RESUMO
Understanding the physiological mechanisms by which common variants predispose to type 2 diabetes requires large studies with detailed measures of insulin secretion and sensitivity. Here we performed the largest genome-wide association study of first-phase insulin secretion, as measured by intravenous glucose tolerance tests, using up to 5,567 individuals without diabetes from 10 studies. We aimed to refine the mechanisms of 178 known associations between common variants and glycemic traits and identify new loci. Thirty type 2 diabetes or fasting glucose-raising alleles were associated with a measure of first-phase insulin secretion at P < 0.05 and provided new evidence, or the strongest evidence yet, that insulin secretion, intrinsic to the islet cells, is a key mechanism underlying the associations at the HNF1A, IGF2BP2, KCNQ1, HNF1B, VPS13C/C2CD4A, FAF1, PTPRD, AP3S2, KCNK16, MAEA, LPP, WFS1, and TMPRSS6 loci. The fasting glucose-raising allele near PDX1, a known key insulin transcription factor, was strongly associated with lower first-phase insulin secretion but has no evidence for an effect on type 2 diabetes risk. The diabetes risk allele at TCF7L2 was associated with a stronger effect on peak insulin response than on C-peptide-based insulin secretion rate, suggesting a possible additional role in hepatic insulin clearance or insulin processing. In summary, our study provides further insight into the mechanisms by which common genetic variation influences type 2 diabetes risk and glycemic traits.
Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/genética , Variação Genética/fisiologia , Insulina/genética , Proteína 2 Semelhante ao Fator 7 de Transcrição/fisiologia , Alelos , Peptídeo C/genética , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Variação Genética/genética , Estudo de Associação Genômica Ampla , Genótipo , Técnicas de Genotipagem , Teste de Tolerância a Glucose/métodos , Humanos , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Modelos Lineares , Fígado/metabolismoRESUMO
STUDY QUESTION: Is routine screening by oral glucose tolerance test (OGTT) needed for all women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Screening for glucose metabolism abnormalities of PCOS patients by an OGTT could potentially be limited to patients who present with a fasting glucose concentration between 6.1 and 7.0 mmol/l only. WHAT IS KNOWN ALREADY: Women with PCOS are at increased risk of developing diabetes. This study proposes a stepwise screening strategy for (pre)diabetes for PCOS patients based on risk stratification by fasting plasma glucose. STUDY DESIGN, SIZE, DURATION: A cross-sectional study of 226 women diagnosed with anovulatory PCOS. PARTICIPANTS AND SETTING: A consecutive series of 226 patients, diagnosed with PCOS at the University Medical Centre Utrecht, the Netherlands, were screened for glucose metabolism abnormalities by OGTT (75 g glucose load). MAIN RESULTS AND ROLE OF CHANCE: The majority of the 226 women (mean age: 29.6 ± 4.3 years; BMI: 27.3 ± 6.7 kg/m(2); 81% Caucasian) presented with a normal OGTT (169 women (75%)). Of the 57 (25%) women presenting with mild to moderate glucose abnormalities, 53 (93%) could be identified by fasting glucose concentrations only. Diabetes was diagnosed in a total of eight women (3.5%). In six women, the diagnosis was based on fasting glucose >7.0 mmol/l. The other two cases of diabetes initially presented with fasting glucose between 6.1 and 7.0 mmol/l and were diagnosed by OGTT assessment. No women diagnosed with diabetes presented with fasting glucose levels below 6.1 mmol/l. We therefore conclude that all diabetes patients could potentially be found by initial fasting glucose assessment followed by OGTT only in patients with fasting glucose between 6.1 and 7.0 mmol/l. LIMITATIONS, REASONS FOR CAUTION: Before general implementation can be advised, this screening algorithm should be validated in a prospective study of a similar or greater number of PCOS women. WIDER IMPLICATIONS OF THE FINDINGS: Our study comprised of a mostly Caucasian (81%) population, therefore generalization to other ethnic populations should be done with caution. STUDY FUNDING/COMPETING INTEREST(S): No external finance was involved in this study. B.C.J.M.F. has received fees and grant support from the following companies (in alphabetic order); Andromed, Ardana, Ferring, Genovum, Merck Serono, MSD, Organon, Pantharei Bioscience, PregLem, Schering, Schering Plough, Serono and Wyeth. A.J.G. has received fees from Abbott, Bayer Schering and IBSA. T.W.H. has received fees from Merck, Sharpe & Dohme, GlaxoSmithKline, NovoNordisk and Eli Lilly. The authors declare complete independence from funders. CLINICAL TRIAL REGISTRATION NUMBER: NCT00821379.
