RESUMEN
BACKGROUND: Observational studies have suggested an inverse association between low serum 25-hydroxyvitamin D [25(OH)D] concentrations and development of type 2 diabetes. High-quality trials are required to test the hypothesis that vitamin D is a direct contributor to type 2 diabetes pathogenesis. OBJECTIVE: The purpose of this double-blind randomized placebo-controlled trial was to investigate the effect of vitamin D3 supplementation on insulin resistance (IR) and ß-cell function in people with prediabetes and suboptimal vitamin D status (<50 nmol/L). METHODS: Sixty-six individuals were randomly assigned to receive 3000 IU (75 µg) vitamin D3 or placebo daily for 26 wk. Compliance was monitored by pill count and change in serum 25(OH)D concentration using LC-MS. The primary endpoint was between-group difference in change in IR assessed using a 2-step euglycemic-hyperinsulinemic clamp combined with infusion of tritiated glucose. An oral-glucose-tolerance test was performed pre- and postintervention to calculate indices of ß-cell function. Between-group comparisons were made using ANCOVA. RESULTS: In total, 64 participants completed the study. Baseline serum 25(OH)D concentrations in the vitamin D3 and placebo group were 30.7 and 30.0 nmol/L, with status increasing by 70.5 nmol/L and 5.3 nmol/L, respectively (between-group difference in vitamin D: 65.8 nmol/L; 95% CI: 54.2, 77.3 nmol/L; P < 0.01), after supplementation. There was no difference between groups in measures of whole-body, peripheral, or hepatic IR or in any measure of glycemic control or ß-cell function. CONCLUSION: This study employed a robust assessment of IR and ß-cell function and targeted a high-risk population with low 25(OH)D status at baseline and found that vitamin D3 supplementation had no effect on insulin action in people with prediabetes.This trial was registered on clinicaltrials.gov as NCT01889810.
Asunto(s)
Colecalciferol/administración & dosificación , Suplementos Dietéticos , Resistencia a la Insulina , Células Secretoras de Insulina/fisiología , Estado Prediabético/fisiopatología , Adulto , Anciano , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
AIMS: Assess insulin sensitivity after treatment with a selective PPAR-alpha agonist compared to an HMG CoA reductase inhibitor in human subjects with type 2 diabetes mellitus. METHODS: Thirteen subjects with Type 2 diabetes mellitus were studied in a double-blind crossover design with 4-week placebo run-in and washout and 12-week treatment periods, randomised to micronised fenofibrate 267 mg or atorvastatin 10mg daily followed by the alternate drug in the second period. Insulin resistance was measured using the isoglycaemic hyperinsulinaemic clamp method with isotope dilution. RESULTS: Weight, physical activity and other medications did not change. Total cholesterol (mean +/- standard error) was 4.60+/-0.21 versus 3.9+/-0.22 mmol/L after fenofibrate and atorvastatin respectively, p<0.05. LDL was 2.70+/-0.19 versus 1.95+/-0.23 mmol/L, p<0.05 and triglyceride 1.64+/-0.23 versus 1.84+/-0.26 mmol/L, p<0.05. Insulin-stimulated whole-body glucose disposal (35.4+/-3.1 versus 33.2+/-3.0 µmol/kg/min) and nadir endogenous glucose production (6.2+/-1.4 versus 7.0+/-1.1 µmol/kg/min) revealed no significant differences in effects of the treatments. CONCLUSIONS: In human subjects with Type 2 diabetes mellitus there were characteristic differences in lipid profile changes but no difference in insulin sensitivity after treatment with micronised fenofibrate compared to atorvastatin. This study finds no evidence of increased insulin sensitivity using this selective PPAR-alpha agonist over a commonly used statin at these doses.
