RESUMO
OBJECTIVE: Although debated, metabolic health characterizes 10-25% of obese individuals and reduces risk of developing life-threatening co-morbidities. Adipose tissue is a recognized endocrine organ important for the maintenance of whole-body metabolic health. Adipocyte transcriptional signatures of healthy and unhealthy obesity are largely unknown. METHODS: Here, we used a small cohort of highly characterized obese individuals discordant for metabolic health, characterized their adipocytes transcriptional signatures, and cross-referenced them to mouse phenotypic and human GWAs databases. RESULTS AND CONCLUSIONS: Our study showed that glucose intolerance and insulin resistance co-operate to remodel adipocyte transcriptome. We also identified the Nuclear Export Mediator Factor (NEMF) and the Ectoderm-Neural Cortex 1 (ENC1) as novel potential targets in the management of metabolic health in human obesity.
Assuntos
Adipócitos/metabolismo , Intolerância à Glucose , Resistência à Insulina , Obesidade/metabolismo , Transcriptoma , Adulto , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Células Cultivadas , Feminino , Humanos , Masculino , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Pessoa de Meia-Idade , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas de Transporte Nucleocitoplasmático/genética , Proteínas de Transporte Nucleocitoplasmático/metabolismo , Obesidade/genéticaRESUMO
BACKGROUND: In clinical practice, there is a strong interest in non-invasive markers of non-alcoholic fatty liver disease (NAFLD). Our hypothesis was that the fold-change in plasma triglycerides (TG) during a 2-h oral glucose tolerance test (fold-change TGOGTT) in concert with blood glucose and lipid parameters, and the rs738409 C>G single nucleotide polymorphism (SNP) in PNPLA3 might improve the power of the widely used fatty liver index (FLI) to predict NAFLD. METHODS: The liver fat content of 330 subjects was quantified by 1H-magnetic resonance spectroscopy. Blood parameters were measured during fasting and after a 2-h OGTT. A subgroup of 213 subjects underwent these measurements before and after 9 months of a lifestyle intervention. RESULTS: The fold-change TGOGTT was closely associated with liver fat content (r=0.51, P<0.0001), but had less power to predict NAFLD (AUROC=0.75) than the FLI (AUROC=0.79). Not only was the fold-change TGOGTT independently associated with liver fat content and NAFLD, but so also were the 2-h blood glucose level and rs738409 C>G SNP in PNPLA3. In fact, a novel index (extended FLI) generated from these and the usual FLI parameters considerably increased its power to predict NAFLD (AUROC=0.79-0.86). The extended FLI also increased the power to predict changes in liver fat content with a lifestyle intervention (n=213; standardized beta coefficient: 0.23-0.29). CONCLUSION: This study has provided novel data confirming that the OGTT-derived fold-change TGOGTT and 2-h glucose level, together with the rs738409 C>G SNP in PNPLA3, allow calculation of an extended FLI that considerably improves its power to predict NAFLD.
Assuntos
Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Adulto , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Valor Preditivo dos Testes , Curva ROC , Triglicerídeos/sangueRESUMO
Although over a hundred thermal indices can be used for assessing thermal health hazards, many ignore the human heat budget, physiology and clothing. The Universal Thermal Climate Index (UTCI) addresses these shortcomings by using an advanced thermo-physiological model. This paper assesses the potential of using the UTCI for forecasting thermal health hazards. Traditionally, such hazard forecasting has had two further limitations: it has been narrowly focused on a particular region or nation and has relied on the use of single 'deterministic' forecasts. Here, the UTCI is computed on a global scale, which is essential for international health-hazard warnings and disaster preparedness, and it is provided as a probabilistic forecast. It is shown that probabilistic UTCI forecasts are superior in skill to deterministic forecasts and that despite global variations, the UTCI forecast is skilful for lead times up to 10 days. The paper also demonstrates the utility of probabilistic UTCI forecasts on the example of the 2010 heat wave in Russia.