Assuntos
Glicemia , Síndrome do Ovário Policístico/sangue , Adulto , Estudos Transversais , Jejum , Feminino , Teste de Tolerância a Glucose , Humanos , Resistência à Insulina , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/metabolismoRESUMO
The incretin hormone glucagon-like peptide 1 (GLP-1) promotes glucose homeostasis and enhances ß-cell function. GLP-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, which inhibit the physiological inactivation of endogenous GLP-1, are used for the treatment of type 2 diabetes. Using the Metabochip, we identified three novel genetic loci with large effects (30-40%) on GLP-1-stimulated insulin secretion during hyperglycemic clamps in nondiabetic Caucasian individuals (TMEM114; CHST3 and CTRB1/2; n = 232; all P ≤ 8.8 × 10(-7)). rs7202877 near CTRB1/2, a known diabetes risk locus, also associated with an absolute 0.51 ± 0.16% (5.6 ± 1.7 mmol/mol) lower A1C response to DPP-4 inhibitor treatment in G-allele carriers, but there was no effect on GLP-1 RA treatment in type 2 diabetic patients (n = 527). Furthermore, in pancreatic tissue, we show that rs7202877 acts as expression quantitative trait locus for CTRB1 and CTRB2, encoding chymotrypsinogen, and increases fecal chymotrypsin activity in healthy carriers. Chymotrypsin is one of the most abundant digestive enzymes in the gut where it cleaves food proteins into smaller peptide fragments. Our data identify chymotrypsin in the regulation of the incretin pathway, development of diabetes, and response to DPP-4 inhibitor treatment.
Assuntos
Quimotripsina/genética , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipoglicemiantes/uso terapêutico , Incretinas/metabolismo , Receptores de Glucagon/metabolismo , Adulto , Idoso , Diabetes Mellitus , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Feminino , Genótipo , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1 , Humanos , Hipoglicemiantes/farmacocinética , Insulina/metabolismo , Masculino , Pessoa de Meia-Idade , Receptores de Glucagon/agonistas , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genéticaRESUMO
BACKGROUND: In normal platelets, insulin inhibits agonist-induced Ca(2+) mobilization by raising cyclic AMP. Platelet from patients with type 2 diabetes are resistant to insulin and show increased Ca(2+) mobilization, aggregation and procoagulant activity. We searched for the cause of this insulin resistance. DESIGN AND METHODS: Platelets, the megakaryocytic cell line CHRF-288-11 and primary megakaryocytes were incubated with adipokines and with plasma from individuals with a disturbed adipokine profile. Thrombin-induced Ca(2+) mobilization and signaling through the insulin receptor and insulin receptor substrate 1 were measured. Abnormalities induced by adipokines were compared with abnormalities found in platelets from patients with type 2 diabetes. RESULTS: Resistin, leptin, plasminogen activator inhibitor-1 and retinol binding protein 4 left platelets unchanged but induced insulin resistance in CHRF-288-11 cells. Interleukin-6, tumor necrosis factor-α and visfatin had no effect. These results were confirmed in primary megakaryocytes. Contact with adipokines for 2 hours disturbed insulin receptor substrate 1 Ser(307)-phosphorylation, while contact for 72 hours caused insulin receptor substrate 1 degradation. Plasma with a disturbed adipokine profile also made CHRF-288-11 cells insulin-resistant. Platelets from patients with type 2 diabetes showed decreased insulin receptor substrate 1 expression. CONCLUSIONS: Adipokines resistin, leptin, plasminogen activator-1 and retinol binding protein 4 disturb insulin receptor substrate 1 activity and expression in megakaryocytes. This might be a cause of the insulin resistance observed in platelets from patients with type 2 diabetes.
