RESUMEN
AIMS/HYPOTHESIS: The aim of this study was to assess whether the dual-hormone (insulin and glucagon) artificial pancreas reduces hypoglycaemia compared with the single-hormone (insulin alone) artificial pancreas during two types of exercise. METHODS: An open-label randomised crossover study comparing both systems in 17 adults with type 1 diabetes (age, 37.2 ± 13.6 years; HbA1c, 8.0 ± 1.0% [63.9 ± 10.2 mmol/mol]) during two exercise types on an ergocycle and matched for energy expenditure: continuous (60% [Formula: see text] for 60 min) and interval (2 min alternating periods at 85% and 50% [Formula: see text] for 40 min, with two 10 min periods at 45% [Formula: see text] at the start and end of the session). Blocked randomisation (size of four) with a 1:1:1:1 allocation ratio was computer generated. The artificial pancreas was applied from 15:30 hours until 19:30 hours; exercise was started at 18:00 hours and announced 20 min earlier to the systems. The study was conducted at the Institut de recherches cliniques de Montréal. RESULTS: During single-hormone control compared with dual-hormone control, exercise-induced hypoglycaemia (plasma glucose <3.3 mmol/l with symptoms or <3.0 mmol/l regardless of symptoms) was observed in four (23.5%) vs two (11.8%) interventions (p = 0.5) for continuous exercise and in six (40%) vs one (6.25%) intervention (p = 0.07) for interval exercise. For the pooled analysis (single vs dual hormone), the median (interquartile range) percentage time spent at glucose levels below 4.0 mmol/l was 11% (0.0-46.7%) vs 0% (0-0%; p = 0.0001) and at glucose levels between 4.0 and 10.0 mmol/l was 71.4% (53.2-100%) vs 100% (100-100%; p = 0.003). Higher doses of glucagon were needed during continuous (0.126 ± 0.057 mg) than during interval exercise (0.093 ± 0.068 mg) (p = 0.03), with no reported side-effects in all interventions. CONCLUSIONS/INTERPRETATION: The dual-hormone artificial pancreas outperformed the single-hormone artificial pancreas in regulating glucose levels during announced exercise in adults with type 1 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01930110 FUNDING: : Société Francophone du Diabète and Diabète Québec.
Asunto(s)
Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/fisiopatología , Ejercicio Físico/fisiología , Glucagón/uso terapéutico , Insulina/uso terapéutico , Páncreas Artificial , Adulto , Algoritmos , Glucemia/efectos de los fármacos , Estudios Cruzados , Femenino , Humanos , Hipoglucemiantes/uso terapéutico , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Patients with cardiovascular disease and impaired glucose tolerance are at increased risk of cardiovascular events and type 2 diabetes mellitus (T2DM). Lifestyle modification or pharmacological intervention can delay progression to T2DM, but there is no clear evidence that they reduce cardiovascular risk in this population. Acarbose, an α-glucosidase inhibitor that lowers postprandial blood glucose, has been shown to reduce T2DM risk by 25%, and possibly cardiovascular risk in impaired glucose tolerance subjects without cardiovascular disease.
