RESUMO
AIM: To examine the hypothesis that, based on their glucose curves during a seven-point oral glucose tolerance test, people at elevated type 2 diabetes risk can be divided into subgroups with different clinical profiles at baseline and different degrees of subsequent glycaemic deterioration. METHODS: We included 2126 participants at elevated type 2 diabetes risk from the Diabetes Research on Patient Stratification (IMI-DIRECT) study. Latent class trajectory analysis was used to identify subgroups from a seven-point oral glucose tolerance test at baseline and follow-up. Linear models quantified the associations between the subgroups with glycaemic traits at baseline and 18 months. RESULTS: At baseline, we identified four glucose curve subgroups, labelled in order of increasing peak levels as 1-4. Participants in Subgroups 2-4, were more likely to have higher insulin resistance (homeostatic model assessment) and a lower Matsuda index, than those in Subgroup 1. Overall, participants in Subgroups 3 and 4, had higher glycaemic trait values, with the exception of the Matsuda and insulinogenic indices. At 18 months, change in homeostatic model assessment of insulin resistance was higher in Subgroup 4 (ß = 0.36, 95% CI 0.13-0.58), Subgroup 3 (ß = 0.30; 95% CI 0.10-0.50) and Subgroup 2 (ß = 0.18; 95% CI 0.04-0.32), compared to Subgroup 1. The same was observed for C-peptide and insulin. Five subgroups were identified at follow-up, and the majority of participants remained in the same subgroup or progressed to higher peak subgroups after 18 months. CONCLUSIONS: Using data from a frequently sampled oral glucose tolerance test, glucose curve patterns associated with different clinical characteristics and different rates of subsequent glycaemic deterioration can be identified.
Assuntos
Glicemia/metabolismo , Peptídeo C/metabolismo , Diabetes Mellitus Tipo 2/epidemiologia , Intolerância à Glucose/metabolismo , Resistência à Insulina , Secreção de Insulina , Insulina/metabolismo , Idoso , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Intolerância à Glucose/classificação , Teste de Tolerância a Glucose , Humanos , Análise de Classes Latentes , Masculino , Pessoa de Meia-Idade , Medição de RiscoRESUMO
AIMS: Increased visit-to-visit glycaemic variability is independently associated with adverse outcomes in Type 2 diabetes. Our aim was to identify the patient characteristics associated with raised visit-to-visit glycaemic variability in people with Type 2 diabetes. METHODS: A case-control study was conducted to establish associations between HbA1c variability and clinical covariates in 10 130 people with Type 2 diabetes. Variability was calculated by two metrics [sd and coefficient of variation (CV)] from a minimum of four HbA1c readings obtained over a 4-year period. High and low variability groups were defined as the top and bottom tertile of the sd or CV, and used in logistic regression analyses including a number of clinical and biochemical covariates. The analyses were stratified into low mean (< 53 mmol/mol; 7%) and high mean (≥ 53 mmol/mol; 7%) HbA1c groups. RESULTS: Findings were consistent across both HbA1c groups and variability metrics. Treatment, independent of other factors, was the most strongly associated covariate for the risk of high HbA1c variability. A six-fold increased risk was observed in the low HbA1c group, between the most and least intense treatment regimens (P < 0.001). Similar findings were present in the high HbA1c group with a three-fold increase in risk (P < 0.001). In addition, male gender, younger age, reduced HDL-cholesterol and increased BMI were all found to be independently associated with raised visit-to-visit glycaemic variability. CONCLUSIONS: Intensive treatment resulting in low mean HbA1c was associated with marked increase in HbA1c variability. Irrespective of diabetes control, the greatest visit-to-visit variability was observed in young, insulin resistant men.