Assuntos
Temperatura Baixa/efeitos adversos , Previsões/métodos , Temperatura Alta/efeitos adversos , Modelos Teóricos , Estresse Fisiológico , Clima , Transtornos de Estresse por Calor/prevenção & controle , Humanos , Probabilidade , Reprodutibilidade dos Testes , Federação Russa , Luz Solar , VentoRESUMO
The dopamine agonist bromocriptine has been approved for the treatment of type 2 diabetes in the United States. Bromocriptine inhibits prolactin secretion, and patients with hyperprolactinaemia display impaired insulin sensitivity. We therefore hypothesized that low prolactin levels are associated with lower glycaemia and higher insulin sensitivity in healthy subjects. Prolactin levels were determined from fasting serum in participants without diabetes from the cross-sectional Tübingen family study for type 2 diabetes (m/f = 562/1,121, age = 40 ± 13 years, BMI = 30 ± 9 kg/m(2)). A 75 g oral glucose tolerance test was performed, and the area under the glucose curve (AUC(0-120)Glucose) and insulin sensitivity index were calculated. A subgroup (n = 494) underwent hyperinsulinaemic-euglycaemic clamp tests. Prolactin associated positively with insulin sensitivity (p = 0.001, adjusted for gender, age, and BMI). Age strongly interacted (p < 0.0001) with the effect of prolactin on insulin sensitivity, inverting the positive relationship to a negative one in younger participants. Glycated haemoglobin (HbA1c) and AUC(0-120)Glucose correlated negatively with prolactin, and an interaction with age was found as well. Higher prolactin levels are associated with improved insulin sensitivity and lower glucose in individuals without diabetes. This relationship turns to its opposite in younger persons. As prolactin is a proxy for the dopaminergic tone in the central nervous system, these associations may indicate an age-dependent influence of the brain on peripheral insulin sensitivity.
Assuntos
Glicemia/metabolismo , Resistência à Insulina , Prolactina/sangue , Adulto , Fatores Etários , Pesos e Medidas Corporais , Estudos Transversais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Saúde da Família , Jejum/sangue , Jejum/metabolismo , Feminino , Teste de Tolerância a Glucose , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
Genetic variation in the FTO gene is associated with increased body weight and reduced insulin sensitivity. We investigated whether genetic variation in FTO is associated with polycystic ovary syndrome (PCOS), a condition also characterized by insulin resistance. Furthermore, we tested whether insulin resistance is specifically associated with genetic variation in FTO in women with PCOS. Sixty-two nondiabetic patients with PCOS defined by the Rotterdam criteria were compared to BMI and age-matched women. Each PCOS case was matched to 2 controls. All participants underwent an oral glucose tolerance test and were genotyped for the single nucleotide polymorphism rs8050136 in the FTO gene. There was no difference in the frequency of FTO genotypes between the PCOS and the non-PCOS groups. In non-PCOS participants, genetic variation in FTO is associated with insulin sensitivity (p=0.03). This association remained significant after adjustment for age and/or BMI (p<= 0.03). In subjects with PCOS, however, FTO did not associate with insulin sensitivity (p=0.67). Genetic variation in FTO does not have an impact on insulin sensitivity in women with PCOS and is therefore not involved in the pathogenesis of the insulin resistant phenotype seen in patients with PCOS.