Asunto(s)
Diabetes Mellitus Tipo 2/fisiopatología , Fenofibrato/farmacología , Ácidos Heptanoicos/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Hipolipemiantes/farmacología , Resistencia a la Insulina/fisiología , PPAR alfa/agonistas , Pirroles/farmacología , Atorvastatina , Glucemia/metabolismo , Colesterol/sangre , Estudios Cruzados , Diabetes Mellitus Tipo 2/sangre , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Técnica de Clampeo de la Glucosa , Humanos , Insulina/sangre , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: The purpose of this randomized controlled trial was to investigate the dose-response effect of fruit and vegetable (F&V) intake on insulin resistance (IR) in people who are overweight and at high risk of cardiovascular disease (CVD). RESEARCH DESIGN AND METHODS: A total of 105 participants (mean age 56 years) followed a 4-week washout diet (one to two portions of F&Vs per day). Ninety-two participants completed the washout and were randomized to receive one to two, four, or seven portions of F&Vs per day for 12 weeks. IR was assessed at the start and end of this 12-week period by the two-step euglycemic-hyperinsulinemic clamp. Compliance was monitored using a combination of 4-day food diaries and plasma biomarkers of F&V intake. RESULTS: A total of 89 participants completed the study. Participants attained self-reported F&V intakes of 1.8, 3.8, and 7.0 portions per day (P < 0.001) per group. There was a significant linear increase in serum lutein status across the groups, indicating good compliance (P < 0.001), and body weight was maintained (P = 0.77). No significant difference was found between groups in terms of a change in measures of whole-body, peripheral, or hepatic IR or adiponectin multimers. CONCLUSIONS: Increased consumption of F&Vs, as advocated in public-health advice, has no effect on IR in overweight individuals who are at high risk of CVD when body weight is maintained. Recent evidence from systematic reviews indicates that particular classes or types of F&Vs may have particular antidiabetic properties; hence, it is possible that benefits may only be observed in response to a more specific fruit or vegetable intervention.
Asunto(s)
Enfermedades Cardiovasculares/prevención & control , Conducta Alimentaria , Frutas , Resistencia a la Insulina , Sobrepeso/dietoterapia , Verduras , Biomarcadores/sangre , Peso Corporal , Enfermedades Cardiovasculares/etiología , Registros de Dieta , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Sobrepeso/complicaciones , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Concern exists regarding adverse metabolic effects of antihypertensive agents. In the United States, diuretics are recommended first-line but additional agents, usually angiotensin-converting enzyme (ACE) inhibitors, are often required to meet blood pressure targets. We have previously shown that the combination of low-dose diuretic with an ACE inhibitor has detrimental effects on insulin action compared with ACE inhibitor alone in hypertensive type 2 diabetic patients. Our aim was to establish whether similar effects occur in nondiabetic hypertensive patients using this combination. A randomized double-blind placebo-controlled crossover design was used. After a 6-week run-in, when regular antihypertensive medications were withdrawn and placebo substituted, patients received captopril 50 mg twice daily with either bendroflumethiazide 1.25 mg (CB) or placebo (CP) for 12 weeks with a 6-week wash-out between treatments. Insulin action was assessed by hyperinsulinemic euglycemic clamp after the 6-week run-in and at the end of each treatment period. There were no differences between treatments in fasting glucose or insulin concentrations. Glucose infusion rates required to maintain euglycemia were the same with each treatment (CP 22.1±2.2 vs CB 22.2±2.2 µmol/kg per minute). There was no difference in endogenous glucose production in the basal state (CP 8.9±0.5 vs CB 9.5±0.7 µmol/kg per minute; P=0.23) or during hyperinsulinemia (CP 2.2±0.6 vs CB 1.5±0.3 µmol/kg per minute; P=0.30). In contrast to the situation in type 2 diabetes mellitus, ACE inhibitor combined with low-dose thiazide diuretic does not adversely affect insulin action when compared with ACE inhibitor alone in nondiabetic hypertensive patients.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Glucemia/metabolismo , Presión Sanguínea/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Resistencia a la Insulina , Insulina/sangre , Tiazidas/administración & dosificación , Adulto , Anciano , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Hipertensión/sangre , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Resultado del TratamientoRESUMEN
AIMS: The effect of dietary sucrose on insulin resistance and the pathogenesis of diabetes and vascular disease is unclear. We assessed the effect of 5% versus 15% sucrose intakes as part of a weight maintaining, eucaloric diet in overweight/obese subjects. METHODS: Thirteen subjects took part in a randomised controlled crossover study (M:F 9:4, median age 46 years, range 37-56 years, BMI 31.7±0.9 kg/m(2)). Subjects completed two 6 week dietary periods separated by 4 week washout. Diets were designed to have identical macronutrient profile. Insulin action was assessed using a two-step hyperinsulinaemic euglycaemic clamp; glucose tolerance, vascular compliance, body composition and lipid profiles were also assessed. RESULTS: There was no change in weight or body composition between diets. There was no difference in peripheral glucose utilization or suppression of endogenous glucose production. Fasting glucose was significantly lower after the 5% diet. There was no demonstrated effect on lipid profiles, blood pressure or vascular compliance. CONCLUSION: A low-sucrose diet had no beneficial effect on insulin resistance as measured by the euglycaemic glucose clamp. However, reductions in fasting glucose, one hour insulin and insulin area under the curve with the low sucrose diet on glucose tolerance testing may indicate a beneficial effect and further work is required to determine if this is the case. Clinical Trial Registration number ISRCTN50808730.