Assuntos
Diabetes Mellitus Tipo 2/sangue , Hemoglobinas Glicadas/metabolismo , Idoso , Análise de Variância , Estudos de Casos e Controles , Feminino , Humanos , Resistência à Insulina/fisiologia , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
Therapeutic response to metformin, a first-line drug for type 2 diabetes (T2D), is highly variable, in part likely due to genetic factors. To date, metformin pharmacogenetic studies have mainly focused on the impact of variants in metformin transporter genes, with inconsistent results. To clarify the significance of these variants in glycemic response to metformin in T2D, we performed a large-scale meta-analysis across the cohorts of the Metformin Genetics Consortium (MetGen). Nine candidate polymorphisms in five transporter genes (organic cation transporter [OCT]1, OCT2, multidrug and toxin extrusion transporter [MATE]1, MATE2-K, and OCTN1) were analyzed in up to 7,968 individuals. None of the variants showed a significant effect on metformin response in the primary analysis, or in the exploratory secondary analyses, when patients were stratified according to possible confounding genotypes or prescribed a daily dose of metformin. Our results suggest that candidate transporter gene variants have little contribution to variability in glycemic response to metformin in T2D.
Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Proteínas de Membrana Transportadoras/genética , Metformina/uso terapêutico , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Glicemia/metabolismo , Bases de Dados Factuais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Feminino , Genótipo , Hemoglobinas Glicadas/metabolismo , Humanos , Masculino , Proteínas de Membrana Transportadoras/metabolismo , Pessoa de Meia-Idade , Fator 1 de Transcrição de Octâmero/genética , Fator 1 de Transcrição de Octâmero/metabolismo , Proteínas de Transporte de Cátions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Transportador 2 de Cátion Orgânico , Fenótipo , Simportadores , Resultado do TratamentoRESUMO
Personalized medicine, otherwise called stratified or precision medicine, aims to better target intervention to the individual to maximize benefit and minimize harm. This review discusses how diabetes aetiology, pathophysiology and patient genotype influence response to or side effects of the commonly used diabetes treatments. C-peptide is a useful biomarker that is underused to guide treatment choice, severe insulin deficiency predicts non-response to glucagon-like peptide-1 receptor agonists, and thiazolidinediones are more effective in insulin-resistant patients. The field of pharmacogenetics is now yielding clinically important results, with three examples outlined: sulphonylurea sensitivity in patients with HNF1A maturity-onset diabetes of the young; sulphonylurea sensitivity in patients with Type 2 diabetes with reduced function alleles at CYP2C9, resulting in reduced metabolism of sulphonylureas; and severe metformin intolerance associated with reduced function organic cation transporter 1 (OCT1) variants, exacerbated by drugs that also inhibit OCT1. Genome-wide approaches and the potential of other 'omics', including metagenomics and metabolomics, are then outlined, highlighting the complex interacting networks that we need to understand before we can truly personalize diabetes treatments.
Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Medicina de Precisão/métodos , Biomarcadores/metabolismo , Citocromo P-450 CYP2C9/genética , Estudo de Associação Genômica Ampla , Genômica/métodos , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacologia , Insulina/deficiência , Metabolômica/métodos , Transportador 1 de Cátions Orgânicos/antagonistas & inibidoresRESUMO
BACKGROUND: A syndrome of young-onset diabetes mellitus associated with microcephaly, epilepsy and intellectual disability caused by mutations in the tRNA methyltransferase 10 homologue A (TRMT10A) gene has recently been described. CASE REPORT: We report two siblings from the fourth family reported to have diabetes mellitus as a result of a TRMT10A mutation. A homozygous nonsense mutation p.Glu27Ter in TRMT10A was identified using targeted next-generation sequencing and confirmed by PCR/Sanger sequencing. Diabetes was diagnosed while the subjects were in their 20s and was characterized by insulin resistance. Epilepsy and intellectual disability were features in common. Mild microcephaly was present at birth but their final head circumferences were normal. CONCLUSION: Our report provides independent confirmation of the role of TRMT10A mutations in this syndrome and expands its phenotypic description. TRMT10A sequencing should be considered in children or adults with young-onset diabetes who have a history of intellectual disability, microcephaly and epilepsy. This report also shows the advantages of using a targeted panel to identify previously unsuspected monogenic diabetes among young-onset non-insulin-dependent diabetes in the absence of obesity and autoimmunity.