Asunto(s)
Acarbosa/uso terapéutico , Glucemia/metabolismo , Enfermedad Coronaria/prevención & control , Diabetes Mellitus Tipo 2/prevención & control , Intolerancia a la Glucosa/tratamiento farmacológico , Prevención Secundaria/métodos , Glucemia/efectos de los fármacos , Enfermedad Coronaria/sangre , Enfermedad Coronaria/complicaciones , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Progresión de la Enfermedad , Método Doble Ciego , Estudios de Seguimiento , Intolerancia a la Glucosa/sangre , Intolerancia a la Glucosa/complicaciones , Humanos , Hipoglucemiantes/uso terapéutico , Estudios Prospectivos , Resultado del TratamientoAsunto(s)
Acarbosa/administración & dosificación , Glucemia/metabolismo , Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Enfermedades Cardiovasculares/etiología , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Prueba de Tolerancia a la Glucosa , Inhibidores de Glicósido Hidrolasas/administración & dosificación , HumanosRESUMEN
Glomerular endothelial cell (GEC) dysfunction occurs in diabetic kidney disease (DKD) and generally precedes albuminuria. We recently reported that hedgehog interacting protein (Hhip), highly expressed in GECs, contributes to DKD development in diabetic mice. Here, we hypothesized that urinary Hhip (uHhip) could identify early DKD; we tested uHhip in mice and humans with diabetes (DM). In both type 1 (Akita) and type 2 (db/db) DM mice, uHhip is elevated prior to the development of albuminuria, while non-DM controls excrete minimal amount of uHhip. In 87 type 2 DM patients and 39 healthy controls, the uHhip/creatinine (Cr) ratio provides a significant discrimination between non-DM and DM groups; 0 [0-69.5] in non-DM, 9.9 [1.7-39.5] in normoalbuminuric DM, 167.7 [95.7-558.7] in microalbuminuric DM, and 207.9 [0-957.2] in macroalbuminuric DM (median [IQR] ng/mmol, P < 0.0001). The log-uHhip/Cr is positively correlated with urine albumin/Cr ratio (UACR) (spearman correlation coefficient 0.47, P < 0.0001). The log-uHhip/Cr is also associated with eGFR, pulse pressure, and urinary cytokines (IL-1ß, IL-6, IL-8, and TGFß1) independent of UACR. By immunostaining, Hhip is localized in glomeruli and tubules, and is increased in human DM kidneys compared with non-DM kidneys. TGFß1 shares the similar staining pattern as Hhip in human DM kidneys. Thus, uHhip appears to be a novel indicator of diabetic GEC injury and is elevated in early DKD before the development of microalbuminuria in mice and humans. Clinical value for detecting early DKD warrants further investigation.
Asunto(s)
Proteínas Portadoras/orina , Nefropatías Diabéticas/orina , Glicoproteínas de Membrana/orina , Adulto , Anciano , Albuminuria/orina , Animales , Creatinina/orina , Células Endoteliales/patología , Femenino , Humanos , Riñón/química , Glomérulos Renales/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Estudios Prospectivos , Factor de Crecimiento Transformador beta1/análisisRESUMEN
The relevance of endogenous 4ß-hydroxycholesterol (4ß-OHC) plasma concentrations or of the 4ß-OHC/total cholesterol concentration ratio (4ß-OHC ratio) as surrogate markers of cytochrome P450 3A (CYP3A) activity was evaluated in individuals with (n = 38) or without (n = 35) type 2 diabetes (T2D). Midazolam was used as a comparator to validate exploratory measures of phenotypic CYP3A activity. Metabolic ratios of orally administered midazolam in nondiabetic and diabetic populations correlated significantly with 4ß-OHC (rs = 0.64 and 0.48; P ≤ 0.003) and 4ß-OHC ratio (rs = 0.69 and 0.46; P ≤ 0.003), respectively. Activity of CYP3A was lower in the T2D population compared with nondiabetic subjects; this decrease was reflected in 4ß-OHC concentrations (24.33 vs. 12.58 ng/mL; P < 0.0001) and 4ß-OHC ratio (0.13 vs. 0.09 (× 104 ); P < 0.0002). These results suggest that 4ß-OHC should be considered as a valid, convenient, and easy to use endogenous biomarker of CYP3A activity in patients.
Asunto(s)
Citocromo P-450 CYP3A/metabolismo , Diabetes Mellitus Tipo 2 , Hidroxicolesteroles/sangre , Midazolam/farmacocinética , Variación Biológica Poblacional , Biomarcadores/sangre , Colesterol/sangre , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/enzimología , Endofenotipos , Femenino , Humanos , Hipnóticos y Sedantes/farmacocinética , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Reproducibilidad de los ResultadosRESUMEN
We conducted a comprehensive in vivo study evaluating the influence of type 2 diabetes (T2D) on major cytochrome P450 (CYP450) activities. These activities were assessed in 38 T2D and 35 non-T2D subjects after a single oral administration of a cocktail of probe drugs: 100 mg caffeine (CYP1A2), 100 mg bupropion (CYP2B6), 250 mg tolbutamide (CYP2C9), 20 mg omeprazole (CYP2C19), 30 mg dextromethorphan (CYP2D6), 2 mg midazolam (CYP3As), and 250 mg chlorzoxazone (alone; CYP2E1). Mean metabolic activity for CYP2C19, CYP2B6, and CYP3A was decreased in subjects with T2D by about 46%, 45%, and 38% (P < 0.01), respectively. CYP1A2 and CYP2C9 activities seemed slightly increased in subjects with diabetes, and no difference was observed for CYP2D6 or CYP2E1 activities. Several covariables, such as inflammatory markers (interleukin (IL)-1ß, IL-6, gamma interferon, and tumor necrosis factor alpha), genotypes, and diabetes-related and demographic-related factors were considered in our analyses. Our results indicate that low chronic inflammatory status associated with T2D modulates CYP450 activities in an isoform-specific manner.
