. Diabetic nephropathy (DN) was defined as micro- or macroalbuminuria and/or end-stage renal disease. Estimated glomerular filtration rate (eGFR) was assessed using the MDRD-4 formula. Replication genotyping of rs1531343 was performed in diabetic (Steno type 2 diabetes [n = 345], Genetics of Diabetes Audit and Research in Tayside Scotland [Go-DARTS] [n = 784]) and non-diabetic (Malmö Preventive Project [n = 2,523], Botnia study [n = 2,247]) cohorts. RESULTS: In the SDR, HMGA2 single-nucleotide polymorphism rs1531343 was associated with DN (OR 1.50, 95% CI 1.20, 1.87, p = 0.00035). In the combined analysis totalling 3,358 patients with type 2 diabetes (n = 1,233 cases, n = 2,125 controls), carriers of the C-allele had a 1.45-fold increased risk of developing nephropathy (95% CI 1.20, 1.75, p = 0.00010). Furthermore, the risk C-allele was associated with lower eGFR in patients with type 2 diabetes (n = 2,499, ß ± SEM, -3.7 ± 1.2 ml/min, p = 0.002) and also in non-diabetic individuals (n = 17,602, ß ± SEM, -0.008 ± 0.003 ml/min (log( e )), p = 0.006). CONCLUSIONS/INTERPRETATION: These data demonstrate that the HMGA2 variant seems to be associated with increased risk of developing nephropathy in patients with type 2 diabetes and lower eGFR in both diabetic and non-diabetic individuals and could thus be a common denominator in the pathogenesis of type 2 diabetes and kidney complications.
Assuntos
Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/genética , Proteína HMGA2/genética , Adulto , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
AIM/HYPOTHESIS: Individuals at risk of developing type 2 diabetes show a progressive decline in insulin secretion and increased insulin resistance over time. However, inability of the beta cells to compensate for the increased insulin resistance represents a key defect leading to overt type 2 diabetes. The aims of the present study were to replicate the association between genetic variants of the PCSK2 gene and insulin secretion, and to explore the effect on risk of type 2 diabetes. METHODS: Replication of PCSK2 variants against insulin secretion included 7,682 non-diabetic Scandinavian individuals. Insulin secretion was measured as the corrected insulin response or disposition index, i.e. insulin secretion adjusted for the degree of insulin resistance. Risk of type 2 diabetes was studied in 28,287 Scandinavian individuals. RESULTS: The C-allele of PCSK2 rs2208203 was associated with reduced insulin secretion measured as the corrected insulin response (n = 8,151; ß = -0.112, p = 1.3 × 10(-6)) as well as disposition index (n = 8,078, ß = -0.128, p = 1.6 × 10(-7)). The variant was also associated with lower fasting glucagon levels (ß = -0.084, p = 0.005) in non-diabetic individuals with a fasting plasma glucose of over 5.5 mmol/l. In human pancreatic islets, PCSK2 expression correlated negatively with HbA(1c) (n = 133, r = -0.196, p = 0.038), and showed a tendency to be lower in hyperglycaemic (HbA(1c) ≥6.0% or type 2 diabetes; n = 47, p = 0.13) than normoglycaemic (HbA(1c) >6.0%; n = 66) donors. The presence of the PCSK2 rs2208203 risk allele did not influence gene expression, nor did it show an apparent risk in terms of type 2 diabetes. CONCLUSIONS/INTERPRETATION: A variant of the PCSK2 gene was associated with reduced glucose-stimulated insulin secretion, but also with lower glucagon levels, which could potentially counteract the effects of decreased insulin secretion on the risk of type 2 diabetes.