Assuntos
Diabetes Mellitus Tipo 2/genética , Epilepsia/genética , Deficiência Intelectual/genética , Metiltransferases/genética , Microcefalia/genética , Adulto , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Epilepsia/complicações , Feminino , Humanos , Resistência à Insulina , Deficiência Intelectual/complicações , Masculino , Microcefalia/complicações , Mutação , Linhagem , Irmãos , Adulto JovemRESUMO
AIM: To investigate glucose and insulin metabolism in participants with ataxia telangiectasia in the absence of a diagnosis of diabetes. METHODS: A standard oral glucose tolerance test was performed in participants with ataxia telangiectasia (n = 10) and in a control cohort (n = 10). Serial glucose and insulin measurements were taken to permit cohort comparisons of glucose-insulin homeostasis and indices of insulin secretion and sensitivity. RESULTS: During the oral glucose tolerance test, the 2-h glucose (6.75 vs 4.93 mmol/l; P = 0.029), insulin concentrations (285.6 vs 148.5 pmol/l; P = 0.043), incremental area under the curve for glucose (314 vs 161 mmol/l/min; P = 0.036) and incremental area under the curve for insulin (37,720 vs 18,080 pmol/l/min; P = 0.03) were higher in participants with ataxia telangiectasia than in the controls. There were no significant differences between groups in fasting glucose, insulin concentrations or insulinogenic index measurement (0.94 vs 0.95; P = 0.95). The Matsuda index, reflecting whole-body insulin sensitivity, was lower in participants with ataxia telangiectasia (5.96 vs 11.03; P = 0.019) than in control subjects. CONCLUSIONS: Mutations in Ataxia Telangiectasia Mutated (ATM) that cause ataxia telangiectasia are associated with elevated glycaemia and low insulin sensitivity in participants without diabetes. This indicates a role of ATM in glucose and insulin metabolic pathways.
Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Genes Recessivos , Transtornos do Metabolismo de Glucose/genética , Resistência à Insulina/genética , Metformina/uso terapêutico , Adulto , Biomarcadores Farmacológicos , Glicemia/genética , Estudos de Casos e Controles , Feminino , Genes Neoplásicos , Loci Gênicos/efeitos dos fármacos , Teste de Tolerância a Glucose , Humanos , Masculino , Redes e Vias Metabólicas/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
AIMS: Metformin is the most widely used oral anti-diabetes agent and has considerable benefits over other therapies, yet 20-30% of people develop gastrointestinal side effects, and 5% are unable to tolerate metformin due to the severity of these side effects. The mechanism for gastrointestinal side effects and their considerable inter-individual variability is unclear. We have recently shown the association between organic cation transporter 1 (OCT1) variants and severe intolerance to metformin in people with Type 2 diabetes. The aim of this study was to explore the association of OCT1 reduced-function polymorphisms with common metformin-induced gastrointestinal side effects in Type 2 diabetes. METHODS: This prospective observational cohort study included 92 patients with newly diagnosed Type 2 diabetes, incident users of metformin. Patients were genotyped for two common loss-of-function variants in the OCT1 gene (SLC22A1): R61C (rs12208357) and M420del (rs72552763). The association of OCT1 reduced-function alleles with gastrointestinal side effects was analysed using logistic regression. RESULTS: Forty-three patients (47%) experienced gastrointestinal adverse effects in the first 6 months of metformin treatment. Interestingly, the number of OCT1 reduced-function alleles was significantly associated with over two-fold higher odds of the common metformin-induced gastrointestinal side effects (odds ratio = 2.31, 95% confidence interval 1.07-5.01, P = 0.034). CONCLUSIONS: In conclusion, we showed for the first time the association between OCT1 variants and common metformin-induced gastrointestinal side effects. These results confirm recent findings related to the role of OCT1 in severe metformin intolerance, and suggest that high inter-individual variability in mild/moderate and severe gastrointestinal intolerance share a common underlying mechanism. These data could contribute to more personalized and safer metformin treatment.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Gastroenterite/induzido quimicamente , Predisposição Genética para Doença , Hipoglicemiantes/efeitos adversos , Metformina/efeitos adversos , Transportador 1 de Cátions Orgânicos/genética , Polimorfismo Genético , Idoso , Alelos , Substituição de Aminoácidos , Bósnia e Herzegóvina , Estudos de Coortes , Feminino , Gastroenterite/genética , Gastroenterite/metabolismo , Gastroenterite/fisiopatologia , Deleção de Genes , Estudos de Associação Genética , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Transportador 1 de Cátions Orgânicos/metabolismo , Estudos Prospectivos , Índice de Gravidade de Doença , Caracteres SexuaisAssuntos