Asunto(s)
Sistema Enzimático del Citocromo P-450/metabolismo , Diabetes Mellitus Tipo 2/enzimología , Adulto , Anciano , Bupropión/farmacocinética , Cafeína/farmacocinética , Estudios de Casos y Controles , Clorzoxazona/farmacocinética , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP2B6/metabolismo , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP2E1/metabolismo , Citocromo P-450 CYP3A/metabolismo , Dextrometorfano/farmacocinética , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Humanos , Interferón gamma/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Midazolam/farmacocinética , Persona de Mediana Edad , Omeprazol/farmacocinética , Tolbutamida/farmacocinética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Peroxisome proliferator-activated receptor (PPAR) alpha, a transcription factor of the nuclear receptor superfamily, regulates fatty acid oxidation. We evaluated the association of single nucleotide polymorphisms (SNPs) of the PPAR-alpha gene (PPARA) with the conversion from impaired glucose tolerance to type 2 diabetes in 767 subjects of the STOP-NIDDM trial in order to investigate the effect of acarbose in comparison with placebo on the prevention of diabetes. In the placebo group, the G (162V) allele of rs1800206 increased the risk for diabetes by 1.9-fold (95% CI 1.05-3.58) and was associated with elevated levels of plasma glucose and insulin. The effect of this allele on the risk of diabetes in the placebo group was enhanced by the simultaneous presence of the risk alleles of the PPAR-gamma2, PPAR-gamma coactivator 1alpha, and hepatic nuclear factor 4alpha genes (odds ratios 2.2, 2.5, and 3.4, respectively). In the acarbose group, subjects carrying the minor G allele of rs4253776 and the CC genotype of rs4253778 of PPARA had a 1.7- and 2.7-fold increased risk for diabetes. Our data indicate that SNPs of PPARA increase the risk of type 2 diabetes alone and in combination with the SNPs of other genes acting closely with PPAR-alpha.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Intolerancia a la Glucosa/genética , PPAR alfa/genética , Polimorfismo de Nucleótido Simple , Susceptibilidad a Enfermedades , Método Doble Ciego , Femenino , Genoma , Humanos , Masculino , Placebos , ARN Mensajero/genéticaRESUMEN
To define the effects of acute hyperglycemia per se (i.e., without the confounding effect of hyperinsulinemia) in human tissues in vivo, we performed global gene expression analysis using microarrays in vastus lateralis muscle and subcutaneous abdominal adipose tissue of seven healthy men during a hyperglycemic-euinsulinemic clamp with infusion of somatostatin to inhibit endogenous insulin release. We found that doubling fasting blood glucose values while maintaining plasma insulin in the fasting range modifies the expression of 316 genes in skeletal muscle and 336 genes in adipose tissue. More than 80% of them were downregulated during the clamp, indicating a drastic effect of acute high glucose, in the absence of insulin, on mRNA levels in human fat and muscle tissues. Almost all the biological pathways were affected, suggesting a generalized effect of hyperglycemia. The induction of genes from the metallothionein family, related to detoxification and free radical scavenging, indicated that hyperglycemia-induced oxidative stress could be involved in the observed modifications. Because the duration and the concentration of the experimental hyperglycemia were close to what is observed during a postprandial glucose excursion in diabetic patients, these data suggest that modifications of gene expression could be an additional effect of glucose toxicity in vivo.