Assuntos
Glicemia/metabolismo , Variação Genética , Resistência à Insulina/genética , Insulina/genética , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Pró-Proteína Convertase 2/genética , Idoso , Jejum , Feminino , Finlândia/epidemiologia , Seguimentos , Genótipo , Humanos , Secreção de Insulina , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Medição de Risco , Suécia/epidemiologiaRESUMO
AIMS/HYPOTHESIS: Impaired glucose tolerance and impaired insulin secretion have been reported in families with PAX6 mutations and it is suggested that they result from defective proinsulin processing due to lack of prohormone convertase 1/3, encoded by PCSK1. We investigated whether a common PAX6 variant would mimic these findings and explored in detail its effect on islet function in man. METHODS: A PAX6 candidate single nucleotide polymorphism (rs685428) was associated with fasting insulin levels in the Diabetes Genetics Initiative genome-wide association study. We explored its potential association with glucose tolerance and insulin processing and secretion in three Scandinavian cohorts (N = 8,897 individuals). In addition, insulin secretion and the expression of PAX6 and transcriptional target genes were studied in human pancreatic islets. RESULTS: rs685428 G allele carriers had lower islet mRNA expression of PAX6 (p = 0.01) and PCSK1 (p = 0.001) than AA homozygotes. The G allele was associated with increased fasting insulin (p (replication) = 0.02, p (all) = 0.0008) and HOMA-insulin resistance (p (replication) = 0.02, p (all) = 0.001) as well as a lower fasting proinsulin/insulin ratio (p (all) = 0.008) and lower fasting glucagon (p = 0.04) and gastric inhibitory peptide (GIP) (p = 0.05) concentrations. Arginine-stimulated (p = 0.02) insulin secretion was reduced in vivo, which was further reflected by a reduction of glucose- and potassium-stimulated insulin secretion (p = 0.002 and p = 0.04, respectively) in human islets in vitro. CONCLUSIONS/INTERPRETATION: A common variant in PAX6 is associated with reduced PAX6 and PCSK1 expression in human islets and reduced insulin response, as well as decreased glucagon and GIP concentrations and decreased insulin sensitivity. These findings emphasise the central role of PAX6 in the regulation of islet function and glucose metabolism in man.
Assuntos
Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/fisiopatologia , Proteínas do Olho/genética , Proteínas de Homeodomínio/genética , Resistência à Insulina , Ilhotas Pancreáticas/fisiopatologia , Fatores de Transcrição Box Pareados/genética , Polimorfismo de Nucleotídeo Único , Proteínas Repressoras/genética , Adolescente , Adulto , Idoso , Estudos de Coortes , Diabetes Mellitus Tipo 2/metabolismo , Regulação para Baixo , Proteínas do Olho/metabolismo , Feminino , Finlândia , Estudos de Associação Genética , Proteínas de Homeodomínio/metabolismo , Humanos , Ilhotas Pancreáticas/metabolismo , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Fator de Transcrição PAX6 , Fatores de Transcrição Box Pareados/metabolismo , Pró-Proteína Convertase 1/genética , Pró-Proteína Convertase 1/metabolismo , RNA Mensageiro/metabolismo , Proteínas Repressoras/metabolismo , Técnicas de Cultura de Tecidos , Adulto JovemRESUMO
AIMS/HYPOTHESIS: To study the heritability and familiality of type 2 diabetes and related quantitative traits in families from the Botnia Study in Finland. METHODS: Heritability estimates for type 2 diabetes adjusted for sex, age and BMI are provided for different age groups of type 2 diabetes and for 34 clinical and metabolic traits in 5,810 individuals from 942 families using a variance component model (SOLAR). In addition, family means of these traits and their distribution across families are calculated. RESULTS: The strongest heritability for type 2 diabetes was seen in patients with age at onset 35-60 years (h (2) = 0.69). However, including patients with onset up to 75 years dropped the h (2) estimates to 0.31. Among quantitative traits, the highest h (2) estimates in all individuals and in non-diabetic individuals were seen for lean body mass (h (2) = 0.53-0.65), HDL-cholesterol (0.52-0.61) and suppression of NEFA during OGTT (0.63-0.76) followed by measures of insulin secretion (insulinogenic index [IG(30)] = 0.41-0.50) and insulin action (insulin sensitivity index [ISI] = 0.37-0.40). In contrast, physical activity showed rather low heritability (0.16-0.18), whereas smoking showed strong heritability (0.57-0.59). Family means of these traits differed two- to fivefold between families belonging to the lowest and highest quartile of the trait (p < 0.00001). CONCLUSIONS/INTERPRETATION: To detect stronger genetic effects in type 2 diabetes, it seems reasonable to restrict inclusion of patients to those with age at onset 35-60 years. Sequencing of families with extreme quantitative traits could be an important next step in the dissection of the genetics of type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/fisiopatologia , Saúde da Família , Predisposição Genética para Doença , Adolescente , Adulto , Idade de Início , Idoso , Índice de Massa Corporal , HDL-Colesterol/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Ácidos Graxos não Esterificados/sangue , Feminino , Finlândia/epidemiologia , Teste de Tolerância a Glucose , Humanos , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Atividade Motora , Risco , Fumar/genética , Adulto JovemRESUMO
AIMS/HYPOTHESIS: We studied the impact of a family history of type 2 diabetes on physical fitness, lifestyle factors and diabetes-related metabolic factors. METHODS: The Prevalence, Prediction and Prevention of Diabetes (PPP)-Botnia study is a population-based study in Western Finland, which includes a random sample of 5,208 individuals aged 18 to 75 years identified through the national Finnish Population Registry. Physical activity, dietary habits and family history of type 2 diabetes were assessed by questionnaires and physical fitness by a validated 2 km walking test. Insulin secretion and action were assessed based upon OGTT measurements of insulin and glucose. RESULTS: A family history of type 2 diabetes was associated with a 2.4-fold risk of diabetes and lower physical fitness (maximal aerobic capacity 29.2 +/- 7.2 vs 32.1 +/- 7.0, p = 0.01) despite having similar reported physical activity to that of individuals with no family history. The same individuals also had reduced insulin secretion adjusted for insulin resistance, i.e. disposition index (p < 0.001) despite having higher BMI (27.4 +/- 4.6 vs 26.0 +/- 4.3 kg/m(2), p < 0.001). CONCLUSIONS/INTERPRETATION: Individuals with a family history of type 2 diabetes are characterised by lower physical fitness, which cannot solely be explained by lower physical activity. They also have an impaired capacity of beta cells to compensate for an increase in insulin resistance imposed by an increase in BMI. These defects should be important targets for interventions aiming at preventing type 2 diabetes in individuals with inherited susceptibility to the disease.
Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Estilo de Vida , Aptidão Física/fisiologia , Adolescente , Adulto , Idoso , Glicemia/metabolismo , Composição Corporal , Diabetes Mellitus Tipo 2/metabolismo , Família , Feminino , Finlândia , Predisposição Genética para Doença , Humanos , Resistência à Insulina , Células Secretoras de Insulina/metabolismo , Masculino , Pessoa de Meia-Idade , Prevalência , Sistema de Registros , Análise de Regressão , Fatores de Risco , Fatores Sexuais , Inquéritos e QuestionáriosRESUMO
Melatonin is a circulating hormone that is primarily released from the pineal gland. It is best known as a regulator of seasonal and circadian rhythms; its levels are high during the night and low during the day. Interestingly, insulin levels also exhibit a nocturnal drop, which has previously been suggested to be controlled, at least in part, by melatonin. This regulation can be explained by the proposed inhibitory action of melatonin on insulin release. Indeed, both melatonin receptor 1A (MTNR1A) and MTNR1B are expressed in pancreatic islets. The role of melatonin in the regulation of glucose homeostasis has been highlighted by three independent publications based on genome-wide association studies of traits connected with type 2 diabetes, such as elevated fasting glucose, and, subsequently, of