Diabetes Gestacional/fisiopatologia , Retinopatia Diabética/diagnóstico , Gravidez em Diabéticas/fisiopatologia , Adulto , Glicemia/análise , Estudos de Coortes , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Gestacional/sangue , Retinopatia Diabética/epidemiologia , Retinopatia Diabética/etiologia , Feminino , Humanos , Programas de Rastreamento , Gravidez , Gravidez em Diabéticas/sangue , Diagnóstico Pré-Natal , Escócia/epidemiologiaRESUMO
There is an increase in type 2 diabetes (T2D) in children, yet little evidence to guide management. The TODAY study aimed to assess the impact of three treatment interventions in this demographic group.1 In this study 927 children were converted from their current medication to metformin monotherapy. This run-in phase proceeded to randomisation if an HbA1c <8% (64 millimoles per mole [mmol/mol]) was achieved with adherence to medication >80% for at least six weeks. The randomisation cohort consisted of 699 children, aged between 10 and 17 years with T2D diagnosed within the past two years and a body mass index (BMI) >85th percentile. The ethnicity split was 41% Hispanic, 31.5% non-Hispanic Black, and 20% non-Hispanic White. The children were randomly assigned to stay on metformin alone, to have rosiglitazone added to their regime, or to continue on metformin and undergo a family based behavioural weight loss programme. This consisted of weekly visits for the first six months, then biweekly for six months, then bimonthly for the remainder of the study. The primary endpoint was either an HbA1c >8% for more than six months, or sustained insulin treatment for more than three months. Treatment failure was observed in 45.6% of children; 50% by 11.5 months after randomisation. Treatment failure was seen less in those with rosiglitazone added (38.6%) compared to those who stayed on metformin alone (51.7%, p=0.006). Intensive lifestyle intervention had an intermediate result (46.6% failure) but this did not differ significantly from those taking metformin alone. The authors conclude that whatever the intervention, progression of diabetes is rapid in this age group and that multiple oral treatments or insulin will be required within a few years for the majority of this group.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Tiazolidinedionas/uso terapêutico , Feminino , Humanos , MasculinoRESUMO
AIMS: To systematically review the evidence for the effect of vitamin D supplementation on glycaemia, insulin resistance, progression to diabetes and complications of diabetes. METHODS: Systematic review and meta-analysis. We searched databases including MEDLINE, EMBASE and the Cochrane Library for randomized controlled trials comparing vitamin D or analogues with placebo. We extracted data on fasting glucose, glycaemic control, insulin resistance, insulin/C-peptide levels, micro- and macrovascular outcomes and progression from non-diabetes to diabetes. Studies were assessed independently by two reviewers according to a pre-specified protocol. RESULTS: Fifteen trials were included in the systematic review. Trial reporting was of moderate, variable quality. Combining all studies, no significant improvement was seen in fasting glucose, HbA(1c) or insulin resistance in those treated with vitamin D compared with placebo. For patients with diabetes or impaired glucose tolerance, meta-analysis showed a small effect on fasting glucose (-0.32 mmol/l, 95%CI -0.57 to -0.07) and a small improvement in insulin resistance (standard mean difference -0.25, 95%CI -0.48 to -0.03). No effect was seen on glycated haemoglobin in patients with diabetes and no differences were seen for any outcome in patients with normal fasting glucose. Insufficient data were available to draw conclusions regarding micro- or macrovascular events; two trials failed to show a reduction in new cases of diabetes in patients treated with vitamin D. CONCLUSIONS: There is currently insufficient evidence of beneficial effect to recommend vitamin D supplementation as a means of improving glycaemia or insulin resistance in patients with diabetes, normal fasting glucose or impaired glucose tolerance.