Asunto(s)
Tejido Adiposo/fisiología , Regulación de la Expresión Génica , Hiperglucemia/genética , Músculo Esquelético/fisiología , Enfermedad Aguda , Adulto , Técnica de Clampeo de la Glucosa , Humanos , Insulina/sangre , Insulina/metabolismo , Secreción de Insulina , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , Regiones Promotoras Genéticas , ARN Mensajero/genética , Valores de ReferenciaRESUMEN
BACKGROUND: The optimal source and amount of dietary carbohydrate for managing type 2 diabetes (T2DM) are unknown. OBJECTIVE: We aimed to compare the effects of altering the glycemic index or the amount of carbohydrate on glycated hemoglobin (HbA1c), plasma glucose, lipids, and C-reactive protein (CRP) in T2DM patients. DESIGN: Subjects with T2DM managed by diet alone (n=162) were randomly assigned to receive high-carbohydrate, high-glycemic-index (high-GI), high-carbohydrate, low-glycemic-index (low-GI), or low-carbohydrate, high-monounsaturated-fat (low-CHO) diets for 1 y. RESULTS: The high-GI, low-GI, and low-CHO diets contained, respectively, 47%, 52%, and 39% of energy as carbohydrate and 31%, 27%, and 40% of energy as fat; they had GIs of 63, 55, and 59, respectively. Body weight and HbA1c did not differ significantly between diets. Fasting glucose was higher (P=0.041), but 2-h postload glucose was lower (P=0.010) after 12 mo of the low-GI diet. With the low-GI diet, overall mean triacylglycerol was 12% higher and HDL cholesterol 4% lower than with the low-CHO diet (P<0.05), but the difference in the ratio of total to HDL cholesterol disappeared by 6 mo (time x diet interaction, P=0.044). Overall mean CRP with the low-GI diet, 1.95 mg/L, was 30% less than that with the high-GI diet, 2.75 mg/L (P=0.0078); the concentration with the low-CHO diet, 2.35 mg/L, was intermediate. CONCLUSIONS: In subjects with T2DM managed by diet alone with optimal glycemic control, long-term HbA1c was not affected by altering the GI or the amount of dietary carbohydrate. Differences in total:HDL cholesterol among diets had disappeared by 6 mo. However, because of sustained reductions in postprandial glucose and CRP, a low-GI diet may be preferred for the dietary management of T2DM.
Asunto(s)
Proteína C-Reactiva/metabolismo , Diabetes Mellitus Tipo 2/dietoterapia , Carbohidratos de la Dieta/administración & dosificación , Grasas de la Dieta/administración & dosificación , Hemoglobina Glucada/análisis , Índice Glucémico , Adulto , Anciano , Área Bajo la Curva , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Colesterol/sangre , HDL-Colesterol/sangre , Diabetes Mellitus Tipo 2/sangre , Carbohidratos de la Dieta/clasificación , Carbohidratos de la Dieta/metabolismo , Femenino , Humanos , Lípidos/sangre , Masculino , Persona de Mediana EdadRESUMEN
1. Levels of insulin-signalling molecules are altered in streptozotocin (STZ)-induced diabetes, a model of Type 1 diabetes. However, the tissue-specific regulation of these changes and the effect of insulin supplementation on signalling molecule protein levels have not been well characterized. 2. In the present study, we evaluated the level of proximal insulin-signalling intermediates in the heart and in red and white gastrocnemius muscles of 2 week diabetic rats and diabetic rats supplemented with insulin. 3. Diabetes augmented levels of the insulin receptor and the p85 regulatory subunit of phosphatidylinositol 3-kinase in the red gastrocnemius, but not in the white gastrocnemius or the heart. Furthermore, diabetes reduced insulin receptor substrate-1 levels in both the red and white gastrocnemius, but not in the heart. Examination of the levels and basal activities of distal insulin-signalling intermediates (protein kinase B (PKB)/Akt, extracellular signal-regulated kinase (ERK) 1/2, p38 mitogen-activated protein kinase (MAPK)) also failed to reveal a specific pattern in these changes. Thus, diabetes reduced basal ERK1/2 and PKB/Akt phosphorylation in the heart and white gastrocnemius, respectively, whereas it augmented basal p38 MAPK activity in the red gastrocnemius. Insulin supplementation normalized the levels and activities of some but not all proteins. 4. In conclusion, the results of the present study demonstrate that adaptation to STZ-induced diabetes varies among skeletal muscle fibre types and the heart, emphasizing the complex tissue-specific responses to diabetes.