Assuntos
Resistência à Insulina , Leptina/metabolismo , Megacariócitos/metabolismo , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Resistina/metabolismo , Proteínas Plasmáticas de Ligação ao Retinol/metabolismo , Adipocinas/metabolismo , Plaquetas/metabolismo , Cálcio/metabolismo , Linhagem Celular , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Insulina/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Masculino , Síndrome Metabólica/metabolismoRESUMO
BACKGROUND: Genome-wide association studies in Japanese populations recently identified common variants in the KCNQ1 gene to be associated with type 2 diabetes. We examined the association of these variants within KCNQ1 with type 2 diabetes in a Dutch population, investigated their effects on insulin secretion and metabolic traits and on the risk of developing complications in type 2 diabetes patients. METHODOLOGY: The KCNQ1 variants rs151290, rs2237892, and rs2237895 were genotyped in a total of 4620 type 2 diabetes patients and 5285 healthy controls from the Netherlands. Data on macrovascular complications, nephropathy and retinopathy were available in a subset of diabetic patients. Association between genotype and insulin secretion/action was assessed in the additional sample of 335 individuals who underwent a hyperglycaemic clamp. PRINCIPAL FINDINGS: We found that all the genotyped KCNQ1 variants were significantly associated with type 2 diabetes in our Dutch population, and the association of rs151290 was the strongest (OR 1.20, 95% CI 1.07-1.35, p = 0.002). The risk C-allele of rs151290 was nominally associated with reduced first-phase glucose-stimulated insulin secretion, while the non-risk T-allele of rs2237892 was significantly correlated with increased second-phase glucose-stimulated insulin secretion (p = 0.025 and 0.0016, respectively). In addition, the risk C-allele of rs2237892 was associated with higher LDL and total cholesterol levels (p = 0.015 and 0.003, respectively). We found no evidence for an association of KCNQ1 with diabetic complications. CONCLUSIONS: Common variants in the KCNQ1 gene are associated with type 2 diabetes in a Dutch population, which can be explained at least in part by an effect on insulin secretion. Furthermore, our data suggest that KCNQ1 is also associated with lipid metabolism.
Assuntos
Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Técnica Clamp de Glucose , Hiperglicemia/metabolismo , Insulina/metabolismo , Canal de Potássio KCNQ1/genética , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Complicações do Diabetes/genética , Diabetes Mellitus Tipo 2/mortalidade , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Predisposição Genética para Doença/genética , Humanos , Secreção de Insulina , Masculino , Pessoa de Meia-IdadeRESUMO
CONTEXT: Single-nucleotide polymorphisms (SNPs) within the G6PC2 locus are associated with fasting glucose and insulin secretion. These SNPs are not associated with type 2 diabetes risk. OBJECTIVE: Our objective was to investigate whether the impact of the SNP on variables of glucose-stimulated insulin secretion is influenced by glucose tolerance status. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTION: In this cross-sectional study, we genotyped 1505 healthy Caucasian subjects [normal glucose tolerance (NGT), 1098; impaired glucose tolerance (IGT)/impaired fasting glucose (IFG), 407] for SNP rs560887 within the G6PC2 locus. A subgroup of 326 subjects underwent an iv glucose tolerance test, and 512 participants took part in a hyperinsulinemic-euglycemic clamp. For replication, SNP rs560887 was genotyped in 457 subjects (NGT, 265; IGT, 192) from four independent German and Dutch studies who underwent a hyperglycemic clamp. MAIN OUTCOME MEASURE: Insulin secretion was evaluated. RESULTS: Carriers of the major G-allele exhibited increased fasting glycemia (P<0.0001). Insulin sensitivity and secretion were not associated with the SNP (P≥0.06). Glucose tolerance status and genotype interacted on insulin secretion (P=0.036), such that in NGT subjects, the minor A-allele of rs560887 was associated with decreased insulinogenic index (P=0.044), which was not the case in subjects with IFG/IGT (P=1.0). During the iv glucose tolerance test, an association of A-allele carriers with decreased first-phase insulin secretion was also observed only in NGT subjects (P=0.0053). Likewise, in the hyperglycemic clamp group, the A-allele was associated with decreased first-phase insulin secretion only in the NGT group (P=0.022) but not in the IGT group. CONCLUSIONS: The effects of hyperglycemia on insulin secretion override the more subtle effects of genetic variation in the G6PC2 locus on insulin secretion.