Assuntos
Glicemia/metabolismo , Suplementos Nutricionais , Resistência à Insulina/fisiologia , Deficiência de Vitamina D/tratamento farmacológico , Vitamina D/administração & dosagem , Vitaminas/administração & dosagem , Adulto , Idoso , Glicemia/efeitos dos fármacos , Complicações do Diabetes/sangue , Complicações do Diabetes/prevenção & controle , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/prevenção & controle , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/prevenção & controle , Jejum/sangue , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Vitamina D/análogos & derivados , Vitamina D/sangueRESUMO
AIMS/HYPOTHESIS: In this study we aimed to replicate the previously reported association between the glycaemic response to metformin and the SNP rs11212617 at a locus that includes the ataxia telangiectasia mutated (ATM) gene in multiple additional populations. METHODS: Incident users of metformin selected from the Diabetes Care System West-Friesland (DCS, n = 929) and the Rotterdam Study (n = 182) from the Netherlands, and the CARDS Trial (n = 254) from the UK were genotyped for rs11212617 and tested for an association with both HbA(1c) reduction and treatment success, defined as the ability to reach the treatment target of an HbA(1c) ≤ 7 % (53 mmol/mol). Finally, a meta-analysis including data from literature was performed. RESULTS: In the DCS cohort, we observed an association between rs11212617 genotype and treatment success on metformin (OR 1.27, 95% CI 1.03, 1.58, p = 0.028); in the smaller Rotterdam Study cohort, a numerically similar but non-significant trend was observed (OR 1.45, 95% CI 0.87, 2.39, p = 0.15); while in the CARDS cohort there was no significant association. In meta-analyses of these three cohorts separately or combined with the previously published cohorts, rs11212617 genotype is associated with metformin treatment success (OR 1.24, 95% CI 1.04, 1.49, p = 0.016 and OR 1.25, 95% CI 1.33, 1.38, p = 7.8 × 10(-6), respectively). CONCLUSIONS/INTERPRETATION: A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetic patients from the Netherlands and the UK. This is the first robustly replicated common susceptibility locus found to be associated with metformin treatment response.
Assuntos
Replicação do DNA/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Polimorfismo de Nucleotídeo Único , Idoso , Estudos de Coortes , Replicação do DNA/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Relação Dose-Resposta a Droga , Feminino , Estudo de Associação Genômica Ampla , Hemoglobinas Glicadas/metabolismo , Humanos , Hipoglicemiantes/farmacologia , Masculino , Metformina/farmacologia , Pessoa de Meia-Idade , Países Baixos , Estudos Prospectivos , Resultado do TratamentoRESUMO
SLCO1B1 gene variants are associated with severe statin-induced myopathy. We examined whether these variants are also associated with general statin intolerance in a large population of patients with type 2 diabetes receiving statins as part of routine clinical care. A total of 4,196 individuals were genotyped for rs4149056 (Val174Ala) and rs2306283 (Asp130Asn). Intolerance was defined by serum biochemistry and also by discontinuation, switching, or reduction in dose of the prescribed statin drug. Ala174 was associated with higher intolerance (odds ratio = 2.05, P = 0.043), whereas Asp130 was associated with lower intolerance (odds ratio = 0.71, P = 0.026). Ala174 was associated with a lower low-density lipoprotein cholesterol (LDLc) response to statins (P = 0.01) whereas 130D was associated with a greater LDLc response to statins (P = 0.048), as previously reported; however, this association was no longer present when data for statin-intolerant individuals were removed from the analysis. This study suggests that common genetic variants selected for an extreme phenotype of statin-induced myopathy also predispose to more common milder statin intolerance and may, for this reason, impact lipid-lowering efficacy.