Asunto(s)
Diabetes Mellitus Experimental/metabolismo , Insulina/metabolismo , Músculo Esquelético/metabolismo , Miocardio/metabolismo , Transducción de Señal/fisiología , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Diabetes Mellitus Experimental/tratamiento farmacológico , Insulina/uso terapéutico , Proteínas Sustrato del Receptor de Insulina , Masculino , Fosfatidilinositol 3-Quinasas/metabolismo , Subunidades de Proteína/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas WistarRESUMEN
INTRODUCTION: Diabetes affects more than 9% of the adult population worldwide. Patients with type 2 diabetes mellitus (T2DM) show variable responses to some drugs which may be due, in part, to variability in the functional activity of drug-metabolising enzymes including cytochromes P450 (CYP450s). CYP450 is a superfamily of enzymes responsible for xenobiotic metabolism. Knowledge must be gained on the impact of T2DM and related inflammatory processes on drug metabolism and its consequences on drug response. The aim of this study is to characterise the activity of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5 in T2DM versus non-T2DM subjects following the administration of a cocktail of probe drug substrates. METHODS AND ANALYSIS: This single-centre clinical study proposes the first detailed characterisation of T2DM impacts on major CYP450 drug-metabolising enzyme activities. We intend to recruit 42 patients with controlled T2DM (A1C≤7%), 42 patients with uncontrolled T2DM (A1C>7%) and 42 non-diabetic control subjects. The primary objective is to determine and compare major CYP450 activities in patients with T2DM versus non-diabetic subjects by dosing in plasma and urine probe drug substrates and metabolites following the oral administration of a drug cocktail: caffeine (CYP1A2), bupropion (CYP2B6), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), chlorzoxazone (CYP2E1) and midazolam (CYP3A4/5). Secondary objectives will evaluate the influence of variables such as glycaemia, insulinaemia, genetic polymorphisms and inflammation. The value of an endogenous biomarker of CYP3A activity is also evaluated. The first patient was recruited in May 2015 and patients will be enrolled up to completion of study groups. ETHICS AND DISSEMINATION: Approval was obtained from the ethic review board of the CHUM research centre (Montreal, Canada). TRIAL REGISTRATION NUMBER: NCT02291666.
Asunto(s)
Sistema Enzimático del Citocromo P-450/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/enzimología , Índice de Masa Corporal , Canadá , Estudios de Casos y Controles , Interacciones Farmacológicas , Humanos , Análisis de Regresión , Proyectos de InvestigaciónRESUMEN
We investigated whether renal hedgehog interacting protein (Hhip) expression contributes to the progression of diabetic nephropathy (DN) and studied its related mechanism(s) in vivo and in vitro. Here, we show that Hhip expression is highly elevated in glomerular endothelial cells of adult type 1 diabetic (T1D) Akita and T2D db/db mouse kidneys as compared to non-diabetic control littermates. Hyperglycemia enhances reactive oxygen species (ROS) generation via NADPH oxidase 4 (Nox4) activation and stimulates renal Hhip gene expression, and that elevated renal Hhip gene expression subsequently activates the TGFß1- Smad2/3 cascade and promotes endothelial to mesenchymal transition associated with endothelial cell fibrosis/apoptosis in vivo and in vitro. Furthermore, kidneys of low-dose streptozotocin-induced diabetic heterozygous Hhip deficient (Hhip+/-) mice displayed a normal albumin/creatinine ratio with fewer features of DN (glomerulosclerosis/fibrosis and podocyte apoptosis/loss) and less evidence of renal compensation (glomerular hypertrophy and hyperfiltration) as compared to diabetic wild type controls (Hhip+/+). Thus, our studies demonstrated that renal Hhip expression is associated with nephropathy development in diabetes and that hyperglycemia-induced renal Hhip expression may mediate glomerular endothelial fibrosis and apoptosis in diabetes, a novel finding.
