RESUMEN
AIMS: We wished to investigate the influence of metal debris exposure on the subsequent immune response and resulting soft-tissue injury following metal-on-metal (MoM) hip arthroplasty. Some reports have suggested that debris generated from the head-neck taper junction is more destructive than equivalent doses from metal bearing surfaces. PATIENTS AND METHODS: We investigated the influence of the source and volume of metal debris on chromium (Cr) and cobalt (Co) concentrations in corresponding blood and hip synovial fluid samples and the observed agglomerated particle sizes in excised tissues using multiple regression analysis of prospectively collected data. A total of 199 explanted MoM hips (177 patients; 132 hips female) were analysed to determine rates of volumetric wear at the bearing surfaces and taper junctions. RESULTS: The statistical modelling suggested that a greater source contribution of metal debris from the taper junction was associated with smaller aggregated particle sizes in the local tissues and a relative reduction of Cr ion concentrations in the corresponding synovial fluid and blood samples. Metal debris generated from taper junctions appears to be of a different morphology, composition and therefore, potentially, immunogenicity to that generated from bearing surfaces. CONCLUSION: The differences in debris arising from the taper and the articulating surfaces may provide some understanding of the increased incidence of soft-tissue reactions reported in patients implanted with MoM total hip arthroplasties compared with patients with hip resurfacings. Cite this article: Bone Joint J 2016;98-B:925-33.
Asunto(s)
Artroplastia de Reemplazo de Cadera , Cromo/análisis , Cobalto/análisis , Prótesis de Cadera , Prótesis Articulares de Metal sobre Metal , Líquido Sinovial/química , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tamaño de la Partícula , Estudios Prospectivos , Diseño de Prótesis , Adulto JovenRESUMEN
PurposeTo assess the preoperative features of patients with idiopathic macular hole (IMH) and vitreomacular adhesion (VMA) treated with ocriplasmin (OCP) that can predict successful closure.MethodData were prospectively collected on all patients with IMH treated with OCP in three British ophthalmic centres. Several preoperative variables were recorded including the IMH base diameter (BD), minimum linear diameter (MLD), and VMA width measured on spectral domain optical coherence tomography. Several other IMH indices were derived including a 'width factor', defined as the BD minus the MLD in µm. The occurrence of VMA release and hole closure were used as the main outcome measures.ResultsThirty-three patients in total with IMH were treated with OCP. Two patients developed rhegmatogenous retinal detachment and were excluded. The mean age of the remaining 31 patients was 71 years, and 71% were female. VMA release occurred in 19 of the 31 (61%) patients and macular hole closure in 11 (35%). Width factor was the most predictive feature for closure on multivariate analysis. The deviance R(2) was 67% (P<0.001). An IMH with a width factor of <60 µm had a 95% certainty of closure, whereas if >290 µm then there was less than a 5% chance of closure. Neither VMA width nor MLD alone was associated with VMA release or closure.ConclusionsPatients with macular holes where the BD was close in size to the MLD had an improved probability of closure than holes with wider base configurations.
Asunto(s)
Fibrinolisina/uso terapéutico , Fibrinolíticos/uso terapéutico , Fragmentos de Péptidos/uso terapéutico , Perforaciones de la Retina/diagnóstico por imagen , Perforaciones de la Retina/tratamiento farmacológico , Tomografía de Coherencia Óptica , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Inyecciones Intravítreas , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Retina/efectos de los fármacos , Perforaciones de la Retina/fisiopatología , Adherencias Tisulares/tratamiento farmacológico , Adherencias Tisulares/fisiopatología , Agudeza Visual/fisiología , Cuerpo Vítreo/efectos de los fármacosAsunto(s)
Anticoagulantes/farmacocinética , Hidrocarburo de Aril Hidroxilasas/genética , Coagulación Sanguínea/efectos de los fármacos , Oxigenasas de Función Mixta/genética , Warfarina/farmacocinética , Adolescente , Factores de Edad , Anticoagulantes/administración & dosificación , Anticoagulantes/efectos adversos , Anticoagulantes/sangre , Hidrocarburo de Aril Hidroxilasas/metabolismo , Biotransformación , Niño , Preescolar , Estudios Transversales , Citocromo P-450 CYP2C9 , Monitoreo de Drogas/métodos , Inglaterra , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Hemorragia/inducido químicamente , Hemorragia/genética , Humanos , Lactante , Relación Normalizada Internacional , Masculino , Oxigenasas de Función Mixta/metabolismo , Ontario , Farmacogenética , Fenotipo , Estudios Retrospectivos , Factores de Riesgo , Vitamina K Epóxido Reductasas , Warfarina/administración & dosificación , Warfarina/efectos adversos , Warfarina/sangreRESUMEN