Assuntos
Diabetes Mellitus Tipo 2/genética , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Transportadores de Ânions Orgânicos/genética , Idoso , LDL-Colesterol/sangue , Feminino , Genótipo , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado , Modelos Logísticos , Masculino , Pessoa de Meia-IdadeRESUMO
AIMS: To investigate all-cause and cardiovascular mortality in subjects with diabetes caused by a mutation in the hepatocyte nuclear factor 1alpha gene (HNF1A). METHODS: We identified 39 British families with HNF1A mutations. Consenting individuals were asked details of age and cause of death of parents and siblings. Copies of death certificates were requested from the family or were obtained via the Offices for National Statistics. RESULTS: Data were collated on 241 control subjects and 153 mutation carriers. Of those who died, 66% of mutation carriers died from a cardiovascular-related illness compared with 43% of control subjects (P = 0.02). Family members with HNF1A mutations died at a younger age than familial control subjects [all-cause hazard ratio, adjusting for sex and smoking status: 1.9 (95% confidence interval 1.2, 2.9, P = 0.006; cardiovascular hazard ratio: 2.3, confidence interval 1.3, 4.2, P = 0.006)]. CONCLUSIONS: We have shown that individuals known to have diabetes caused by a mutation in the HNF1A gene have an increased risk of cardiovascular mortality compared with their unaffected family members. As with other forms of diabetes, consideration should be given to early statin therapy despite a seemingly protective lipid profile.
Assuntos
Doenças Cardiovasculares/mortalidade , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/genética , Fator 1-alfa Nuclear de Hepatócito/genética , Mortalidade , Mutação/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/etiologia , Análise Mutacional de DNA , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/mortalidade , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/mortalidade , Família , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Risco , Análise de Sequência de DNA , Análise de SobrevidaRESUMO
Sulfonylureas are metabolized mainly by the cytochrome p450 2C9 (CYP2C9) enzyme. Two CYP2C9 variants--*2 (Arg144Cys) and *3 (Ile359Leu)--are associated with reduced enzyme activity and impaired substrate metabolism. We identified 1,073 incident users of sulfonylureas in Tayside, Scotland, and assessed the impact of the combined CYP2C9*2 and CYP2C9*3 genotypes on early and sustained sulfonylurea response. We found that patients with two copies of a loss-of-function allele were 3.4 times (P = 0.0009) more likely to achieve a treatment hemoglobin A(1c) (HbA(1c)) level <7% than patients with two wild-type CYP2C9 alleles. This corresponds to a 0.5% (P = 0.003) greater reduction in HbA(1c) concentration. In addition, *2 and *3 allele carriers were less likely to experience treatment failure with sulfonylurea monotherapy (P = 0.04; per-allele hazard ratio 0.79; 95% confidence interval 0.63-0.99). In conclusion, CYP2C9 loss-of-function alleles are associated with greater response to sulfonylureas and decreased failure of therapy consistent with the pharmacokinetic role of CYP2C9.
Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Variação Genética/genética , Compostos de Sulfonilureia/uso terapêutico , Idoso , Alelos , Hidrocarboneto de Aril Hidroxilases/farmacocinética , Citocromo P-450 CYP2C9 , Bases de Dados Genéticas , Diabetes Mellitus Tipo 2/enzimologia , Feminino , Variação Genética/efeitos dos fármacos , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , EscóciaRESUMO
AIM: Metformin is the most commonly prescribed oral agent used in the treatment of type 2 diabetes. It is effective at reducing glycosylated Haemoglobin (HbA1c) and decreasing microvascular and macrovascular disease. However, up to 25% of patients develop gastrointestinal side effects leading to cessation in 5-10% of users. Metformin XL (glucophage SR) is a once a day preparation that delays absorption, leading to decreased peak metformin concentrations. We hypothesised that the XL preparation of metformin would be better tolerated than the standard immediate release (IR) preparation leading to improved adherence to therapy. METHODS: In a retrospective observational study, we studied adherence and glycaemic control in patients prescribed metformin IR and XL preparations in Tayside, UK. RESULTS: Metformin XL was used by 137 patients during the study period. Overall adherence was greater in the XL group (80%) compared with the 10,772 patients in the IR group (72%, p = 0.0026). In the 40 patients who changed from metformin IR to metformin XL who had sufficient data to determine adherence, the adherence increased from 62% in the IR group to 81% in the XL group (p < 0.0001). This was associated with an HbA1c reduction from 9.1 to 8.4% (p = 0.0739, n = 29). CONCLUSIONS: Metformin XL use is associated with increased adherence compared with the IR preparation, although the mechanism for this cannot be determined from this study. In patients intolerant of metformin IR the XL preparation should be considered.