the disease itself. The studies demonstrate a link between variations in the MTNR1B gene, hyperglycaemia, impaired early phase insulin secretion and beta cell function. The risk genotype predicts the future development of type 2 diabetes. Carriers of the risk genotype exhibit increased expression of MTNR1B in islets. This suggests that these individuals may be more sensitive to the actions of melatonin, leading to impaired insulin secretion. Blocking the inhibition of insulin secretion by melatonin may be a novel therapeutic avenue for type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Receptores de Melatonina/genética , Receptores de Melatonina/metabolismo , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/epidemiologia , Estudo de Associação Genômica Ampla , Humanos , Fatores de RiscoRESUMO
AIMS/HYPOTHESIS: Early environmental factors and genetic variants have been reported to be involved in the pathogenesis of type 2 diabetes. The aim of this study was to investigate whether there is an interaction between birthweight and common variants in the TCF7L2, HHEX, PPARG, KCNJ11, SLC30A8, IGF2BP2, CDKAL1, CDKN2A/2B and JAZF1 genes in the risk of developing type 2 diabetes. METHODS: A total of 2,003 participants from the Helsinki Birth Cohort Study, 311 of whom were diagnosed with type 2 diabetes by an OGTT, were genotyped for the specified variants. Indices for insulin sensitivity and secretion were calculated. RESULTS: Low birthweight was associated with type 2 diabetes (p = 0.008) and impaired insulin secretion (p = 0.04). Of the tested variants, the risk variant in HHEX showed a trend towards a low birthweight (p = 0.09) and the risk variant in the CDKN2A/2B locus was associated with high birthweight (p = 0.01). The TCF7L2 risk allele was associated with increased risk of type 2 diabetes. Pooling across all nine genes, each risk allele increased the risk of type 2 diabetes by 14%. [corrected] Risk variants in the HHEX, CDKN2A/2B and JAZF1 genes interacted with birthweight, so that the risk of type 2 diabetes was highest in those with lower birthweight (p Assuntos
Peso ao Nascer
, Diabetes Mellitus Tipo 2/epidemiologia
, Diabetes Mellitus Tipo 2/genética
, Desenvolvimento Embrionário/fisiologia
, Recém-Nascido de Baixo Peso
, PPAR gama/genética
, Polimorfismo de Nucleotídeo Único
, Idoso
, Proteínas Correpressoras
, Proteínas de Ligação a DNA
, Feminino
, Finlândia/epidemiologia
, Variação Genética
, Genótipo
, Humanos
, Recém-Nascido
, Masculino
, Pessoa de Meia-Idade
, Proteínas de Neoplasias/genética
, Reação em Cadeia da Polimerase
, Polimorfismo Conformacional de Fita Simples
, Gravidez
, Medição de Risco
, Fatores de Transcrição TCF/genética
, Proteína 2 Semelhante ao Fator 7 de Transcrição
RESUMO
AIMS/HYPOTHESIS: Recent reports have suggested that genotypes at the FTO locus interact with physical activity to modify levels of obesity-related traits. We tested this hypothesis in two non-diabetic population-based cohorts, the first from southern Sweden and the second from the Botnia region of western Finland. METHODS: In total 2,511 Finnish and 15,925 Swedish non-diabetic middle-aged adults were genotyped for the FTO rs9939609 variant. Physical activity was assessed by questionnaires and standard clinical procedures were conducted, including measures of height and weight and glucose regulation. Tests of gene x physical activity interaction were performed using linear interaction effects to determine whether the effect of this variant on BMI is modified by physical activity. RESULTS: The minor A allele at rs9939609 was associated with higher BMI in both cohorts, with the per allele difference in BMI being about 0.13 and 0.43 kg/m(2) in the Swedish and Finnish cohorts, respectively (p < 0.0001). The test of interaction between physical activity and the rs9939609 variant on BMI was not statistically significant after controlling for age and sex in either cohort (Sweden: p = 0.71, Finland: p = 0.18). CONCLUSIONS/INTERPRETATION: The present report does not support the notion that physical activity modifies the effects of the FTO rs9939609 variant on obesity risk in the non-diabetic Swedish or Finnish adults studied here.