Asunto(s)
Apoptosis/fisiología , Proteínas Portadoras/metabolismo , Diabetes Mellitus Experimental/metabolismo , Células Endoteliales/metabolismo , Fibrosis/metabolismo , Glomérulos Renales/metabolismo , Glicoproteínas de Membrana/metabolismo , Albúminas/metabolismo , Animales , Creatinina/metabolismo , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/patología , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/patología , Fibrosis/inducido químicamente , Fibrosis/patología , Glomérulos Renales/efectos de los fármacos , Glomérulos Renales/patología , Masculino , Ratones , Ratones Endogámicos C57BL , NADPH Oxidasa 4/metabolismo , Podocitos/metabolismo , Podocitos/fisiología , Especies Reactivas de Oxígeno/metabolismo , Estreptozocina/farmacología , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Peroxisome proliferator-activated receptor (PPAR)-delta regulates fatty acid oxidation and improves insulin sensitivity. We screened six single nucleotide polymorphisms (SNPs) of the PPAR-delta gene (PPARD) for an association with the conversion from impaired glucose tolerance (IGT) to type 2 diabetes in 769 subjects participating in the STOP-NIDDM trial. A 2.7-fold increase in the risk of diabetes was observed in female carriers of the C allele of rs6902123 (95% CI 1.44-5.30; adjusted P = 0.002). In the placebo group, subjects possessing both the 482Ser allele of the PPAR-gamma coactivator-1alpha gene (PGC-1A) and the rare allele of two SNPs of PPARD (rs6902123 and rs3734254) had up to 2.5-fold increased risk for diabetes. Furthermore, women carrying the C allele of rs6902123 of PPARD and the Pro12Pro genotype of the PPAR-gamma2 gene (PPARG2) had a 3.9-fold (95% CI 1.79-8.63; P = 0.001)-higher risk for diabetes than women with protective genotypes. Expression levels of PPAR-delta in subcutaneous adipose tissue of 87 offspring of Finnish patients with type 2 diabetes did not differ among the genotype groups of SNPs of PPARD. We conclude that SNPs in PPARD modify the conversion from IGT to type 2 diabetes, particularly in combination with the SNPs of PGC-1A and PPARG2.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Intolerancia a la Glucosa/genética , Proteínas de Choque Térmico/genética , PPAR delta/genética , PPAR gamma/genética , Polimorfismo de Nucleótido Simple , Factores de Transcripción/genética , Sustitución de Aminoácidos , Diabetes Mellitus Tipo 2/epidemiología , Progresión de la Enfermedad , Femenino , Intolerancia a la Glucosa/epidemiología , Glicina , Humanos , Masculino , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Factores de Riesgo , SerinaRESUMEN
BACKGROUND: Heterogeneity in circulating lipid concentrations in response to dietary polyunsaturated fatty acids (PUFAs) may be due, in part, to genetic variations. Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine that can induce hyperlipidemia and is known to be modulated by dietary PUFAs. OBJECTIVE: The objective was to determine whether TNF-alpha genotypes modify the association between dietary PUFA intake and serum lipid concentrations. DESIGN: The study involved 53 men and 56 women aged 42-75 y with type 2 diabetes. Dietary intakes were assessed with the use of a 3-d food record, and blood samples were collected to determine fasting serum lipids. DNA was isolated from blood for genotyping by polymerase chain reaction-restriction fragment length polymorphism for the TNF-alpha -238G-->A and -308G-->A polymorphisms. RESULTS: PUFA intake was positively associated with serum HDL cholesterol in carriers of the -238A allele (beta = 0.06 +/- 0.03 mmol/L per 1% of energy from PUFAs; P = 0.03), but negatively associated in those with the -238GG genotype (beta = -0.03 +/- 0.01, P = 0.03) (P = 0.004 for interaction). PUFA intake was inversely associated with HDL cholesterol in carriers of the -308A allele (beta = -0.07 +/- 0.02, P = 0.002), but not in those with the -308GG genotype (beta = 0.02 +/- 0.02, P = 0.13) (P = 0.001 for interaction). A stronger gene x diet interaction was observed when the polymorphisms at the 2 positions (-238/-308) were combined (P = 0.0003). Similar effects were observed for apolipoprotein A-I, but not with other dietary fatty acids and serum lipids. CONCLUSION: TNF-alpha genotypes modify the relation between dietary PUFA intake and HDL-cholesterol concentrations. These findings suggest that genetic variations affecting inflammation may explain some of the inconsistencies between previous studies relating PUFA intake and circulating HDL.