Asunto(s)
Composición Corporal/efectos de los fármacos , Dieta , Glucosa/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Obesidad , Sobrepeso , Sacarosa/administración & dosificación , Resistencia Vascular/efectos de los fármacos , Adulto , Composición Corporal/fisiología , Dieta/métodos , Relación Dosis-Respuesta a Droga , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Femenino , Humanos , Resistencia a la Insulina/fisiología , Masculino , Metaboloma/efectos de los fármacos , Metaboloma/fisiología , Persona de Mediana Edad , Obesidad/sangre , Obesidad/dietoterapia , Obesidad/metabolismo , Obesidad/fisiopatología , Concentración Osmolar , Sobrepeso/sangre , Sobrepeso/dietoterapia , Sobrepeso/metabolismo , Sobrepeso/fisiopatología , Resistencia Vascular/fisiologíaRESUMEN
OBJECTIVE: Addition of dehydroepiandrosterone sulphate (DHEAS) to standard pituitary replacement may improve quality of life and glucose metabolism. Conflicting results from the previous work probably relate to differences in populations studied and assessment techniques used. We examined the effects of DHEAS on insulin action and the quality of life in female patients with hypopituitary hypoadrenalism. DESIGN: Randomized, double-blind, placebo-controlled, crossover design was used. Patients received either DHEAS 50 mg daily or placebo for 12 weeks. PATIENTS: Fourteen hypopituitary females on stable standard replacement therapy and with low DHEAS were enrolled. MEASUREMENTS: Insulin action by euglycaemic hyperinsulinaemic clamp and extensive quality of life parameters were assessed after each treatment. RESULTS: Serum DHEAS (DHEAS 5·4 ± 0·8 vs placebo <0·8 ± 0·0 µm; P < 0·001) and androstenedione (DHEAS 4·1 ± 0·8 vs placebo 1·3 ± 0·2 nm; P < 0·05) rose to within the normal range after DHEAS 50 mg daily. There were no differences between treatments in testosterone, sex hormone-binding globulin (SHBG) or IGF-1. Quality of life measures were unchanged after DHEAS. There were no differences between treatments in fasting glucose, serum insulin, HbA1c or in insulin action (glucose infusion rates required to maintain euglycaemia; DHEAS 21·9 ± 2·5 vs placebo 24·5 ± 2·1 µmol/kg/min; P = 0·4). Triglyceride concentrations were lower following DHEAS (DHEAS 1·24 ± 0·18 vs placebo 1·41 ± 0·19 mm; P < 0·05) but other lipid parameters remained unchanged. CONCLUSION: There were no differences compared with placebo in quality of life or insulin action after DHEAS replacement therapy for 12 weeks. These results do not provide evidence for the addition of DHEAS to standard hypopituitary replacement therapy.
Asunto(s)
Sulfato de Deshidroepiandrosterona/uso terapéutico , Hipopituitarismo/sangre , Hipopituitarismo/tratamiento farmacológico , Insulina/sangre , Insuficiencia Suprarrenal/sangre , Insuficiencia Suprarrenal/complicaciones , Insuficiencia Suprarrenal/tratamiento farmacológico , Adulto , Anciano , Glucemia/metabolismo , Estudios Cruzados , Sulfato de Deshidroepiandrosterona/efectos adversos , Método Doble Ciego , Femenino , Técnica de Clampeo de la Glucosa , Humanos , Hipopituitarismo/complicaciones , Lípidos/sangre , Persona de Mediana Edad , Calidad de VidaRESUMEN
OBJECTIVE: Low-fat hypocaloric diets reduce insulin resistance and prevent type 2 diabetes in those at risk. Low-carbohydrate, high-fat diets are advocated as an alternative, but reciprocal increases in dietary fat may have detrimental effects on insulin resistance and offset the benefits of weight reduction. RESEARCH DESIGN AND METHODS: We investigated a low-fat (20% fat, 60% carbohydrate) versus a low-carbohydrate (60% fat, 20% carbohydrate) weight reduction diet in 24 overweight/obese subjects ([mean +/- SD] BMI 33.6 +/- 3.7 kg/m(2), aged 39 +/- 10 years) in an 8-week randomized controlled trial. All food was weighed and distributed, and intake was calculated to produce a 500 kcal/day energy deficit. Insulin action was assessed by the euglycemic clamp and insulin secretion by meal tolerance test. Body composition, adipokine levels, and vascular compliance by pulse-wave analysis were also measured. RESULTS: Significant weight loss occurred in both groups (P < 0.01), with no difference between groups (P = 0.40). Peripheral glucose uptake increased, but there was no difference between groups (P = 0.28), and suppression of endogenous glucose production was also similar between groups. Meal tolerance-related insulin secretion decreased with weight loss with no difference between groups (P = 0.71). The change in overall systemic arterial stiffness was, however, significantly different between diets (P = 0.04); this reflected a significant decrease in augmentation index following the low-fat diet, compared with a nonsignificant increase within the low-carbohydrate group. CONCLUSIONS: This study demonstrates comparable effects on insulin resistance of low-fat and low-carbohydrate diets independent of macronutrient content. The difference in augmentation index may imply a negative effect of low-carbohydrate diets on vascular risk.