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Metformina/administração & dosagem , Cooperação do Paciente/estatística & dados numéricos , Idoso , Preparações de Ação Retardada , Diabetes Mellitus Tipo 2/sangue , Esquema de Medicação , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Masculino , Registro Médico Coordenado , Pessoa de Meia-Idade , Estudos Retrospectivos , EscóciaRESUMO
AIMS/HYPOTHESIS: The gene encoding transcription factor 7-like 2 (TCF7L2) has been identified as a type 2 diabetes locus from genome-wide linkage studies and subsequent association analysis. We investigated the role of two common variants in TCF7L2 in a large case-control study recruited from the Tayside region of Scotland, UK. SUBJECTS AND METHODS: We genotyped 6,516 participants for rs12255372 and rs7903146 and analysed the role in type 2 diabetes susceptibility using binary logistic regression. Age, sex and obesity status were examined as covariates. The distribution of the genotypes within different treatment groups of cases was examined. RESULTS: Both variants were associated with type 2 diabetes (p < 10(-13)). The variants were present at very similar frequencies and were in strong linkage disequilibrium (R(2) = 0.88, D' = 0.89). A gene dosage effect of the rare allele of both variants was observed, the heterozygote CT group of rs7903146 having an odds ratio of 1.36 (95% CI 1.2-1.5, p=1.54 x 10(-7)) for type 2 diabetes and the TT homozygote having a greater risk (OR = 2.03, 95% CI 1.7-2.5, p=1.40 x 10(-12)). An interaction with sex was observed, the males displaying a higher degree of genotype-associated risk compared with the females (p = 0.023). The T allele was associated with increased HbA(1c) levels in both cases and controls, and with decreased BMI and waist circumference in case but not controls. The T allele was overrepresented in individuals requiring insulin treatment and underrepresented in the patients being managed by diet alone (p = 0.006). CONCLUSIONS: We have confirmed TCF7L2 to be a diabetes locus in a large case-control study in Tayside, UK. Our data suggest that variants of TCF7L2 may be associated with increased disease severity and therapeutic failure.
Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/genética , Fatores de Transcrição TCF/genética , Idoso , Índice de Massa Corporal , Tamanho Corporal , Primers do DNA , Diabetes Mellitus/sangue , Diabetes Mellitus/genética , Diabetes Mellitus Tipo 2/sangue , Dosagem de Genes , Predisposição Genética para Doença , Variação Genética , Homeostase , Humanos , Lipídeos/sangue , Pessoa de Meia-Idade , Razão de Chances , Valores de Referência , Proteína 2 Semelhante ao Fator 7 de TranscriçãoRESUMO
AIMS/HYPOTHESIS: There is strong evidence that maternal diabetes while offspring are in utero results in offspring beta cell dysfunction and diabetes or glucose intolerance. Offspring born to mothers with a mutation in the glucokinase gene (GCK) are a good model for studying exposure to moderate hyperglycaemia, as mutation carriers have fasting hyperglycaemia throughout life including during pregnancy. We assessed the long term effects of exposure to maternal hyperglycaemia in utero on beta cell function and glucose tolerance in adult offspring. MATERIALS AND METHODS: We studied 86 adult offspring (mean age 40 years), 49 born to glucokinase mothers (exposed to hyperglycaemia in utero) and 37 born to glucokinase fathers (controls). We measured glucose tolerance during an OGTT and beta cell function using early insulin response (EIR); we also measured anthropometric data including birthweight. RESULTS: Offspring of glucokinase mothers had a higher birthweight by 450 g (p<0.001), but no evidence of deterioration in glucose tolerance (2-h glucose 9.1 vs 8.6 mmol/l p=0.50) or reduced beta cell function (log EIR 1.40 vs 1.26, p=0.11) compared with offspring born to glucokinase fathers. CONCLUSIONS/INTERPRETATION: The marked increase in birthweight shows that offspring born to affected mothers were exposed to increased glycaemia in utero. Despite this, there was no evidence of altered beta cell function or glucose tolerance. As previous human examples of marked programming by hyperglycaemia in utero have been in genetically predisposed offspring, we propose that our finding reflects the lack of genetic predisposition in the offspring to progressive beta cell dysfunction.