Assuntos
Glicemia/metabolismo , Variação Genética , Glucose-6-Fosfatase/genética , Insulina/metabolismo , Polimorfismo de Nucleotídeo Único , Adulto , Portador Sadio , Estudos Transversais , Diabetes Mellitus Tipo 2/genética , Jejum , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Técnica Clamp de Glucose , Intolerância à Glucose/genética , Teste de Tolerância a Glucose , Humanos , Secreção de Insulina , Células Secretoras de Insulina/fisiologia , Masculino , Pessoa de Meia-IdadeRESUMO
The endocrine system is a frequent target in pathogenic autoimmune responses. Type 1 diabetes and autoimmune thyroid disease are the prevailing examples. When several diseases cluster together in one individual, the phenomenon is called autoimmune polyglandular syndrome. Progress has been made in understanding the genetic factors involved in endocrine autoimmune diseases. Studies on monogenic autoimmune diseases such as autoimmune polyglandular syndrome type 1, immunodysregulation, polyendocrinopathy, enteropathy, X-linked and primary immune deficiencies helped uncover the role of key regulators in the preservation of immune tolerance. Alleles of the major histocompatibility complex have been known to contribute to the susceptibility to most forms of autoimmunity for more than 3 decades. Furthermore, sequencing studies revealed three non-major histocompatibility complex loci and some disease specific loci, which control T lymphocyte activation or signalling. Recent genome-wide association studies (GWAS) have enabled acceleration in the identification of novel (non-HLA) loci and hence other relevant immune response pathways. Interestingly, several loci are shared between autoimmune diseases, and surprisingly some work in opposite direction. This means that the same allele which predisposes to a certain autoimmune disease can be protective in another. Well powered GWAS in type 1 diabetes has led to the uncovering of a significant number of risk variants with modest effect. These studies showed that the innate immune system may also play a role in addition to the adaptive immune system. It is anticipated that next generation sequencing techniques will uncover other (rare) variants. For other autoimmune disease (such as autoimmune thyroid disease) GWAS are clearly needed.
Assuntos
Doenças Autoimunes/genética , Doenças do Sistema Endócrino/genética , Doenças Autoimunes/imunologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Sistema Endócrino/imunologia , Doenças do Sistema Endócrino/imunologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Complexo Principal de Histocompatibilidade/genética , Poliendocrinopatias Autoimunes/genética , Poliendocrinopatias Autoimunes/imunologia , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Excessive accumulation of body fat, in particular in the visceral fat depot, is a major risk factor to develop a variety of diseases such as type 2 diabetes. The mechanisms underlying the increased risk of obese individuals to develop co-morbid diseases are largely unclear.We aimed to identify genes expressed in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) that are related to blood parameters involved in obesity co-morbidity, such as plasma lipid and glucose levels, and to compare gene expression between the fat depots. METHODS: Whole-transcriptome SAT and VAT gene expression levels were determined in 75 individuals with a BMI >35 kg/m2. Modules of co-expressed genes likely to be functionally related were identified and correlated with BMI, plasma levels of glucose, insulin, HbA1c, triglycerides, non-esterified fatty acids, ALAT, ASAT, C-reactive protein, and LDL- and HDL cholesterol. RESULTS: Of the approximately 70 modules identified in SAT and VAT, three SAT modules were inversely associated with plasma HDL-cholesterol levels, and a fourth module was inversely associated with both plasma glucose and plasma triglyceride levels (p < 5.33 x 10(-5)). These modules were markedly enriched in immune and metabolic genes. In VAT, one module was associated with both BMI and insulin, and another with plasma glucose (p < 4.64 x 10(-5)). This module was also enriched in inflammatory genes and showed a marked overlap in gene content with the SAT modules related to HDL. Several genes differentially expressed in SAT and VAT were identified. CONCLUSIONS: In obese subjects, groups of co-expressed genes were identified that correlated with lipid and glucose metabolism parameters; they were enriched with immune genes. A number of genes were identified of which the expression in SAT correlated with plasma HDL cholesterol, while their expression in VAT correlated with plasma glucose. This underlines both the singular importance of these genes for lipid and glucose metabolism and the specific roles of these two fat depots in this respect.
Assuntos
Glicemia/análise , HDL-Colesterol/sangue , Gordura Intra-Abdominal/metabolismo , Obesidade/genética , Gordura Subcutânea/metabolismo , Adolescente , Adulto , Idoso , Índice de Massa Corporal , Feminino , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Insulina/metabolismo , Metabolismo dos Lipídeos/genética , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , Obesidade/imunologia , Obesidade/metabolismo , Triglicerídeos/sangueRESUMO
OBJECTIVE: Patients with type 2 diabetes have an increased risk of cardiovascular disease and show abnormalities in the coagulation cascade. We investigated whether increased synthesis of tissue factor (TF) by platelets could contribute to the hypercoagulant state. RESEARCH DESIGN AND METHODS: Platelets from type 2 diabetic patients and matched control subjects were adhered to different surface-coated proteins, and TF premRNA splicing, TF protein, and TF procoagulant activity were measured. RESULTS: Different adhesive proteins induced different levels of TF synthesis. A mimetic of active clopidogrel metabolite (AR-C69931 MX) reduced TF synthesis by 56 +/- 10%, an aspirin-like inhibitor (indomethacin) by 82 +/- 9%, and the combination by 96 +/- 2%, indicating that ADP release and thromboxane A(2) production followed by activation of P2Y12 and thromboxane receptors mediate surface-induced TF synthesis. Interference with intracellular pathways revealed inhibition by agents that raise cAMP and interfere with phosphatidylinositol 3-kinase/protein kinase B. Insulin is known to raise cAMP in platelets and inhibited collagen III-induced TF premRNA splicing and reduced TF activity by 35 +/- 5 and 47 +/- 5% at 1 and 100 nmol/l. Inhibition by insulin was reduced in type 2 diabetes platelets resulting in an approximately 1.6-fold higher TF synthesis than in matched control subjects. CONCLUSIONS: We characterized the extra- and intracellular mechanisms that couple surface activation to TF synthesis in adhering platelets. In healthy individuals, TF synthesis is inhibited by insulin, but in patients with type 2 diabetes inhibition is impaired. This leads to the novel finding that platelets from type 2 diabetic patients produce more TF than platelets from matched control subjects.