Patient-reported outcome measures (PROMs) are increasingly being used to assess functional outcome and patient satisfaction. They provide a framework for comparisons between surgical units, and individual surgeons for benchmarking and financial remuneration. Better performance may bring the reward of more customers as patients and commissioners seek out high performers for their elective procedures. Using National Joint Registry (NJR) data linked to PROMs we identified 22,691 primary total knee replacements (TKRs) undertaken for osteoarthritis in England and Wales between August 2008 and February 2011, and identified the surgical factors that influenced the improvements in the Oxford knee score (OKS) and EuroQol-5D (EQ-5D) assessment using multiple regression analysis. After correction for patient factors the only surgical factors that influenced PROMs were implant brand and hospital type (both p < 0.001). However, the effects of surgical factors upon the PROMs were modest compared with patient factors. For both the OKS and the EQ-5D the most important factors influencing the improvement in PROMs were the corresponding pre-operative score and the patient's general health status. Despite having only a small effect on PROMs, this study has shown that both implant brand and hospital type do influence reported subjective functional scores following TKR. In the current climate of financial austerity, proposed performance-based remuneration and wider patient choice, it would seem unwise to ignore these effects and the influence of a range of additional patient factors.
Asunto(s)
Artroplastia de Reemplazo de Rodilla/métodos , Osteoartritis de la Rodilla/cirugía , Satisfacción del Paciente/estadística & datos numéricos , Artroplastia de Reemplazo de Rodilla/rehabilitación , Inglaterra , Femenino , Indicadores de Salud , Humanos , Prótesis de la Rodilla , Masculino , Osteoartritis de la Rodilla/rehabilitación , Diseño de Prótesis , Calidad de Vida , Resultado del Tratamiento , GalesRESUMEN
Following arthroplasty of the knee, the patient's perception of improvement in symptoms is fundamental to the assessment of outcome. Better clinical outcome may offset the inferior survival observed for some types of implant. By examining linked National Joint Registry (NJR) and patient-reported outcome measures (PROMs) data, we aimed to compare PROMs collected at a minimum of six months post-operatively for total (TKR: n = 23,393) and unicondylar knee replacements (UKR: n = 505). Improvements in knee-specific (Oxford knee score, OKS) and generic (EuroQol, EQ-5D) scores were compared and adjusted for case-mix differences using multiple regression. Whereas the improvements in the OKS and EQ-5D were significantly greater for TKR than for UKR, once adjustments were made for case-mix differences and pre-operative score, the improvements in the two scores were not significantly different. The adjusted mean differences in the improvement of OKS and EQ-5D were 0.0 (95% confidence interval (CI) -0.9 to 0.9; p = 0.96) and 0.009 (95% CI -0.034 to 0.015; p = 0.37), respectively. We found no difference in the improvement of either knee-specific or general health outcomes between TKR and UKR in a large cohort of registry patients. With concerns about significantly higher revision rates for UKR observed in worldwide registries, we question the widespread use of an arthroplasty that does not confer a significant benefit in clinical outcome.
Asunto(s)
Artroplastia de Reemplazo de Rodilla/métodos , Satisfacción del Paciente , Anciano , Artroplastia de Reemplazo de Rodilla/efectos adversos , Índice de Masa Corporal , Femenino , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias , Psicometría , Calidad de Vida , Sistema de Registros , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
A significant proportion of the interindividual variability in warfarin dose requirements can be explained on the basis of CYP2C9 and VKORC1 genotypes. We report the development of a novel pharmacogenetics-based 3-day warfarin initiation dose (ID) algorithm based on the International Warfarin Pharmacogenetics Consortium (IWPC) maintenance dose algorithm and the CYP2C9 genotype-based variance in warfarin half-life. The predictive value of the pharmacogenetics-based ID was assessed in a large cohort of 671 newly diagnosed patients with thromboembolic disorders who were about to commence anticoagulation therapy in accordance with standard induction regimens. In patients with mean international normalized ratio (INR)days 4-7>4.0 (n=63) after warfarin initiation, the pharmacogenetics-based ID algorithm predicted a markedly lower dose requirement (median reduction=4.2 mg), whereas in those with mean INRdays 4-7<2.0 (n=145), the predicted dose requirement was very similar to that in the standard regimen. The use of a pharmacogenetics-based ID may avoid overshooting of INR in warfarin-sensitive patients without unduly affecting the time taken to reach target range in the majority of patients.