Asunto(s)
Enfermedades Cardiovasculares/etiología , Dieta Reductora/métodos , Carbohidratos de la Dieta/administración & dosificación , Grasas de la Dieta/administración & dosificación , Resistencia a la Insulina , Resistencia Vascular , Pérdida de Peso , Adulto , Enfermedades Cardiovasculares/prevención & control , Dieta Baja en Carbohidratos , Dieta con Restricción de Grasas , Ingestión de Energía , Femenino , Técnica de Clampeo de la Glucosa , Humanos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
The long-term impact of dietary carbohydrate type, in particular sucrose, on insulin resistance and the development of diabetes and atherosclerosis is not established. Current guidelines for the healthy population advise restriction of sucrose intake. We investigated the effect of high- versus low-sucrose diet (25 vs. 10%, respectively, of total energy intake) in 13 healthy subjects aged 33 +/- 3 years (mean +/- SE), BMI 26.6 +/- 0.9 kg/m(2), in a randomized crossover design with sequential 6-week dietary interventions separated by a 4-week washout. Weight maintenance, eucaloric diets with identical macronutrient profiles and fiber content were designed. All food was weighed and distributed. Insulin action was assessed using a two-step euglycemic clamp; glycemic profiles were assessed by the continuous glucose monitoring system and vascular compliance by pulse-wave analysis. There was no change in weight across the study. Peripheral glucose uptake and suppression of endogenous glucose production were similar after each diet. Glycemic profiles and measures of vascular compliance did not change. A rise in total and LDL cholesterol was observed. In this study, a high-sucrose intake as part of an eucaloric, weight-maintaining diet had no detrimental effect on insulin sensitivity, glycemic profiles, or measures of vascular compliance in healthy nondiabetic subjects.
Asunto(s)
Dieta Baja en Carbohidratos , Resistencia a la Insulina/fisiología , Sacarosa , Enfermedades Vasculares/epidemiología , Adulto , Glucemia/metabolismo , LDL-Colesterol/sangre , Ingestión de Energía , Humanos , Masculino , Valores de Referencia , Factores de RiesgoRESUMEN
Essential hypertension is associated with impairment of both endothelial function and insulin action, and this has provided rationale for the use of antihypertensive agents that are at least neutral, if not beneficial, in these areas. This study examines the effect of the alpha-adrenergic blocker, doxazosin, on endothelial function and insulin action. Sixteen patients with essential hypertension were recruited with 13 (3 men/10 women; median age, 55 years; range, 38 to 65 years) completing the study. A double-blind, placebo-controlled crossover study design was used. After a 6-week placebo run-in, there were two 12-week treatment periods of either placebo or doxazosin, separated by a 6-week wash out period. Subjects were studied at the end of each treatment period with endothelial function assessed by forearm plethysmography and insulin action by the hyperinsulinemic clamp technique. Blood pressure was significantly lowered by doxazosin (doxazosin 144 +/-3/86 +/- 2 mm Hg; placebo 159 +/- 3/96 +/- 1 mm Hg, P <.005 for both systolic and diastolic pressure; mean +/- SEM). Baseline forearm blood flow (FBF) was unchanged (doxazosin 4.9 +/- 0.9; placebo 4.0 +/- 0.7 mL x 100 mL(-1) x min(-1), P >.05), however, FBF responses (area under dose response curve, percentage change in infused:control arm ratio) to acetylcholine (endothelium-dependent vasodilation) were improved by doxazosin (doxazosin 58.6 +/- 11.7 standard units [SU]; placebo 22.1 +/- 7.0 SU, P =.03) with responses to sodium nitroprusside (endothelium-independent vasodilation) unchanged (doxazosin 40.3 +/- 5.5 SU; placebo 46.3 +/- 8.1 SU, P >.05). Exogenous glucose infusion rates to maintain euglycemia during hyperinsulinemia were not significantly different (doxazosin 30.4 +/- 0.9; placebo 32.3 +/- 1.0 micromol x kg(-1) min(-1), P >.05). Suppression of postabsorptive endogenous glucose production by insulin was also unchanged by treatment (doxazosin 65.6% +/- 7.5% suppression; placebo 68.3% +/- 11.2% suppression, P >.05). Doxazosin has a neutral effect on both peripheral and hepatic insulin action, but improves endothelium-dependent vasodilation. These results indicate that doxazosin can be used safely in patients with insulin resistance, while its positive effect on endothelial function may lessen the subsequent incidence of atherosclerosis.