Assuntos
Plaquetas/fisiologia , Diabetes Mellitus Tipo 2/sangue , Insulina/farmacologia , Tromboplastina/biossíntese , Fosfatase Alcalina/metabolismo , Coagulação Sanguínea/efeitos dos fármacos , Pressão Sanguínea , Diabetes Mellitus Tipo 2/fisiopatologia , Fator X/efeitos dos fármacos , Fator X/metabolismo , Hemoglobinas Glicadas/metabolismo , Humanos , Insulina/genética , Pessoa de Meia-Idade , Ativação Plaquetária , Agregação Plaquetária/efeitos dos fármacos , Precursores de RNA/genética , Splicing de RNA , Proteínas Recombinantes/farmacologia , Tromboplastina/efeitos dos fármacos , Tromboplastina/genéticaRESUMO
OBJECTIVE: Recently, results from a meta-analysis of genome-wide association studies have yielded a number of novel type 2 diabetes loci. However, conflicting results have been published regarding their effects on insulin secretion and insulin sensitivity. In this study we used hyperglycemic clamps with three different stimuli to test associations between these novel loci and various measures of beta-cell function. RESEARCH DESIGN AND METHODS: For this study, 336 participants, 180 normal glucose tolerant and 156 impaired glucose tolerant, underwent a 2-h hyperglycemic clamp. In a subset we also assessed the response to glucagon-like peptide (GLP)-1 and arginine during an extended clamp (n = 123). All subjects were genotyped for gene variants in JAZF1, CDC123/CAMK1D, TSPAN8/LGR5, THADA, ADAMTS9, NOTCH2/ADAMS30, DCD, VEGFA, BCL11A, HNF1B, WFS1, and MTNR1B. RESULTS: Gene variants in CDC123/CAMK1D, ADAMTS9, BCL11A, and MTNR1B affected various aspects of the insulin response to glucose (all P < 6.9 x 10(-3)). The THADA gene variant was associated with lower beta-cell response to GLP-1 and arginine (both P < 1.6 x 10(-3)), suggesting lower beta-cell mass as a possible pathogenic mechanism. Remarkably, we also noted a trend toward an increased insulin response to GLP-1 in carriers of MTNR1B (P = 0.03), which may offer new therapeutic possibilities. The other seven loci were not detectably associated with beta-cell function. CONCLUSIONS: Diabetes risk alleles in CDC123/CAMK1D, THADA, ADAMTS9, BCL11A, and MTNR1B are associated with various specific aspects of beta-cell function. These findings point to a clear diversity in the impact that these various gene variants may have on (dys)function of pancreatic beta-cells.