Assuntos
Variação Genética , Resistência à Insulina , Síndrome do Ovário Policístico/genética , Proteínas/genética , Adulto , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Estudos de Coortes , Feminino , Genótipo , Teste de Tolerância a Glucose , Humanos , Fenótipo , Síndrome do Ovário Policístico/metabolismo , Polimorfismo de Nucleotídeo Único , Proteínas/metabolismo , Adulto JovemAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Folicular/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/efeitos adversos , Anticorpos Monoclonais Murinos/economia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/economia , Biomarcadores Tumorais , Análise Custo-Benefício , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Ciclofosfamida/economia , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/economia , Humanos , Estimativa de Kaplan-Meier , Linfoma Folicular/economia , Linfoma Folicular/genética , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Prednisona/economia , Modelos de Riscos Proporcionais , Indução de Remissão , Rituximab , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Vincristina/economia , Adulto JovemRESUMO
AIM: Glucocorticoids are efficacious anti-inflammatory agents, but, in susceptible individuals, these drugs may induce glucose intolerance and diabetes by affecting ß-cell function and insulin sensitivity. We assessed whether polymorphisms in the glucocorticoid receptor gene NR3C1 associate with measures of ß-cell function and insulin sensitivity derived from hyperglycaemic clamps in subjects with normal or impaired glucose tolerance. METHODS: A cross-sectional cohort study was conducted in four academic medical centres in the Netherlands and Germany. Four hundred and forty-nine volunteers (188 men; 261 women) were recruited with normal glucose tolerance (n=261) and impaired glucose tolerance (n=188). From 2-h hyperglycaemic clamps, first- and second-phase glucose-stimulated insulin secretion, as well as insulin sensitivity index and disposition index, were calculated. All participants were genotyped for the functional NR3C1 polymorphisms N363S (rs6195), BclI (rs41423247), ER22/23EK (rs6189/6190), 9ß A/G (rs6198) and ThtIIII (rs10052957). Associations between these polymorphisms and ß-cell function parameters were assessed. RESULTS: In women, but not in men, the N363S polymorphism was associated with reduced disposition index (P=1.06 10(-4) ). Also only in women, the ER22/23EK polymorphism was associated with reduced first-phase glucose-stimulated insulin secretion (P=0.011) and disposition index (P=0.003). The other single-nucleotide polymorphisms were not associated with ß-cell function. Finally, none of the polymorphisms was related to insulin sensitivity. CONCLUSION: The N363S and ER22/23EK polymorphisms of the NR3C1 gene are negatively associated with parameters of ß-cell function in women, but not in men.
Assuntos
Intolerância à Glucose/genética , Resistência à Insulina/genética , Células Secretoras de Insulina/fisiologia , Polimorfismo de Nucleotídeo Único/genética , Receptores de Glucocorticoides/genética , Estudos Transversais , Feminino , Genótipo , Haplótipos , Humanos , Hiperglicemia/genética , Insulina/metabolismo , Secreção de Insulina , Masculino , Fatores SexuaisRESUMO
AIMS/HYPOTHESIS: Impaired insulin sensitivity is a major factor leading to type 2 diabetes. Animal studies suggest that the brain is involved in the regulation of insulin sensitivity. We investigated whether insulin action in the human brain regulates peripheral insulin sensitivity and examined which brain areas are involved. METHODS: Insulin and placebo were given intranasally. Plasma glucose, insulin and C-peptide were measured in 103 participants at 0, 30 and 60 min. A subgroup (n = 12) was also studied with functional MRI, and blood sampling at 0, 30 and 120 min. For each time-point, the HOMA of insulin resistance (HOMA-IR) was calculated as an inverse estimate of peripheral insulin sensitivity. RESULTS: Plasma insulin increased and subsequently decreased. This excursion was accompanied by slightly decreased plasma glucose, resulting in an initially increased HOMA-IR. At 1 h after insulin spray, the HOMA-IR subsequently decreased and remained lower up to 120 min. An increase in hypothalamic activity was observed, which correlated with the increased HOMA-IR at 30 min post-spray. Activity in the putamen, right insula and orbitofrontal cortex correlated with the decreased HOMA-IR at 120 min post-spray. CONCLUSIONS/INTERPRETATION: Central insulin action in specific brain areas, including the hypothalamus, may time-dependently regulate peripheral insulin sensitivity. This introduces a potential novel mechanism for the regulation of peripheral insulin sensitivity and underlines the importance of cerebral insulin action for the whole organism.
Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Resistência à Insulina/fisiologia , Insulina/farmacologia , Administração Intranasal , Adulto , Idoso , Feminino , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Humanos , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Pessoa de Meia-IdadeRESUMO
AIMS/HYPOTHESIS: We have previously found that the mass of perivascular adipose tissue (PVAT) correlates negatively with insulin sensitivity and post-ischaemic increase in blood flow. To understand how PVAT communicates with vascular vessels, interactions between perivascular, subcutaneous and visceral fat cells with endothelial cells (ECs) were examined with regard to inflammatory, metabolic and angiogenic proteins. To test for possible in vivo relevance of these findings, circulating levels of the predominant secretion product, hepatocyte growth factor (HGF), was measured in individuals carefully phenotyped for fat distribution patterns. METHODS: Mono- and co-cultures of human primary fat cells with ECs were performed. mRNA expression and protein production were studied using Luminex, cytokine array, RealTime Ready and ELISA systems. Effects of HGF on vascular cells were determined by WST assays. In patients, HGF levels were measured by ELISA, and the mass of different fat compartments was determined by whole-body MRI. RESULTS: In contrast with other fat cell types, PVAT cells released higher amounts of angiogenic factors, e.g. HGF, acidic fibroblast growth factor, thrombospondin-1, serpin-E1, monocyte chemotactic protein-1 and insulin-like growth factor-binding protein -3. Cocultures showed different expression profiles from monocultures, and mature adipocytes differed from pre-adipocytes. HGF was preferentially released by PVAT cells and stimulated EC growth and smooth muscle cell cytokine release. Finally, in 95 patients, only PVAT, not visceral or subcutaneous mass, correlated independently with serum HGF levels (p = 0.03; r = 0.225). CONCLUSIONS: Perivascular (pre-)adipocytes differ substantially from other fat cells with regard to mRNA expression and protein production of angiogenic factors. This may contribute to fat tissue growth and atherosclerotic plaque complications. Higher levels of angiogenic factors, such as HGF, in patients with increased perivascular fat mass may have pathological relevance.
Assuntos
Adipócitos/metabolismo , Fator de Crescimento de Hepatócito/metabolismo , Gordura Abdominal/metabolismo , Adulto , Idoso , Indutores da Angiogênese/metabolismo , Proteínas Angiogênicas/metabolismo , Células Cultivadas , Técnicas de Cocultura , Células Endoteliais/metabolismo , Feminino , Perfilação da Expressão Gênica , Fator de Crescimento de Hepatócito/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Gordura Subcutânea/metabolismo , Adulto JovemRESUMO
AIMS: To give an overview on the relationship between diabetes mellitus and increased cancer risk. METHODS: We identified studies evaluating the association between diabetes mellitus, its treatment with insulin and insulin analogues and malignancies, paying special attention to studies on in vitro and in vivo effects of the long-acting analogue insulin glargine. RESULTS: Even although the pathophysiological mechanisms underlying the relationship between elevated cancer risk and Type 2 diabetes mellitus are not completely understood, hyperinsulinaemia in the presence of insulin resistance appears to be a key factor. Because of the mitogenic actions of insulin at high concentrations, hyperinsulinaemia may favour tumorigenesis. In line with this, an insulin-based therapy is associated with an increased cancer risk, whereas an insulin-sensitizing treatment results in a cancer risk reduction. Furthermore, alterations of the insulin receptor profile on tumour cells may contribute to an enhanced susceptibility towards insulin. Studies on the analogue insulin glargine have been controversial. In vitro data pointed to an elevated mitogenicity of insulin glargine, whereas in vivo data did not confirm cancerogenous effects. Moreover, recently published clinical studies on the association of insulin glargine (Lantus®) and cancer suggest that treatment with insulin glargine is not associated with increased cancer risk. CONCLUSIONS: The relationship between elevated cancer risk and Type 2 diabetes mellitus has been shown by numerous epidemiological studies, with endogenous and exogenous hyperinsulinaemia in the presence of insulin resistance as potential underlying pathophysiological mechanisms. Recent clinical studies do not support an increased cancer risk in patients treated with insulin glargine.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hiperinsulinismo/induzido quimicamente , Insulina/análogos & derivados , Insulina/efeitos adversos , Neoplasias/induzido quimicamente , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Insulina Glargina , Insulina de Ação Prolongada , Masculino , Fatores de RiscoRESUMO