Asunto(s)
Antagonistas Adrenérgicos alfa/uso terapéutico , Doxazosina/uso terapéutico , Endotelio Vascular/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Insulina/farmacología , Acetilcolina , Adulto , Anciano , Velocidad del Flujo Sanguíneo , Glucemia/análisis , Estudios Cruzados , Método Doble Ciego , Endotelio Vascular/fisiopatología , Femenino , Antebrazo/irrigación sanguínea , Técnica de Clampeo de la Glucosa , Hemoglobina Glucada/análisis , Humanos , Insulina/sangre , Resistencia a la Insulina , Lípidos/sangre , Masculino , Persona de Mediana Edad , Nitroprusiato , PlacebosRESUMEN
The presence and biological significance of circulating glycated insulin has been evaluated by high-pressure liquid chromatography (HPLC), electrospray ionization mass spectrometry (ESI-MS), radioimmunoassay (RIA), receptor binding, and hyperinsulinemic-euglycemic clamp techniques. ESI-MS analysis of an HPLC-purified plasma pool from four male type 2 diabetic subjects (HbA(1c) 8.1 +/- 0.2%, plasma glucose 8.7 +/- 1.3 mmol/l [means +/- SE]) revealed two major insulin-like peaks with retention times of 14-16 min. After spectral averaging, the peak with retention time of 14.32 min exhibited a prominent triply charged (M+3H)(3+) species at 1,991.1 m/z, representing monoglycated insulin with an intact M(r) of 5,970.3 Da. The second peak (retention time 15.70 min) corresponded to native insulin (M(r) 5,807.6 Da), with the difference between the two peptides (162.7 Da) representing a single glucitol adduct (theoretical 164 Da). Measurement of glycated insulin in plasma of type 2 diabetic subjects by specific RIA gave circulating levels of 10.1 +/- 2.3 pmol/l, corresponding to approximately 9% total insulin. Biological activity of pure synthetic monoglycated insulin (insulin B-chain Phe(1)-glucitol adduct) was evaluated in seven overnight-fasted healthy nonobese male volunteers using two-step euglycemic-hyperinsulinemic clamps (2 h at 16.6 micro g x kg(-1) x min(-1), followed by 2 h at 83.0 micro g x kg(-1) x min(-1); corresponding to 0.4 and 2.0 mU x kg(-1) x min(-1)). At the lower dose, the exogenous glucose infusion rates required to maintain euglycemia during steady state were significantly lower with glycated insulin (P < 0.01) and approximately 70% more glycated insulin was required to induce a similar rate of insulin-mediated glucose uptake. Maximal responses at the higher rates of infusion were similar for glycated and control insulin. Inhibitory effects on endogenous glucose production, insulin secretion, and lipolysis, as indicated by measurements of C-peptide, nonesterified free fatty acids, and glycerol, were also similar. Receptor binding to CHO-T cells transfected with human insulin receptor and in vivo metabolic clearance revealed no differences between glycated and native insulin, suggesting that impaired biological activity is due to a postreceptor effect. The present demonstration of glycated insulin in human plasma and related impairment of physiological insulin-mediated glucose uptake suggests a role for glycated insulin in glucose toxicity and impaired insulin action in type 2 diabetes.