Assuntos
Proteínas ADAM/genética , Proteína Quinase Tipo 1 Dependente de Cálcio-Calmodulina/genética , Proteínas de Transporte/genética , Proteínas de Ciclo Celular/genética , Mapeamento Cromossômico , Diabetes Mellitus Tipo 2/genética , Variação Genética , Células Secretoras de Insulina/fisiologia , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Proteína ADAMTS9 , Adulto , Idoso , Portador Sadio , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Técnica Clamp de Glucose , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Repressoras , Medição de RiscoRESUMO
OBJECTIVE: At least 20 type 2 diabetes loci have now been identified, and several of these are associated with altered beta-cell function. In this study, we have investigated the combined effects of eight known beta-cell loci on insulin secretion stimulated by three different secretagogues during hyperglycemic clamps. RESEARCH DESIGN AND METHODS: A total of 447 subjects originating from four independent studies in the Netherlands and Germany (256 with normal glucose tolerance [NGT]/191 with impaired glucose tolerance [IGT]) underwent a hyperglycemic clamp. A subset had an extended clamp with additional glucagon-like peptide (GLP)-1 and arginine (n = 224). We next genotyped single nucleotide polymorphisms in TCF7L2, KCNJ11, CDKAL1, IGF2BP2, HHEX/IDE, CDKN2A/B, SLC30A8, and MTNR1B and calculated a risk allele score by risk allele counting. RESULTS: The risk allele score was associated with lower first-phase glucose-stimulated insulin secretion (GSIS) (P = 7.1 x 10(-6)). The effect size was equal in subjects with NGT and IGT. We also noted an inverse correlation with the disposition index (P = 1.6 x 10(-3)). When we stratified the study population according to the number of risk alleles into three groups, those with a medium- or high-risk allele score had 9 and 23% lower first-phase GSIS. Second-phase GSIS, insulin sensitivity index and GLP-1, or arginine-stimulated insulin release were not significantly different. CONCLUSIONS: A combined risk allele score for eight known beta-cell genes is associated with the rapid first-phase GSIS and the disposition index. The slower second-phase GSIS, GLP-1, and arginine-stimulated insulin secretion are not associated, suggesting that especially processes involved in rapid granule recruitment and exocytosis are affected in the majority of risk loci.
Assuntos
Diabetes Mellitus Tipo 2/genética , Glucose/farmacologia , Insulina/metabolismo , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Alelos , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Genótipo , Alemanha/epidemiologia , Técnica Clamp de Glucose , Intolerância à Glucose/epidemiologia , Intolerância à Glucose/genética , Humanos , Hiperglicemia/sangue , Hiperglicemia/induzido quimicamente , Secreção de Insulina , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Valores de Referência , Medição de Risco , Fatores de RiscoRESUMO
Diabetes mellitus type 2 (DM2) is the most prevalent form of diabetes, and is caused by a combination of genetic and non-genetic factors. Genome-wide association studies have led to the identification of 20 genetic risk factors for DM2, for which the actual causal mutations are not yet known. Nevertheless, some of the genes connected with diabetes suggest that the pancreatic beta cell plays a central role in the development of the disease. In the meantime, detailed knowledge of the genetics of some specific forms of diabetes has already lead to changes in pharmacological therapy; patients could be put on sulfonylurea derivatives and no longer need insulin. This is the case, in particular, for 'maturity-onset diabetes of the young' (MODY) and for permanent neonatal diabetes mellitus (PNDM). It is not yet possible to predict whether genetic research into regular DM2 will lead to changes in therapy.
Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença/genética , Diabetes Mellitus Tipo 2/prevenção & controle , Humanos , Mutação , Prognóstico , Fatores de Risco , Fatores de Transcrição/genéticaRESUMO
To assess whether an increased genetic predisposition for type 2 diabetes mellitus (T2DM) influences the contributions of insulin resistance and impaired insulin secretion to impaired glucose tolerance (IGT), 437 subjects not known to have T2DM underwent an oral glucose tolerance test and a 3-hour hyperglycemic clamp. Plasma insulin responses and insulin sensitivity were compared between all subjects (unselected for demographic or anthropometric characteristics) who had normal glucose homeostasis and no first-degree T2DM relative (n = 133), IGT with a first-degree T2DM relative (IGT/FH+, n = 74), or IGT without a first-degree T2DM relative (IGT/FH-, n = 50). Compared with those with normal glucose homeostasis, first- and second-phase plasma insulin responses were reduced approximately 45% and 30%, respectively (both P < .001), in IGT/FH+, whereas insulin sensitivity was only approximately 20% reduced (P = .011). In contrast, in IGT/FH-, first-phase plasma insulin responses were only approximately 20% reduced (P = .016), second-phase plasma insulin responses were not reduced, but insulin sensitivity was approximately 40% reduced (P < .001). The IGT/FH+ group differed significantly from the IGT/FH- group by having 25% to 30% lower first-phase plasma insulin responses (P = .026) and 25% to 30% greater insulin sensitivity (P = .027). Adjustment for obesity abolished the differences in insulin resistance but not plasma insulin responses. However, when the IGT groups were stratified into subgroups based on body mass index (BMI), first-phase plasma insulin responses were approximately 30% lower in IGT/FH+ with a BMI of at least 27 kg/m(2) (P = .018) but similar in IGT/FH+ with a BMI less than 27 kg/m(2) compared with the corresponding IGT/FH- subgroups. We conclude that, in IGT, an increased genetic predisposition for T2DM increases the contribution of impaired insulin secretion to its pathophysiology. This effect is enhanced by obesity.