Asunto(s)
Anticoagulantes/administración & dosificación , Hidrocarburo de Aril Hidroxilasas/genética , Tromboembolia/tratamiento farmacológico , Warfarina/administración & dosificación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Anticoagulantes/farmacocinética , Anticoagulantes/uso terapéutico , Estudios de Cohortes , Citocromo P-450 CYP2C9 , Relación Dosis-Respuesta a Droga , Femenino , Semivida , Humanos , Relación Normalizada Internacional , Masculino , Persona de Mediana Edad , Farmacogenética/métodos , Estudios Prospectivos , Warfarina/farmacocinética , Warfarina/uso terapéutico , Adulto JovenAsunto(s)
Procedimiento de Fontan , Complicaciones Posoperatorias , Trombosis/tratamiento farmacológico , Trombosis/etiología , Atresia Tricúspide/terapia , Adolescente , Anticoagulantes/administración & dosificación , Anticoagulantes/efectos adversos , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Sistemas de Atención de Punto , Estudios Retrospectivos , Warfarina/administración & dosificación , Warfarina/efectos adversosRESUMEN
The genotype at the C-11377G single-nucleotide polymorphism (SNP) (rs266729) in the adiponectin gene promoter has been shown to affect the prevalence of coronary atherosclerosis and incidence of vascular events in men, and to affect carotid intima media thickness. We have examined the relationship between this polymorphism and blood pressure in a cohort ascertained to express variability in blood pressure measurements. We studied a cohort of 255 families comprising 1425 individuals ascertained via a hypertensive proband. Blood pressure was measured by ambulatory monitoring. The C-11377G SNP was genotyped using a TaqMan assay. There was evidence of association between this SNP and log systolic blood pressure (SBP), having adjusted for significant covariates including gender, age and drug treatment; P=0.009, 0.014 and 0.022, respectively, for daytime, night-time and clinic measurements. Replacing C by G caused an increase of 1.63, 1.83 and 1.61%, respectively, per gene copy. There were smaller effects on diastolic blood pressure and waist-hip ratio, which were of borderline significance. Genotype at the C-11377G (rs266729) polymorphism has independent effects both on waist-hip ratio and SBP. This may help in understanding the complex role that the adiponectin gene has in atherosclerosis.
Asunto(s)
Adiponectina/genética , Presión Sanguínea/genética , Polimorfismo de Nucleótido Simple/genética , Regiones Promotoras Genéticas/genética , Adolescente , Antagonistas Adrenérgicos beta/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Diuréticos/uso terapéutico , Femenino , Genotipo , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/genética , Masculino , Persona de Mediana Edad , Sístole/genética , Relación Cintura-Cadera , Adulto JovenRESUMEN
BACKGROUND: It is uncertain whether the novel single nucleotide polymorphisms (SNPs) that have recently been associated with coronary artery disease (CAD) in genome-wide studies also influence carotid atheroma and stroke risk. The mechanisms of their association with CAD are unknown; relationships to other cardiovascular phenotypes may give mechanistic clues. Carotid artery intima-media thickness (CIMT) is a subclinical marker of atherosclerosis associated with stroke. We investigated association of reported CAD risk variants with CIMT, and with other intermediate phenotypes that may implicate causative pathways. METHODS: We studied 1425 members of 248 British Caucasian families ascertained through a hypertensive proband. We genotyped CAD risk SNPs on chromosomes 9 (rs1333049, rs7044859, rs496892, rs7865618), 6 (rs6922269) and 2 (rs2943634) using TaqMan. Merlin software was used for family-based association testing. RESULTS: No significant association was found between genotype at any SNP and CIMT in 846 individuals with acceptable measurements. Nor were SNPs significantly associated with blood pressure, obesity, cholesterol, CRP, interleukin-6, TNF-alpha, or leptin. CONCLUSIONS: These novel CAD variants are not associated with CIMT and do not appear to mediate the risk of atherothrombosis through known risk factors.