Asunto(s)
Apolipoproteína A-I/sangre , HDL-Colesterol/sangre , Grasas Insaturadas en la Dieta/administración & dosificación , Polimorfismo de Longitud del Fragmento de Restricción , Factor de Necrosis Tumoral alfa/genética , Anciano , Diabetes Mellitus Tipo 2/sangre , Registros de Dieta , Ayuno/sangre , Femenino , Variación Genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Nutrigenómica , Reacción en Cadena de la PolimerasaRESUMEN
Inflammatory markers predict memory dysfunction in elderly patients, but their contribution to memory deficits in adults with Type 2 diabetes mellitus (T2DM) is less well understood. The present study determined whether specific single-nucleotide polymorphisms in the promoter region of tumor necrosis factor-alpha (TNF-alpha) predict verbal memory in older patients with T2DM. Immediate and delayed verbal memory were assessed using word list and paragraph recall tests in a cohort of subjects with T2DM during 2 sessions, separated by 48 weeks. The presence of the TNF-alpha-238A allele, which has been shown to decrease gene expression, consistently predicted better baseline performance and protected against memory decline over a period of 48 weeks. Therefore, inflammatory mediators may be important modulators of memory function in individuals with T2DM.
Asunto(s)
Diabetes Mellitus Tipo 2/complicaciones , Trastornos de la Memoria/etiología , Trastornos de la Memoria/genética , Polimorfismo de Nucleótido Simple , Factor de Necrosis Tumoral alfa/genética , Adulto , Estudios de Cohortes , Femenino , Genotipo , Humanos , Masculino , Recuerdo Mental/fisiología , Persona de Mediana Edad , Pruebas Neuropsicológicas , Regiones Promotoras Genéticas/fisiología , Factores de Tiempo , Aprendizaje Verbal/fisiologíaRESUMEN
Tumor necrosis factor alpha (TNF-alpha) is a proinflammatory cytokine that impairs insulin action and alters lipid metabolism. We investigated the effects of genetic polymorphisms of TNF-alpha on circulating biomarkers of insulin resistance and lipid metabolism during an 8-hour metabolic profile test and a 2-hour oral glucose tolerance test in subjects with type 2 diabetes mellitus. Subjects (N = 123) recruited were type 2 diabetic men (n = 56) and women (n = 67) aged 36 to 75 years with a body mass index of at least 25 kg/m(2). Blood samples were collected to determine postprandial changes in circulating lipid levels and biomarkers of insulin resistance. Subjects were genotyped by polymerase chain reaction-restriction fragment length polymorphism for the TNF-alpha -238G>A, -308G>A, and -863C>A polymorphisms. Compared with subjects who were homozygous for the -238G allele, carriers of the -238A allele had an altered ability to suppress postprandial free fatty acids as shown by an increased net incremental area under the curve (0.26 +/- 2.44 vs -1.33 +/- 2.71 mEq h(-1) L(-1), P = .002) during the 8-hour metabolic profile test. This effect was observed in obese (1.04 +/- 2.42 vs -1.68 +/- 2.70 mEq h(-1) L(-1), P = .0004) but not in non-obese (-0.63 +/- 2.20 vs -0.95 +/- 2.71 mEq h(-1) L(-1), P = .6) individuals. Among obese subjects, carriers of the -308A allele had greater insulin resistance as estimated by the homeostasis model assessment of insulin resistance index (4.36 +/- 2.83 vs 2.85 +/- 1.75, P = .01), but no differences were observed among non-obese subjects (2.19 +/- 1.24 vs 1.97 +/- 0.90, P = .6). Our findings suggest that the -238G>A and -308G>A polymorphisms of TNF-alpha alter circulating free fatty acids and insulin resistance in obese subjects with type 2 diabetes mellitus.