Assuntos
Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Intolerância à Glucose/genética , Intolerância à Glucose/metabolismo , Resistência à Insulina/fisiologia , Adolescente , Adulto , Idoso , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Predisposição Genética para Doença , Técnica Clamp de Glucose , Intolerância à Glucose/sangue , Teste de Tolerância a Glucose , Humanos , Insulina/sangue , Pessoa de Meia-Idade , Adulto JovemRESUMO
Mitochondria play an important role in many processes, like glucose metabolism, fatty acid oxidation and ATP synthesis. In this study, we aimed to identify association of common polymorphisms in nuclear-encoded genes involved in mitochondrial protein synthesis and biogenesis with type II diabetes mellitus (T2DM) using a two-stage design. In the first stage, we analyzed 62 tagging single nucleotide polymorphisms (SNPs) in the Hoorn study (n=999 participants) covering all common variation in 13 biological candidate genes. These 13 candidate genes were selected from four clusters regarded essential for correct mitochondrial protein synthesis and biogenesis: aminoacyl tRNA synthetases, translation initiation factors, tRNA modifying enzymes and mitochondrial DNA transcription and replication. SNPs showing evidence for association with T2DM were measured in second stage genotyping (n=10164 participants). After a meta-analysis, only one SNP in SIRT4 (rs2522138) remained significant (P=0.01). Extending the second stage with samples from the Danish Steno Study (n=1220 participants) resulted in a common odds ratio (OR) of 0.92 (0.85-1.00), P=0.06. Moreover, in a large meta-analysis of three genome-wide association studies, this SNP was also not associated with T2DM (P=0.72). In conclusion, we did not find evidence for association of common variants in 13 nuclear-encoded mitochondrial proteins with T2DM.
Assuntos
Núcleo Celular/genética , Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla , Mitocôndrias/metabolismo , Biossíntese de Proteínas/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Estudos de Coortes , Dinamarca , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
The classical perception of adipose tissue as a storage place of fatty acids has been replaced over the last years by the notion that adipose tissue has a central role in lipid and glucose metabolism and produces a large number of hormones and cytokines, e.g. tumour necrosis factor-alpha, interleukin-6, adiponectin, leptin, and plasminogen activator inhibitor-1. The increased prevalence of excessive visceral obesity and obesity-related cardiovascular risk factors is closely associated with the rising incidence of cardiovascular diseases and type 2 diabetes mellitus. This clustering of vascular risk factors in (visceral) obesity is often referred to as metabolic syndrome. The close relationship between an increased quantity of visceral fat, metabolic disturbances, including low-grade inflammation, and cardiovascular diseases and the unique anatomical relation to the hepatic portal circulation has led to an intense endeavour to unravel the specific endocrine functions of this visceral fat depot. The objective of this paper is to describe adipose tissue dysfunction, delineate the relation between adipose tissue dysfunction and obesity and to describe how adipose tissue dysfunction is involved in the development of diabetes mellitus type 2 and atherosclerotic vascular diseases. First, normal physiology of adipocytes and adipose tissue will be described.
Assuntos
Tecido Adiposo , Aterosclerose/etiologia , Diabetes Mellitus Tipo 2/etiologia , Angiopatias Diabéticas/etiologia , Síndrome Metabólica/etiologia , Obesidade/complicações , Adipócitos/fisiologia , Tecido Adiposo/fisiologia , Aterosclerose/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Metabolismo Energético/fisiologia , Feminino , Humanos , Gordura Intra-Abdominal/fisiologia , Leptina/metabolismo , Masculino , Síndrome Metabólica/metabolismo , Obesidade/fisiopatologia , Comportamento de Redução do Risco , Gordura Subcutânea Abdominal/fisiologia , Fatores de TranscriçãoAssuntos
Diabetes Mellitus Tipo 2/genética , Hipoglicemiantes/uso terapêutico , Receptores de Glucagon/agonistas , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/etiologia , Receptor do Peptídeo Semelhante ao Glucagon 1 , Humanos , Hipoglicemiantes/efeitos adversosRESUMO
Recently, the hematopoietically expressed homeobox (HHEX) gene, encoding a transcription factor, was identified in a large genome-wide scan in French individuals as a type 2 diabetes (T2D)-susceptibility locus. We aimed to check whether this finding could be replicated in a Dutch T2D cohort. Two common variants (rs7923837 and rs1111875) located near the HHEX gene were genotyped in 501 unrelated T2D patients and in 920 healthy controls. The major alleles of both variants were overrepresented in T2D cases compared with controls (66.7 vs 64.1%, P=0.16 for rs7923837 and 64.6 vs 60.4%, P=0.027 for rs1111875). For both polymorphisms, the risk for T2D was significantly increased in carriers of the major alleles (rs7923837: odds ratio (OR): 1.57, 95% confidence interval (CI): 1.08-2.27, P=0.017 and rs1111875: OR: 1.68, 95% CI: 1.19-2.35, P=0.003). The haplotype analysis did not reveal a risk haplotype that provided stronger evidence for association with T2D than each variant individually. Assuming a dominant genetic model, the population-attributable risks for diabetes due to the at-risk alleles of rs7923837 and rs1111875 were estimated to be 33 and 36%, respectively. These data provide evidence that variants near the HHEX gene contribute to the risk of T2D in a Dutch population.
Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Proteínas de Homeodomínio/genética , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Genes Dominantes , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Países BaixosRESUMO
OBJECTIVE: To examine the effect of aging on insulin secretion (first- and second-phase insulin release) and insulin sensitivity in people with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS: First- and second-phase insulin secretion and insulin sensitivity were assessed in hyperglycemic clamp experiments in 266 individuals with NGT and 130 individuals with IGT, ranging in age from approximately 20 to approximately 70 years. Changes in beta-cell function were compared using the disposition index to adjust for differences in insulin sensitivity. RESULTS: As expected, both phases of insulin release and insulin sensitivity were reduced in individuals with IGT (all P < 0.01). Insulin sensitivity was not independently correlated with age in either group. In people with NGT, the disposition index for first- and second-phase insulin release decreased similarly at a rate of approximately 0.7% per year. In people with IGT, the disposition indexes for first- and second-phase insulin release decreased at greater rates ( approximately 2.2 and 1.4% per year, P = 0.002 and 0.009, respectively, vs. NGT), with the decrease in first phase being greater than that of second phase (P = 0.025). CONCLUSIONS: Insulin secretion (both first and second phase) normally decreases at a rate of approximately 0.7% per year with aging; this decrease in beta-cell function is accelerated about two-fold in people with impaired glucose tolerance-first phase to a greater extent than second phase. Finally, aging per se has no effect on insulin sensitivity independent of changes in body composition.
Assuntos
Envelhecimento , Glicemia/metabolismo , Intolerância à Glucose/sangue , Células Secretoras de Insulina/metabolismo , Adulto , Idoso , Índice de Massa Corporal , Feminino , Intolerância à Glucose/metabolismo , Intolerância à Glucose/fisiopatologia , Homeostase/fisiologia , Humanos , Insulina/sangue , Células Secretoras de Insulina/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: In recent years, there has been an ongoing discussion on the relationship between diabetes and driving. As driving performance will inevitably decline at lower levels of glycemia, patients' decisions concerning driving or taking corrective action when hypoglycemia occurs immediately before or during driving seems paramount. RESEARCH DESIGN AND METHODS: Twenty-four type 1 diabetic patients with normal awareness of hypoglycemia (T1Norm group), 21 type 1 diabetic patients with impaired awareness of hypoglycemia (T1Imp group), and 20 type 2 diabetic patients with normal awareness of hypoglycemia (T2 group) were studied. They were asked whether they felt hypoglycemic and whether they would currently drive during experimental euglycemia (5.0 mmol/l) and hypoglycemia (2.7 mmol/l). RESULTS: In the T1Norm group, 1 patient (4.2%) decided to drive during hypoglycemia. In the T1Imp group, 9 patients (42.9%) said they would drive in the hypoglycemic condition. In the T2 group, 5 patients (25%) would drive. This was more frequently the case for patients on oral hypoglycemic agents (chi2 = 4.44; P = 0.04). No effect of sex (chi2 = 0.78; P = 0.38) or age (chi2 = 0.22; P = 0.64) was noted. CONCLUSIONS: Patients with type 1 diabetes and impaired awareness of hypoglycemia frequently decided to drive while hypoglycemic, whereas patients with type 1 diabetes and normal awareness of hypoglycemia appeared to make safe decisions concerning hypoglycemia and driving. Strikingly, patients with type 2 diabetes and normal hypoglycemia awareness frequently made potentially dangerous decisions as well, particularly when using oral hypoglycemic agents. Therefore, early, clear, and consistent education is imperative.