Assuntos
Atividade Motora/genética , Obesidade/epidemiologia , Obesidade/genética , Proteínas/genética , Adulto , Idoso , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Índice de Massa Corporal , Estudos de Coortes , Feminino , Finlândia/epidemiologia , Variação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Suécia/epidemiologiaRESUMO
AIMS/HYPOTHESIS: We studied the physiological, metabolic and hormonal mechanisms underlying the elevated risk of type 2 diabetes in carriers of TCF7L2 gene. METHODS: We undertook genotyping of 81 healthy young Danish men for rs7903146 of TCF7L2 and carried out various beta cell tests including: 24 h glucose, insulin and glucagon profiles; OGTT; mixed meal test; IVGTT; hyperglycaemic clamp with co-infusion of glucagon-like peptide (GLP)-1 or glucose-dependent insulinotropic polypeptide (GIP); and a euglycaemic-hyperinsulinaemic clamp combined with glucose tracer infusion to study hepatic and peripheral insulin action. RESULTS: Carriers of the T allele were characterised by reduced 24 h insulin concentrations (p < 0.05) and reduced insulin secretion relative to glucose during a mixed meal test (beta index: p < 0.003), but not during an IVGTT. This was further supported by reduced late-phase insulinotropic action of GLP-1 (p = 0.03) and GIP (p = 0.07) during a 7 mmol/l hyperglycaemic clamp. Secretion of GLP-1 and GIP during the mixed meal test was normal. Despite elevated hepatic glucose production, carriers of the T allele had significantly reduced 24 h glucagon concentrations (p < 0.02) suggesting altered alpha cell function. CONCLUSIONS/INTERPRETATION: Elevated hepatic glucose production and reduced insulinotropic effect of incretin hormones contribute to an increased risk of type 2 diabetes in carriers of the rs7903146 risk T allele of TCF7L2.
Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Incretinas/sangue , Insulina/sangue , Fatores de Transcrição TCF/genética , Adolescente , Alelos , Diabetes Mellitus Tipo 2/epidemiologia , Genótipo , Peptídeo 1 Semelhante ao Glucagon/administração & dosagem , Peptídeo 1 Semelhante ao Glucagon/sangue , Técnica Clamp de Glucose , Teste de Tolerância a Glucose , Glutaminase/administração & dosagem , Glutaminase/sangue , Humanos , Hiperinsulinismo/epidemiologia , Hiperinsulinismo/genética , Hiperinsulinismo/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/administração & dosagem , Peptídeos e Proteínas de Sinalização Intracelular/sangue , Fígado/metabolismo , Masculino , Fatores de Risco , Fatores de Transcrição TCF/metabolismo , Proteína 2 Semelhante ao Fator 7 de Transcrição , Trítio , Adulto JovemRESUMO
Although the genetic causes of monogenic disorders have been successfully identified in the past, the success in dissecting the genetics of complex polygenic diseases has until now been limited. With the introduction of whole genome wide association studies (WGAS) in 2007, the picture has been dramatically changed. Today we know of about 20 genetic variants increasing the risk of type 2 diabetes (T2D). Most of them seem to influence the capacity of beta-cells to increase insulin secretion to meet the demands imposed by an increase in body weight and insulin resistance. This probably represents only the tip of the iceberg, and over the next few years refined tools will provide a more complete picture of the genetic complexity of T2D. This will not only include the current dissection of common variants increasing the susceptibility of the disease but also rare variants with stronger effects, copy number variations and epigenetic effects like DNA methylation and histone acetylation. For the first time, we can anticipate with some confidence that the genetics of a complex disease like T2D really can be dissected.
Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença/genética , Resistência à Insulina/genética , Células Secretoras de Insulina/fisiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Variação Genética/genética , Estudo de Associação Genômica Ampla , Humanos , Resistência à Insulina/fisiologia , MasculinoRESUMO
AIMS/HYPOTHESIS: The metabolic syndrome is a cluster of factors contributing to increased risk of cardiovascular disease and type 2 diabetes but unifying mechanisms have not been identified. Our aim was to study whether common variations in 17 genes previously associated with type 2 diabetes or components of the metabolic syndrome and variants in nine genes with inconsistent association with at least two components of the metabolic syndrome would also predict future development of components of the metabolic syndrome, individually or in combination. METHODS: Genetic variants were studied in a large prospective study of 16,143 non-diabetic individuals (mean follow-up time 23 years) from the Malmö Preventive Project. In this study, development of at least three of obesity (BMI >or= 30 kg/m(2)), dyslipidaemia (triacylglycerol >or= 1.7 mmol/l and/or lipid-lowering treatment), hypertension (blood pressure >or= 140/90 mmHg and/or antihypertensive medication) and hyperglycaemia (fasting plasma glucose >or= 5.6 mmol/l and/or known diabetes) was defined as development of the metabolic syndrome. The risk of developing at least three components of the metabolic syndrome or the individual components was calculated by logistic regression adjusted for age at baseline, follow-up time and sex. RESULTS: Polymorphisms in TCF7L2 (rs7903146, OR 1.10, 95% CI 1.04-1.17, p = 0.00097), FTO (rs9939609, OR 1.08, 95% CI 1.02-1.14, p = 0.0065), WFS1 (rs10010131, OR 1.07, 95% CI 1.02-1.13, p = 0.0078) and IGF2BP2 (rs4402960, OR 1.07, 95% CI 1.01-1.13, p = 0.021) predicted the development of at least three components of the metabolic syndrome in both univariate and multivariate analysis; in the case of TCF7L2, WFS1 and IGF2BP this was due to their association with hyperglycaemia (p < 0.00001, p = 0.0033 and p = 0.027, respectively) and for FTO it was due to its association with obesity (p = 0.004). A polymorphism in the GCKR gene predicted dyslipidaemia (rs1260326, OR 1.15, 95% CI 1.09-1.22, p < 0.00001) but not the metabolic syndrome. None of the studied polymorphisms was associated with more than two components of the metabolic syndrome. A composite genotype score of the 17 polymorphisms associated with type 2 diabetes predicted the development of at least three components of the metabolic syndrome (OR 1.04, p < 0.00001) and the development of hyperglycaemia (OR 1.06, p < 0.00001). Carriers of >or=19 risk alleles had 51 and 72% increased risk of developing at least three components of the metabolic syndrome and hyperglycaemia, respectively, compared with carriers of Assuntos
Diabetes Mellitus Tipo 2/genética
, Polimorfismo de Nucleotídeo Único/genética
, Diabetes Mellitus Tipo 2/epidemiologia
, Feminino
, Seguimentos
, Genótipo
, Humanos
, Masculino
, Pessoa de Meia-Idade
, Fatores de Risco
RESUMO
BACKGROUND/OBJECTIVES: Data on associations between marine n-3 fatty acids and glucose metabolism are inconsistent. Therefore, we explored effects of the Pro12Ala polymorphism in peroxisome proliferator-activated receptor (PPAR)-gamma2 gene on associations of fish intake and dietary and plasma eicosapentaenoic and docosahexaenoic acid with glucose metabolism. The design comprises of the cross-sectional analysis. SUBJECTS/METHODS: The Pro12Ala variant in the PPAR-gamma2 (PPARG) gene was genotyped in 571 non-diabetic relatives of subjects with type II diabetes. The dietary intake was measured by a 3-day food record, and the plasma cholesterol ester fatty acid composition was analysed with gas chromatography. Associations of dietary and plasma variables with insulin resistance and fasting and 2-h glucose and free fatty acid concentrations were analysed with multiple linear regression analysis. RESULTS: In men, there was a significant interaction between PPARG polymorphism and plasma docosahexaenoic acid on fasting free fatty acid concentration (P=0.036), and genotype-stratified models showed an inverse association in Pro homozygotes only (P=0.028). In women, the proportion of plasma eicosapentaenoic acid was higher in Ala-allele carriers compared to Pro homozygotes (1.67 vs 1.44% respectively, P=0.006). A significant interaction between PPARG polymorphism and fish intake on 2-h glucose was found in women (P=0.021), and genotype-stratified models suggested an inverse association in Ala-allele carriers only (P=0.039). CONCLUSIONS: The findings suggest that PPARG polymorphism might affect the plasma proportion of eicosapentaenoic acid and modulate the associations of fish intake and marine n-3 fatty acids with glucose metabolism and fasting free fatty acids.