Apelin is proposed to possess protective cardiovascular properties and may furthermore promote favorable effects on glucose metabolism. First data in humans seem to support this hypothesis. Therefore we aimed to assess the meaning of apelin as an early risk indicator in young subjects prone to atherosclerosis and type 2 diabetes. Furthermore we examined the association of apelin serum levels with insulin sensitivity/resistance and body fat distribution as probably dependent cardiovascular risk factors. We examined 344 individuals (f/m=216/128, mean age 46±1 years) with an increased risk for type 2 diabetes. Apelin-36 serum levels were measured via ELISA. Endothelial dysfunction and intima media thickness (IMT) were assessed using high resolution ultrasound. Visceral adipose tissue (VAT) was measured with an axial T1-weighted fast spin echo technique with a 1.5 T whole-body imager. According to the study population's age, FMD (6.4±0.2%) and IMT (0.56±0.01 mm) were within the expected ranges. Gender or age had no influence on serum apelin levels. When looked at early stages of atherosclerosis, we could not detect a significant correlation between apelin serum levels and FMD or IMT. Blood pressure as well was unaffected by serum apelin levels. Furthermore, neither parameters of insulin sensitivity like insulin sensitivity index (ISI), nor fat distribution like BMI, grade of adiposity, total adipose tissue or VAT were associated with apelin serum levels. We conclude that apelin serum levels do not add further information on the cardiovascular-, or diabetes risk pattern in a diabetes prone population.
Assuntos
Aterosclerose/sangue , Diabetes Mellitus Tipo 2/sangue , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Adolescente , Adulto , Fatores Etários , Idade de Início , Idoso , Apelina , Aterosclerose/epidemiologia , Aterosclerose/etiologia , Aterosclerose/metabolismo , Distribuição da Gordura Corporal , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Suscetibilidade a Doenças/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Adulto JovemRESUMO
Non-alcoholic fatty liver disease (NAFLD) is strongly associated with insulin resistance and type 2 diabetes in humans. Ongoing research aims to clarify the mechanisms involved in this relationship. Studying pathways that are involved in the dissociation between fatty liver and insulin resistance may help to achieve this goal. Among several enzymes that regulate the fate of hepatic lipids, adipose triacylglycerol lipase (ATGL) is of interest. This article briefly summarises novel information about the impact of ATGL in this process.
Assuntos
Tecido Adiposo/enzimologia , Tecido Adiposo/metabolismo , Fígado Gorduroso/enzimologia , Fígado Gorduroso/metabolismo , Resistência à Insulina/fisiologia , Lipase/metabolismo , Animais , Humanos , Modelos BiológicosRESUMO
Recent genome-wide association studies identified several novel risk genes for type 2 diabetes. The majority of these type 2 diabetes risk variants confer impaired pancreatic beta cell function. Though the molecular mechanisms by which common genetic variation within these loci affects beta cell function are not completely understood, risk variants may alter glucose-stimulated insulin secretion, proinsulin conversion, and incretin signals. In humans, the incretin effect is mediated by the secretion and insulinotropic action of two peptide hormones, glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1. This review article aims to give an overview of the type 2 diabetes risk loci that were found to associate with incretin secretion or incretin action, paying special attention to the potential underlying mechanisms.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Incretinas/metabolismo , Animais , Diabetes Mellitus Tipo 2/genética , Polipeptídeo Inibidor Gástrico/metabolismo , Estudo de Associação Genômica Ampla , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Humanos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologiaRESUMO
Numerous epidemiological studies have demonstrated an association between increased risk of cancer development and progression and type 2 diabetes mellitus as well as obesity. The underlying mechanisms remain elusive, but hyperinsulinaemia in the presence of insulin resistance appears to be an important factor. Hyperinsulinaemia may favour tumorigenesis, as insulin has not only metabolic actions, but is also mitogenic at high concentrations. Besides, susceptibility of tumour cells against insulin may be increased due to changes in the insulin receptor profile. A diabetes therapy with insulin or sulfonylureas, which leads to elevated exogenous or endogenous insulin levels, appears to be related with an increased cancer risk, whereas administration of metformin or thiazolidinediones, which is associated with a decrease of insulin concentrations, results in risk reduction. However, in light of the numerous epidemiological studies showing an association between increased cancer risk and reduced physical activity one cannot exclude that hyperinsulinaemia in the presence of insulin resistance is only a surrogate parameter of reduced physical activity. In the past years, several insulin analogues have been developed which may have altered mitogenic actions compared to human insulin due to their structural changes. For the long-acting analogue insulin glargine, in vitro data, though controversial, pointed to an increased mitogenicity that was, however, not confirmed by in vivo studies. Recently, six clinical studies have been published that analysed the association between the application of insulin glargine (Lantus) and cancer development. The current clinical data do not allow the conclusion that treatment with insulin glargine is associated with increased cancer risk. On the other hand, prospective studies that exclude an impact on cancer risk in risk populations are currently not available. Future studies are required to investigate whether a subpopulation characterised by a less rapid metabolization of insulin glargine in vivo may be at increased cancer risk. In the present article, we give an overview on the association between diabetes mellitus, its treatment with insulin analogues, and cancer.
Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Hipoglicemiantes/efeitos adversos , Insulina/análogos & derivados , Neoplasias/epidemiologia , Obesidade/epidemiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Exercício Físico/fisiologia , Humanos , Hiperinsulinismo/epidemiologia , Hiperinsulinismo/fisiopatologia , Hipoglicemiantes/uso terapêutico , Insulina/efeitos adversos , Insulina/uso terapêutico , Insulina Glargina , Resistência à Insulina/fisiologia , Insulina de Ação Prolongada , Testes de Mutagenicidade , Neoplasias/induzido quimicamente , Neoplasias/fisiopatologia , Obesidade/fisiopatologia , Fatores de RiscoRESUMO
AIMS/HYPOTHESIS: The K121Q (rs1044498) single nucleotide polymorphism (SNP) in the ENPP1 gene has shown association with insulin resistance and type 2 diabetes in various ethnic populations. We hypothesised that K121Q may predict the success of lifestyle intervention in terms of improvement of insulin sensitivity. METHODS: We genotyped 1,563 participants with an increased risk of type 2 diabetes for K121Q and performed correlational analyses with anthropometric data and variables of insulin sensitivity. For metabolic characterisation, all participants underwent an OGTT. A subgroup of 506 participants additionally underwent a euglycaemic-hyperinsulinaemic clamp. In 342 participants, metabolic traits and anthropometric data were re-evaluated after a 9 month lifestyle intervention. RESULTS: In the overall cohort, K121Q was not associated with measures of obesity, indices of glucose tolerance during OGTT and insulin sensitivity estimated from the OGTT or derived from a euglycaemic-hyperinsulinaemic clamp after appropriate adjustment. However, K121Q did significantly influence the change in insulin sensitivity during lifestyle intervention after appropriate adjustment (p (additive) = 0.0067, p (dominant) = 0.0027). Carriers of the minor allele had an impaired increase in OGTT-derived insulin sensitivity. A similar trend was obtained for clamp-derived insulin sensitivity, but did not reach significance. CONCLUSIONS/INTERPRETATION: In our population of European ancestry, the ENPP1 SNP K121Q influenced the change in insulin sensitivity during lifestyle intervention. Thus, this SNP may determine susceptibility to environmental changes and could predict the success of lifestyle intervention.