Asunto(s)
Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/genética , Ácidos Grasos no Esterificados/sangre , Obesidad/sangre , Obesidad/genética , Factor de Necrosis Tumoral alfa/genética , Adulto , Anciano , Alelos , Colesterol/sangre , ADN/química , ADN/genética , Femenino , Genotipo , Prueba de Tolerancia a la Glucosa , Humanos , Resistencia a la Insulina , Metabolismo de los Lípidos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Polimorfismo de Nucleótido Simple , Periodo Posprandial , Triglicéridos/sangreRESUMEN
BACKGROUND: Abnormal glucose tolerance is a frequent co-morbidity in cystic fibrosis patients (CF), and is associated with a worse prognosis. The objectives are to investigate (a) the relative contribution of insulinopenia and insulin resistance (IR) for glucose tolerance and (b) the association between various glucose parameters and CF clinical status. METHODS: Oral glucose tolerance tests were performed in 114 consecutive CF patients not known to be diabetic as well as 14 controls similar for age and BMI. RESULTS: Abnormal glucose tolerance was found in 40% of patients with CF: 28% had impaired glucose tolerance (IGT) and 12% had new cystic fibrosis related diabetes (CFRD). Compared to control subjects, all CF patients were characterized by an increased glucose excursion (AUC). While reduced early insulin release characterised CF, IGT and CFRD patients also present IR thus both mechanisms significantly contribute to glucose tolerance abnormalities. Increased glucose AUC and reduced early insulin release but not glucose tolerance categories were associated with a reduced pulmonary function (FEV(1)). CONCLUSION: In CF, early insulin secretion defect but also IR contribute to glucose intolerance. Early in the course of the disease, increased glucose AUC and reduced early insulin secretion are more closely associated with a worse clinical status than conventional glucose tolerance categories.
Asunto(s)
Glucemia/metabolismo , Fibrosis Quística/diagnóstico , Fibrosis Quística/metabolismo , Intolerancia a la Glucosa/metabolismo , Adulto , Fibrosis Quística/complicaciones , Femenino , Intolerancia a la Glucosa/complicaciones , Prueba de Tolerancia a la Glucosa , Humanos , Insulina/metabolismo , Resistencia a la Insulina , Masculino , Pronóstico , Factores de TiempoRESUMEN
OBJECTIVES: Postprandial glycemic excursions contribute significantly to A1C level. Furthermore, postprandial plasma glucose (PPG) is an independent risk factor for cardiovascular disease. We have evaluated the frequency of monitoring and the level of PPG in type 2 diabetic patients followed by their family physician. PATIENTS AND METHODS: Canadian multicenter observational study, including 185 type 2 diabetic patients. Capillary blood glucose was measured with an Ultrasmart glucose meter (Life Scan) during a routine visit to their general practitioner. The patients also had to answer a questionnaire concerning the time since their last meal before the visit, and the frequency of postprandial monitorings defined as
Asunto(s)
Glucemia/análisis , Diabetes Mellitus Tipo 2/sangre , Monitoreo Fisiológico/estadística & datos numéricos , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/terapia , Humanos , Periodo PosprandialRESUMEN
Hepatocyte nuclear factor 4alpha (HNF4alpha) is a transcription factor, which is necessary for normal function of human liver and pancreatic islets. We investigated whether single nucleotide polymorphisms (SNPs) of HNF4A, encoding HNF4alpha, influenced the conversion from impaired glucose tolerance (IGT) to type 2 diabetes mellitus in subjects of the STOP-NIDDM trial. This trial aimed at evaluating the effect of acarbose compared to placebo in the prevention of type 2 diabetes mellitus. Eight SNPs covering the intragenic and alternate P2 promoter regions of HNF4A were genotyped in study samples using the TaqMan Allelic Discrimination Assays. Three SNPs in the P2 promoter region (rs4810424, rs1884614, and rs2144908) were in almost complete association (D'>0.97, r (2)>0.95) and, therefore, only rs4810424 was included in further analyses. Female carriers of the less frequent C allele of rs4810424 had a 1.7-fold elevated risk [95% confidence interval (CI) 1.09-2.66; P=0.020] for the conversion to diabetes compared to women with the common genotype after the adjustment for age, treatment group (placebo or acarbose), smoking, weight at baseline, and weight change. No association was found in men. Haplotype analysis based on three SNPs (rs4810424, rs2071197, and rs3818247) representing the linkage disequilibrium blocks in our study population indicated that the conversion to type 2 diabetes mellitus was dependent on the number of risk alleles in different haplotypes in women. Our results suggest that SNPs of HNF4A and their haplotypes predispose to type 2 diabetes mellitus in female subjects of the STOP-NIDDM study population.