Assuntos
Alelos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Ácidos Graxos não Esterificados/sangue , Ácidos Graxos Ômega-3/administração & dosagem , PPAR gama/genética , Polimorfismo Genético , Alanina , Estudos Transversais , Diabetes Mellitus Tipo 2/genética , Registros de Dieta , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácidos Docosa-Hexaenoicos/sangue , Ácido Eicosapentaenoico/administração & dosagem , Ácido Eicosapentaenoico/sangue , Ácidos Graxos Ômega-3/sangue , Feminino , Genótipo , Heterozigoto , Homozigoto , Humanos , Insulina/sangue , Resistência à Insulina/genética , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Prolina , Fatores SexuaisRESUMO
We discuss approaches to increase the light outcoupling efficiency in organic microcavity (MC) lasers and organic light-emitting diodes (OLEDs). We find that the introduction of metals into the cavities leads to additional Tamm-plasmon polariton modes, while the corrugation of metal contacts, such as perforated µ-size holes or a periodic array of metal stripes, leads to 2D confinement of the cavity modes, which in turn reduces the lasing threshold in MCs. Furthermore, we elucidate light loss mechanisms in OLEDs and reveal how external dielectric layers and periodic gratings can be used to enhance outcoupling from the OLED cavity.
RESUMO
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/genéticaRESUMO
AIMS/HYPOTHESIS: Recent genome-wide association studies performed in selected patients and control participants have provided strong support for several new type 2 diabetes susceptibility loci. To get a better estimation of the true risk conferred by these novel loci, we tested a completely unselected population of type 2 diabetes patients from a Norwegian health survey (the HUNT study). METHODS: We genotyped single nucleotide polymorphisms (SNPs) in PKN2, IGFBP2, FLJ39370 (also known as C4ORF32), CDKAL1, SLC30A8, CDKN2B, HHEX and FTO using a Norwegian population-based sample of 1,638 patients with type 2 diabetes and 1,858 non-diabetic control participants (the HUNT Study), for all of whom data on BMI, WHR, cholesterol and triacylglycerol levels were available. We used diabetes, measures of obesity and lipid values as phenotypes in case-control and quantitative association study designs. RESULTS: We replicated the association with type 2 diabetes for rs10811661 in the vicinity of CDKN2B (OR 1.20, 95% CI: 1.06-1.37, p=0.004), rs9939609 in FTO (OR 1.14, 95% CI: 1.04-1.25, p=0.006) and rs13266634 in SLC30A8 (OR 1.20, 95% CI: 1.09-1.33, p=3.9 x 10(-4)). We found borderline significant association for the IGFBP2 SNP rs4402960 (OR 1.10, 95% CI: 0.99-1.22). Results for the HHEX SNP (rs1111875) and the CDKAL1 SNP (rs7756992) were non-significant, but the magnitude of effect was similar to previous estimates. We found no support for an association with the less consistently replicated FLJ39370 or PKN2 SNPs. In agreement with previous studies, FTO was most strongly associated with BMI (p=8.4 x 10(-4)). CONCLUSIONS/INTERPRETATION: Our data show that SNPs near IGFBP2, CDKAL1, SLC30A8, CDKN2B, HHEX and FTO are also associated with diabetes in non-selected patients with type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 2/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Glicemia/análise , Estudos de Coortes , Quinases Ciclina-Dependentes/genética , Diabetes Mellitus Tipo 2/enzimologia , Feminino , Genoma Humano , Humanos , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Masculino , Pessoa de Meia-Idade , NoruegaRESUMO
AIMS/HYPOTHESIS: Glucose-stimulated insulin secretion is dependent on the electrical activity of beta cells; hence, genes encoding beta cell ion channels are potential candidate genes for type 2 diabetes. The gene encoding the voltage-dependent Ca(2+) channel Ca(V)2.3 (CACNA1E), telomeric to a region that has shown suggestive linkage to type 2 diabetes (1q21-q25), has been ascribed a role for second-phase insulin secretion. METHODS: Based upon the genotyping of 52 haplotype tagging single nucleotide polymorphisms (SNPs) in a type 2 diabetes case-control sample (n = 1,467), we selected five SNPs that were nominally associated with type 2 diabetes and genotyped them in the following groups (1) a new case-control sample of 6,570 individuals from Sweden; (2) 2,293 individuals from the Botnia prospective cohort; and (3) 935 individuals with insulin secretion data from an IVGTT. RESULTS: The rs679931 TT genotype was associated with (1) an increased risk of type 2 diabetes in the Botnia case-control sample [odds ratio (OR) 1.4, 95% CI 1.0-2.0, p = 0.06] and in the replication sample (OR 1.2, 95% CI 1.0-1.5, p = 0.01 one-tailed), with a combined OR of 1.3 (95% CI 1.1-1.5, p = 0.004 two-tailed); (2) reduced insulin secretion [insulinogenic index at 30 min p = 0.02, disposition index (D (I)) p = 0.03] in control participants during an OGTT; (3) reduced second-phase insulin secretion at 30 min (p = 0.04) and 60 min (p = 0.02) during an IVGTT; and (4) reduced D (I) over time in the Botnia prospective cohort (p = 0.05). CONCLUSIONS/INTERPRETATION: We conclude that genetic variation in the CACNA1E gene contributes to an increased risk of the development of type 2 diabetes by reducing insulin secretion.