Assuntos
Diabetes Mellitus Tipo 2/genética , Diester Fosfórico Hidrolases/genética , Polimorfismo Genético , Pirofosfatases/genética , Adulto , Antropometria/métodos , Feminino , Predisposição Genética para Doença , Teste de Tolerância a Glucose , Humanos , Hiperinsulinismo/patologia , Estilo de Vida , Masculino , Pessoa de Meia-IdadeRESUMO
Obesity-resistance in AHSG-knockout mice indicate an important role of alpha2-Heremans-Schmid glycoprotein/fetuin-A (AHSG) in the development of obesity. We studied whether genetic variation within AHSG affects whole-body adiposity and regional fat distribution in humans. We genotyped 321 subjects at increased risk for type 2 diabetes for five single nucleotide polymorphisms (SNP) rs2248690, rs4831, rs2070635, rs4917, and rs1071592. Body fat distribution and ectopic hepatic and intramyocellular lipids were assessed by magnetic resonance techniques. AHSG levels were determined by immunoturbidimetry. The five chosen SNPs covered 100% of common genetic variation (minor allele frequency >/=0.05) within AHSG (r (2)>/=0.8). All SNPs were significantly associated with AHSG levels (p<0.0001), except for rs4831 (p=0.9) after adjustment for gender, age, and body mass index (BMI). AHSG levels were associated with liver fat content (p=0.0160) and BMI (p=0.0247) after adjustment for gender and age. While rs2248690 was nominally associated with BMI in the dominant model (p=0.0432), none of the SNPs was associated with regional fat distribution. Common genetic variation within AHSG does not appear to influence regional body fat distribution, but may affect whole-body adiposity in humans.
Assuntos
Adiposidade/genética , Proteínas Sanguíneas/genética , Distribuição da Gordura Corporal , Variação Genética/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Alelos , Proteínas Sanguíneas/metabolismo , Índice de Massa Corporal , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , Resistência à Insulina/genética , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , alfa-2-Glicoproteína-HSRESUMO
Apoptosis is involved in the development and progression of atherosclerotic lesions. Protein kinase C (PKC) signalling is of importance in atherosclerosis as well as apoptosis. Therefore, we tested the involvement of PKC in lipid-induced apoptosis of human coronary artery endothelial cells (HCAEC). Protein expression of PKC isoforms alpha, beta I, delta, epsilon, and iota was detected, whereas no relevant protein amounts of PKC isoforms beta II, gamma, eta, theta, and zeta were found. Inhibition of classical and novel PKC isoforms by treatment with bisindolylmaleimide or PKC down-regulation by long-term treatment with 12-O-tetradecanoyl phorbol-13-acetate (TPA) could not prevent apoptosis induced by palmitate or stearate. In contrast, a specific myristoylated, cell-permeable PKC zeta/iota pseudosubstrate prevented lipid-induced apoptosis in HCAEC. Furthermore, saturated fatty acids activated PKC iota as evidenced by PKC iota down-regulation upon long-term treatment with stearate. Our data provide evidence that PKC iota is activated by saturated fatty acids and mediates lipid-induced apoptosis of HCAEC.