Assuntos
Diabetes Mellitus Tipo 2/genética , Glucoquinase/genética , Hiperglicemia/enzimologia , Mutação , Complicações na Gravidez/enzimologia , Adulto , Peso ao Nascer , Diabetes Mellitus Tipo 2/enzimologia , Feminino , Humanos , Hiperglicemia/genética , Masculino , Gravidez , Complicações na Gravidez/genéticaRESUMO
AIMS: A subset of patients who present as if they have Type 2 diabetes have positive pancreatic autoantibodies, and have been referred to as having latent autoimmune diabetes in adults (LADA). We assessed the prevalence and clinical characteristics of patients with glutamic acid decarboxylase antibodies (GADA) in a cohort clinically selected for Type 2 diabetes and determined the presence of diabetes and GADA in their first-degree relatives. METHODS: GADA were measured in 2059 subjects, not known to be related, and clinically selected as having Type 2 diabetes for genetic studies. Clinical characteristics were compared in GADA positive and GADA negative subjects. Diabetes and GAD antibody status were compared in 208 first-degree relatives of GADA positive and GADA negative probands. RESULTS: Of the subjects, 136 (7%) were GADA positive. Compared with the GADA negative subjects, they were slimmer (P < 0.001), diagnosed at a younger age (P = 0.011) and progressed to insulin faster (P < 0.001). Thirty-three per cent of GADA positive subjects had a first-degree relative with diabetes compared with 42% of GADA negative subjects (P = 0.034). The overall prevalence of GADA was similar in the first-degree relatives of GADA positive and GADA negative probands (4 v 5%), and 19 of 22 (86%) diabetic relatives of GADA positive probands were GADA negative. CONCLUSION: Despite clinically selecting a Type 2 diabetes cohort, 7% were GADA positive with an altered phenotype. These GADA positive patients had a strong family history of non-autoimmune diabetes. This suggests that, in this subgroup of patients, autoimmune pancreatic beta-cell destruction occurs on a background of Type 2 diabetes genetic susceptibility.
Assuntos
Anticorpos/sangue , Autoimunidade/genética , Diabetes Mellitus Tipo 2/imunologia , Glutamato Descarboxilase/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Diabetes Mellitus Tipo 2/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , LinhagemRESUMO
AIMS: In treating Type 2 diabetes (T2DM), UK guidelines recommend metformin in obese and overweight patients, and either sulphonylureas or metformin in normal weight patients. Although other factors influence prescribing choice, a key objective in treating T2DM is to lower plasma glucose. There is little data on how glycaemic response to oral agents varies with body mass index (BMI). Therefore, we assessed current prescribing practice and effect of BMI on glycaemic response to sulphonylureas and metformin in a large population T2DM cohort. METHODS: BMI was determined in 3856 T2DM patients on sulphonylurea or metformin monotherapy in 2001-2002. Patients were identified from the Diabetes Audit and Research in Tayside, Scotland (DARTS) database. In a linear regression, the effect of BMI and other confounders on drug response was assessed in 2064 treatment-naïve patients commencing sulphonylureas or metformin between 1994 and 2002. RESULTS: In 2001-2002, metformin was more likely to be used in obese than non-obese patients: 13% normal weight, 33.6% overweight and 62.1% obese patients were treated with metformin. Glycaemic response to sulphonylureas was not influenced by BMI (P = 0.81). Metformin was more effective in lowering glucose in those with a lower BMI (r = -0.02, P = 0.02), although the clinical impact of this was small. The HbA(1c) reduction in non-obese patients was similar to that in obese patients (1.46% vs. 1.34%, P = 0.11). CONCLUSIONS: Glycaemic response to metformin in non-obese and obese patients is similar, suggesting that an individual's BMI should not influence the choice of oral agent. Given the non-glycaemia-related benefits of metformin, it should be used in more non-obese patients than is current practice in Tayside, Scotland.