Assuntos
Canais de Cálcio Tipo R/genética , Proteínas de Transporte de Cátions/genética , Diabetes Mellitus Tipo 2/genética , Resistência à Insulina/genética , Insulina/metabolismo , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/complicações , Feminino , Genótipo , Humanos , Secreção de Insulina , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , SuéciaRESUMO
AIMS/HYPOTHESIS: Mutations in the hepatocyte nuclear factor 1-alpha gene (HNF-1alpha, now known as the transcription factor 1 gene [TCF1]) cause the most common monogenic form of diabetes, MODY3, but it is not known if common variants in HNF-1a are associated with decreased transcriptional activity or phenotypes related to type 2 diabetes, or whether they predict future type 2 diabetes. SUBJECTS AND METHODS: We studied the effect of four common polymorphisms (rs1920792, I27L, A98V and S487N) in and upstream of the HNF-1alpha gene on transcriptional activity in vitro, and their possible association with type 2 diabetes and insulin secretion in vivo. RESULTS: Certain combinations of the I27L and A98V polymorphisms in the HNF-1alpha gene showed decreased transcriptional activity on the target promoters glucose transporter 2 (now known as solute carrier family 2 [facilitated glucose transporter], member 2) and albumin in both HeLa and INS-1 cells. In vivo, these polymorphisms were associated with a modest but significant impairment in insulin secretion in response to oral glucose. Insulin secretion deteriorated over time in individuals carrying the V allele of the A98V polymorphism (n = 2,293; p = 0.003). In a new case-control (n = 1,511 and n = 2,225 respectively) data set, the I27L polymorphism was associated with increased risk of type 2 diabetes, odds ratio (OR) = 1.5 (p = 0.002; multiple logistic regression), particularly in elderly (age > 60 years) and overweight (BMI > 25 kg/m(2)) patients (OR = 2.3, p = 0.002). CONCLUSIONS/INTERPRETATION: This study provides in vitro and in vivo evidence that common variants in the MODY3 gene, HNF-1alpha, influence transcriptional activity and insulin secretion in vivo. These variants are associated with a modestly increased risk of late-onset type 2 diabetes in subsets of elderly overweight individuals.
Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Variação Genética , Fator 1-alfa Nuclear de Hepatócito/genética , Adulto , Substituição de Aminoácidos , Arginina/farmacologia , Glicemia/metabolismo , Peso Corporal , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/genética , Feminino , Glucose/farmacologia , Humanos , Insulina/metabolismo , Secreção de Insulina , Masculino , Pessoa de Meia-Idade , Mutagênese Sítio-Dirigida , Sobrepeso , Plasmídeos , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Transcrição GênicaRESUMO
We investigate the energy spectrum and the electron dynamics of a band in a semiconductor superlattice as a function of the electric field. Linear optical spectroscopy shows that, for high fields, the well-known localization of the Bloch states is followed by a field-induced delocalization, associated with Zener breakdown. Using time-resolved measurements, we observe Bloch oscillations in a regime where they are damped by Zener breakdown.