Asunto(s)
Arterias Carótidas/patología , Enfermedad de la Arteria Coronaria/genética , Variación Genética , Polimorfismo de Nucleótido Simple , Túnica Íntima/patología , Túnica Media/patología , Adulto , Anciano , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , RiesgoRESUMEN
BACKGROUND/OBJECTIVES: Endothelial progenitor cells (EPCs) are circulating mononuclear cells that are released from the bone marrow in response to injury and participate in vascular repair. Some previous studies have suggested an early mobilisation of EPCs following percutaneous coronary intervention (PCI) that could modulate the subsequent risk of restenosis or stent thrombosis. However, those studies did not discriminate between vascular injury caused by PCI and any associated myocardial injury. Myocardial injury alone can influence EPC mobilisation in a non-specific manner, and could therefore confound any association with risk. We investigated the effect of local endothelial trauma following PCI on EPC mobilisation in the absence of myocyte necrosis. DESIGN: We quantified circulating EPCs from 20 patients immediately before, 6 hours and 24 hours following elective PCI in patients without a 24-hour troponin rise. Absolute counts of EPCs expressing combinations of CD45, CD34, CD133 and kinase domain receptor (KDR) were recorded using flow cytometry. RESULTS: There was a fall of 7-15% in EPC numbers between baseline and 6 hours post procedure and a subsequent rise (5-18%) from 6 hours to 24 hours. At 24 hours EPC levels were similar to baseline. CONCLUSIONS: The specific localised vascular injury induced by PCI did not lead to early mobilisation of EPCs. However, the fall in EPCs 6 hours after PCI was significant and its relation to early post-PCI complications such as stent thrombosis requires further exploration.
Asunto(s)
Angioplastia Coronaria con Balón/efectos adversos , Enfermedad Coronaria/patología , Vasos Coronarios/lesiones , Células Endoteliales/fisiología , Células Madre/fisiología , Anciano , Análisis de Varianza , Recuento de Células , Movimiento Celular , Enfermedad Coronaria/terapia , Vasos Coronarios/patología , Femenino , Citometría de Flujo , Humanos , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Miocardio/patología , Necrosis , Factores de TiempoAsunto(s)
Anticoagulantes/farmacología , Oxigenasas de Función Mixta/genética , Polimorfismo Genético , Vitamina K/uso terapéutico , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Vitamina K Epóxido Reductasas , Warfarina/farmacologíaRESUMEN
The endothelins are among the most potent vasoconstrictors known. Pharmacological inhibition of endothelin receptors lowers blood pressure (BP). It is unknown whether naturally occurring genetic variation in the endothelin receptors influences BP. We have evaluated the type A endothelin receptor (EDNRA) as a candidate gene for hypertension in a large family study. A total of 1425 members of 248 families selected via a proband with hypertension were studied. Ambulatory BP monitoring was conducted using the A&D TM2421 device. Four haplotype-tagging single nucleotide polymorphisms (SNPs) spanning the EDNRA gene were typed. There was evidence of association between genotype at the rs5335 (C+70G) SNP and night systolic blood pressure (+1.24% (s.e. 0.64) per G allele; P=0.05); night diastolic blood pressure (+1.64% (s.e. 0.71) per G allele; P=0.021) and night mean BP (+1.51% (s.e. 0.64) per G allele; P=0.017). Borderline significant trends in the same direction were seen for daytime BPs. Proportions of hypertensives in each of the three genotype groups were C/C 34.7%, C/G 37.9%, G/G 42.4% yielding an odds ratio for hypertension per G allele of 1.19 (95% confidence interval 1.00-1.41; P=0.05). In conclusion, the rs5335 (C+70G) polymorphism of the EDNRA gene has small effects on the risk of hypertension. Natural variation in other genes in the endothelin-signalling pathway should be explored to identify additional influences on BP regulation.