Assuntos
Apoptose/efeitos dos fármacos , Vasos Coronários/citologia , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Isoenzimas/metabolismo , Proteína Quinase C/metabolismo , Apoptose/genética , Células Cultivadas , Relação Dose-Resposta a Droga , Endotélio Vascular/citologia , Ativação Enzimática , Ácidos Graxos/farmacologia , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/genética , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/genéticaRESUMO
AIMS/HYPOTHESIS: WFS1 type 2 diabetes risk variants appear to be associated with impaired beta cell function, although it is unclear whether insulin secretion is affected directly or secondarily via alteration of insulin sensitivity. We aimed to investigate the effect of a common WFS1 single-nucleotide polymorphism on several aspects of insulin secretion. METHODS: A total of 1,578 non-diabetic individuals (534 men and 1,044 women, aged 40 +/- 13 years, BMI 28.9 +/- 8.2 kg/m(2) [mean +/- SD]) at increased risk of type 2 diabetes were genotyped for rs10010131 within the WFS1 gene. All participants underwent an OGTT (and a subset additionally an IVGTT [n = 319]) and a hyperglycaemic clamp combined with glucagon-like peptide-1 (GLP-1) and arginine stimuli (n = 102). RESULTS: rs10010131 was associated with reduced OGTT-derived insulin secretion (p = 0.03). In contrast, insulin secretion induced by an i.v. glucose challenge in the IVGTT and hyperglycaemic clamp was not different between the genotypes. GLP-1 infusion combined with a hyperglycaemic clamp showed a significant reduction of the insulin secretion rate during the first and second phases of GLP-1-induced insulin secretion in carriers of the risk allele (reduction of 36% and 26%, respectively; p = 0.007 and p = 0.04, respectively). CONCLUSIONS/INTERPRETATION: A common genetic variant in WFS1 specifically impairs GLP-1-induced insulin secretion independently of insulin sensitivity. This defect might explain the impaired insulin secretion in carriers of the risk allele and confer the increased risk of type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 2/genética , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Insulina/metabolismo , Proteínas de Membrana/genética , Adulto , Feminino , Genótipo , Técnica Clamp de Glucose , Teste de Tolerância a Glucose , Humanos , Secreção de Insulina , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
AIMS/HYPOTHESIS: Among the novel type 2 diabetes risk loci identified by genome-wide association studies, TCF7L2, HHEX, SLC30A8 and CDKAL1 appear to affect beta cell function. In the present study we examined the effect of these genes' risk alleles on the age-dependent decline in insulin secretion. METHODS: The SNPs rs7903146 (TCF7L2), rs7754840(CDKAL1), rs7923837 (HHEX) and rs13266634 (SLC30A8) were genotyped in 1,412 non-diabetic patients, who were subsequently grouped according to their number of risk alleles. All participants underwent an OGTT. Insulin secretion was assessed by validated indices and proinsulin conversion by calculating AUC(proinsulin)/AUC(insulin). RESULTS: The number of risk alleles revealed a Gaussian distribution, with most participants carrying four risk alleles. Stratification into groups with low (LAL, up to three alleles), median (MAL, four alleles) and high (HAL, five to eight alleles) allele load resulted in MAL and HAL participants displaying significantly lower insulin secretion and proinsulin conversion than LAL participants (p Assuntos
Envelhecimento/genética
, Diabetes Mellitus Tipo 2/genética
, Frequência do Gene
, Células Secretoras de Insulina/fisiologia
, Polimorfismo de Nucleotídeo Único
, Adulto
, Análise de Variância
, Glicemia/metabolismo
, Índice de Massa Corporal
, DNA/genética
, Diabetes Mellitus Tipo 2/epidemiologia
, Feminino
, Genoma Humano
, Genótipo
, Alemanha/epidemiologia
, Teste de Tolerância a Glucose
, Humanos
, Masculino
, Medição de Risco
RESUMO
Polymorphisms in the FTO (fat mass- and obesity-associated) gene are associated with obesity. The mechanisms how genetic variation in this gene influences body weight are unknown. Body weight is determined by energy intake/storage and energy expenditure. In this study, we investigated whether genetic variation in FTO influences energy expenditure or food intake in carefully phenotyped subjects. In 380 German subjects, insulin sensitivity was measured by a hyperinsulinemic euglycemic clamp. Lean body mass and body fat were quantified using the bioimpedance method. Indirect calorimetry was used to estimate the metabolic rate. Food intake was assessed using food diaries (mean 11+/-1 d) in 151 subjects participating in a lifestyle intervention program to prevent diabetes. All subjects were genotyped for the FTO single nucleotide polymorphism (SNP) rs8050136. The risk allele of SNP rs8050136 was associated with higher body fat-related parameters (all p< or =0.04, additive inheritance model). Energy expenditure was not affected by the SNP. However, the risk allele of rs8050136 was significantly associated with higher energy intake (p=0.01, dominant inheritance model) during dietary restriction. Our data suggest that the increased body weight in carriers of the risk allele of FTO SNP rs8050136 is a consequence of increased food intake, but not of impaired energy expenditure.