Asunto(s)
Monitoreo Ambulatorio de la Presión Arterial/métodos , Presión Sanguínea/fisiología , ADN/genética , Familia , Hipertensión/genética , Polimorfismo Genético , Receptor de Endotelina A/genética , Anciano , Anciano de 80 o más Años , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Hipertensión/sangre , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Técnicas de Amplificación de Ácido Nucleico , Pronóstico , Receptor de Endotelina A/sangre , Factores de RiesgoRESUMEN
AIMS/HYPOTHESIS: Animal models indicate that even exposure to mild maternal hyperglycaemia in utero is detrimental to the beta cell function of the offspring, but evidence of this in humans is limited. In Europids who are diagnosed with type 2 diabetes before the age of 50 years, the risk of diabetes in the offspring of the diabetic mothers is greatly increased compared with the risk in those born to diabetic fathers. We hypothesised that offspring born to mothers with young-onset type 2 diabetes would have been exposed to mild hyperglycaemia in utero, so we studied the impact of this on their beta cell function. SUBJECTS AND METHODS: We measured beta cell function using early insulin response (EIR) after oral glucose; insulin resistance using HOMA; and HbA(1c) in 568 non-diabetic adult offspring born to parents with type 2 diabetes (mean age 55.8 years), split according to which parent was affected (in 327 it was the mother) and parental age of diagnosis: <50 years (n=117) or > or =50 years. To reduce the impact of genetic susceptibility, the offspring of affected fathers were used as control subjects. RESULTS: Offspring of mothers with young-onset type 2 diabetes had lower EIR (log EIR 4.32, 95% CI [4.14-4.51] vs 4.63 [4.43-4.83] p=0.02) and higher HbA(1c) (4.89% [4.79-4.99] vs 4.68% [4.57-4.79] p=0.02) than the offspring of fathers with young-onset type 2 diabetes. Insulin sensitivity was similar in the two groups. There were no differences in EIR or HbA(1c) between the offspring born to mothers and fathers who were diagnosed after the age of 50 years. CONCLUSIONS/INTERPRETATION: We conclude that the offspring of mothers with young-onset type 2 diabetes have a reduction in beta cell function. This is consistent with exposure to mild maternal hyperglycaemia programming beta cell function.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/fisiopatología , Células Secretoras de Insulina/fisiología , Adulto , Edad de Inicio , Femenino , Humanos , Células Secretoras de Insulina/metabolismo , Masculino , Persona de Mediana Edad , Madres , Núcleo Familiar , HermanosRESUMEN
AIMS/HYPOTHESIS: The aim of this study was to measure the heritability estimates for metabolic traits and the features of the insulin resistance syndrome in families with an increased genetic susceptibility to Type 2 diabetes. METHODS: A total of 811 non-diabetic relatives from 278 pedigrees of northern European extraction in which there was a sib-pair with Type 2 diabetes were recruited and studied at the six Diabetes UK Warren Type 2 diabetes centres. Heritability estimates were calculated, allowing for key covariates (age, sex, BMI and recruitment centre). Values greater than 0.10 were considered statistically significant in comparison to zero. RESULTS: Fasting glucose concentration and homeostasis model assessment of pancreatic beta cell function (HOMA %B) had the highest heritability estimates of 0.72 and 0.78 respectively. Heritability estimates for the features of the insulin resistance syndrome (BMI, WHR, systolic and diastolic blood pressure, serum lipids and homeostasis model assessment of insulin sensitivity [HOMA %S]) were also high. The heritability estimate for fasting glucose was markedly higher in the present study (0.77 vs 0.21 adjusted for age and sex; p<0.001) than in a comparable study of families from the same background population but with no increased susceptibility to diabetes. However, the estimates for the features of the insulin resistance syndrome were similar in the two studies. CONCLUSIONS/INTERPRETATION: In families with a high risk of Type 2 diabetes, the heritability estimates for fasting glucose, pancreatic beta cell function and the features of the insulin resistance syndrome were all high. The higher heritability estimate for pancreatic beta cell function suggests that this resource may be most effective when investigating genetic susceptibility to beta cell dysfunction.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Resistencia a la Insulina/genética , Islotes Pancreáticos/fisiología , Pruebas de Función Pancreática , Adulto , Anciano , Anciano de 80 o más Años , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/fisiopatología , Femenino , Prueba de Tolerancia a la Glucosa , Homeostasis/fisiología , Humanos , Masculino , Persona de Mediana Edad , Linaje , Sistema de Registros , Reino UnidoRESUMEN
Insulin resistance is a feature of non-diabetic relatives of non-insulin-dependent diabetic (NIDDM) families. Tumour necrosis factor-alpha (TNF alpha) expression is linked with insulin resistance, and is under strong genetic control. We examined the relationship between insulin resistance and two polymorphisms of the TNF alpha promoter region (positions -238 and -308). Non-diabetic relatives (n = 123) of NIDDM families and control subjects (n = 126) with no family history of diabetes were studied. Insulin resistance was determined by homeostasis model assessment (HOMA) and short insulin tolerance test (ITT), and genotyping was by restriction digest. The -238 polymorphism (TNFA-A allele) was carried by 14 relatives and 11 control subjects, and all were heterozygotes. To examine the relationship between the -238 polymorphism and insulin resistance independent of potentially confounding factors, the relatives with the TNFA-A allele were individually pair-matched for age, sex, waist-hip ratio, body mass index, and glucose tolerance with relatives homozygous for the wild-type allele. Relatives with the TNFA-A allele had decreased insulin resistance (HOMA index: 2.0, 3.6 +/- 2.1 [means +/- SD of differences], p = 0.03), and this was true for comparable pair-matched control subjects (HOMA index: 1.1, 1.9 +/- 0.8, p = 0.01). Combining relative (n = 7) and control (n = 4) pairs that had undergone an ITT, subjects with the TNFA-A allele had an increased K(ITT) (3.8, 3.0 +/- 1.0%/min, p = 0.04) similarly indicating decreased insulin resistance. There was no significant relationship between the -308 polymorphism and insulin resistance. We conclude that the TNFA-A allele is associated with decreased insulin resistance as assessed by two independent methods, and may protect against the future development of NIDDM in susceptible individuals.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Resistencia a la Insulina/genética , Polimorfismo Genético , Regiones Promotoras Genéticas , Factor de Necrosis Tumoral alfa/genética , Adulto , Alelos , Constitución Corporal , Índice de Masa Corporal , Cartilla de ADN , Familia , Femenino , Tamización de Portadores Genéticos , Genotipo , Prueba de Tolerancia a la Glucosa , Humanos , Insulina/farmacología , Masculino , Reacción en Cadena de la PolimerasaRESUMEN
Non-diabetic first degree relatives of non-insulin-dependent diabetic (NIDDM) families are at increased risk of developing diabetes mellitus, and have been studied to identify early metabolic abnormalities. Hormone concentrations measured by specific enzyme immunoassays were assessed in non-diabetic relatives of North European extraction, and control subjects with no family history of diabetes were matched for age, sex and ethnicity. A 75-g oral glucose tolerance test was conducted and those with newly diagnosed NIDDM were excluded. Basal insulin resistance was determined by homeostasis model assessment (HOMA), and hepatic insulin clearance by C-peptide:insulin molar ratio. Relatives (n = 150) were heavier (BMI: p < 0.0001) than the control subjects (n = 152), and had an increased prevalence of impaired glucose tolerance (15 vs 3%, p < 0.01). The relatives had increased fasting proinsulin levels and decreased C-peptide levels following the glucose load, while insulin levels were increased at all time points. To examine whether the differences in hormone levels were secondary to the differences in glucose tolerance and adiposity, we studied 100 normal glucose tolerant relatives and control subjects pair-matched for age, sex, waist-hip ratio and BMI. The differences in proinsulin levels were no longer apparent. However, the relatives remained more insulin resistant, and had decreased C-peptide levels and C-peptide:insulin ratios at all time points. In conclusion, we have identified several metabolic abnormalities in the normal glucose tolerant relatives, and propose that the decreased hepatic insulin clearance helps to maintain normoglycaemia in the face of combined insulin resistance and decreased insulin secretion.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Resistencia a la Insulina , Insulina/sangre , Adulto , Glucemia/metabolismo , Péptido C/sangre , Estudios de Cohortes , Ácidos Grasos no Esterificados/sangre , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Masculino , Persona de Mediana Edad , Proinsulina/sangre , Valores de ReferenciaRESUMEN
Insulin receptor substrate-1 (IRS-1) occupies a key position in the insulin-signalling pathway. Two mutations of the IRS-1 gene (Gly(972)Arg and Ala(513)Pro) have been described, although their roles in the development of insulin resistance and non-insulin-dependent diabetes mellitus (NIDDM) remain controversial. Insulin resistance has been described in non-diabetic relatives of NIDDM families, suggesting that it may be due to an inherited defect of insulin action. We therefore examined the relationships between the two mutations and insulin sensitivity in 93 non-diabetic first degree relatives from North European families with 2 or more living NIDDM subjects. Anthropometric measurements, an oral glucose tolerance test, and an insulin tolerance test to assess insulin sensitivity (K(ITT)) were performed. Basal insulin sensitivity was assessed by homeostasis model assessment (HOMA). Comparisons were made between the following relative subgroups: with (n = 9) and without (n = 84) the 972 mutation; with (n = 5) and without (n = 88) the 513 mutation; and with either one or both mutations (n = 13) or without either (n = 80). General linear model analysis was used to compare K(ITT) and HOMA between the subgroups with the anthropometric variables known to influence insulin sensitivity as covariates. There were no significant differences between the subgroups for K(ITT) and HOMA. In conclusion, the 513 and 972 mutations, alone and in combination, are not associated with decreased insulin sensitivity in non-diabetic relatives of NIDDM families.