RESUMEN
Kinase suppressor of Ras 2 (KSR2) is an intracellular scaffolding protein involved in multiple signaling pathways. Targeted deletion of Ksr2 leads to obesity in mice, suggesting a role in energy homeostasis. We explored the role of KSR2 in humans by sequencing 2,101 individuals with severe early-onset obesity and 1,536 controls. We identified multiple rare variants in KSR2 that disrupt signaling through the Raf-MEKERK pathway and impair cellular fatty acid oxidation and glucose oxidation in transfected cells; effects that can be ameliorated by the commonly prescribed antidiabetic drug, metformin. Mutation carriers exhibit hyperphagia in childhood, low heart rate, reduced basal metabolic rate and severe insulin resistance. These data establish KSR2 as an important regulator of energy intake, energy expenditure, and substrate utilization in humans. Modulation of KSR2-mediated effects may represent a novel therapeutic strategy for obesity and type 2 diabetes.
Asunto(s)
Resistencia a la Insulina , Obesidad/genética , Proteínas Serina-Treonina Quinasas/genética , Factores de Edad , Edad de Inicio , Secuencia de Aminoácidos , Animales , Niño , Metabolismo Energético , Ácidos Grasos/metabolismo , Femenino , Glucosa/metabolismo , Humanos , Hiperfagia/genética , Hiperfagia/metabolismo , Sistema de Señalización de MAP Quinasas , Masculino , Ratones , Modelos Moleculares , Datos de Secuencia Molecular , Obesidad/epidemiología , Obesidad/metabolismo , Oxidación-Reducción , Proteínas Serina-Treonina Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas B-raf/química , Proteínas Proto-Oncogénicas B-raf/metabolismo , Alineación de SecuenciaRESUMEN
BACKGROUND: We have evaluated the evidence for the association between intake and blood levels of micronutrients and diabetic retinopathy. Treatment for diabetic retinopathy requires significant clinical input and specialist ophthalmologic care. Micronutrients, including vitamin C, vitamin E, and magnesium, may interfere with pathologic mechanisms of diabetic retinopathy and potentially alter its risk. METHODS: We conducted a search of epidemiologic literature in PubMed and Embase from 1988 to May 2008, using keywords for exposures, including magnesium, ascorbic acid, alpha-tocopherol and antioxidants, and outcomes, including diabetic retinopathy. Two authors independently extracted data and assessed the quality of the studies using the Newcastle-Ottawa Scale. The overall quality of evidence was graded as I (highest), II, or III (lowest). RESULTS: Of the 766 studies identified, we reviewed 15 studies, comprising 4094 individuals. For vitamin C, hospital-based studies reported an inverse association between plasma levels with retinopathy, whereas population-based studies showed no association between dietary intake and retinopathy. For vitamin E, there was no association with dietary intake or plasma levels and retinopathy. For magnesium, a single prospective analysis showed an association between low levels in plasma and progression of retinopathy, but cross-sectional studies reported inconsistent results. In the assessment of quality, population-based studies had higher ratings than hospital-based studies. CONCLUSIONS: The evidence suggests that dietary intake or plasma levels of vitamins C and E and magnesium do not seem to be associated with diabetic retinopathy. Because of differences in study designs and measurement of micronutrients, incomplete ascertainment of retinopathy, and residual confounding, these findings require confirmation. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any of the materials discussed in this article.
Asunto(s)
Ácido Ascórbico/sangre , Retinopatía Diabética/sangre , Dieta , Magnesio/sangre , Micronutrientes/sangre , alfa-Tocoferol/sangre , Antioxidantes/metabolismo , HumanosRESUMEN
CONTEXT: Attainment of safe GH and IGF-1 levels is a central goal of acromegaly management. OBJECTIVE: The aim of this study was to determine the extent to which reductions in GH and IGF-1 concentrations correlate with amelioration of radiological, metabolic, vascular, cardiac, and respiratory sequelae in a single unselected patient cohort. STUDY DESIGN: This was a prospective, within-subject comparison in 30 patients with newly diagnosed acromegaly (15 women and 15 men: mean age, 54.3 years; range, 23-78 years) before and after 24 weeks of lanreotide Autogel (ATG) therapy. RESULTS: Reductions in GH and IGF-1 concentrations and tumor volume were observed in all but 2 patients (median changes [Δ]: GH, -6.88 µg/L [interquartile range -16.78 to -3.32, P = .000001]; IGF-1, -1.95 × upper limit of normal [-3.06 to -1.12, P = .000002]; and pituitary tumor volume, -256 mm(3) [-558 to -72.5, P = .0002]). However, apnea/hypopnea index scores showed highly variable responses (P = .11), which were independent of ΔGH or ΔIGF-1, but moderately correlated with Δweight (R(2) = 0.42, P = .0001). Although systolic (P = .33) and diastolic (P = .76) blood pressure were unchanged, improvements in arterial stiffness (aortic pulse wave velocity, -0.4 m/s [-1.2 to +0.2, P = .046]) and endothelial function (flow mediated dilatation, +1.73% [-0.32 to +6.19, P = .0013]) were observed. Left ventricular mass index regressed in men (-11.8 g/cm(2) [-26.6 to -1.75], P = .019) but not in women (P = .98). Vascular and cardiac changes were independent of ΔGH or ΔIGF-1 and also showed considerable interindividual variation. Metabolic parameters were largely unchanged. CONCLUSIONS: Presurgical ATG therapy lowers GH and IGF-1 concentrations, induces tumor shrinkage, and ameliorates/reverses cardiac, vascular, and sleep complications in many patients with acromegaly. However, responses vary considerably between individuals, and attainment of biochemical control cannot be assumed to equate to universal complication control.
Asunto(s)
Acromegalia/tratamiento farmacológico , Hipertensión/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Péptidos Cíclicos/administración & dosificación , Síndromes de la Apnea del Sueño/tratamiento farmacológico , Somatostatina/análogos & derivados , Acromegalia/complicaciones , Acromegalia/cirugía , Adulto , Anciano , Antineoplásicos/administración & dosificación , Femenino , Hormona de Crecimiento Humana/sangre , Humanos , Hipertensión/etiología , Hipertrofia Ventricular Izquierda/etiología , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Persona de Mediana Edad , Cuidados Preoperatorios/métodos , Estudios Prospectivos , Receptores de Somatostatina/antagonistas & inhibidores , Síndromes de la Apnea del Sueño/etiología , Somatostatina/administración & dosificación , Resultado del Tratamiento , Rigidez Vascular/efectos de los fármacos , Adulto JovenRESUMEN
INTRODUCTION: Several studies have suggested an increased prevalence of benign and malignant tumors in acromegaly, particularly colonic neoplasms. The gallbladder's epithelial similarity to the colon raises the possibility that gallbladder polyps (GBP) may occur more frequently in acromegaly. PATIENTS AND METHODS: Thirty-one patients with newly diagnosed acromegaly (14 females, 17 males; mean age 54.7 yr, range 27-76 yr) were referred to our center between 2004 and 2008. All had pituitary adenomas and were treated with somatostatin analogs prior to transsphenoidal surgery. Biliary ultrasonography was performed at the time of referral. In a retrospective case-cohort study, we compared the prevalence of GBP in these scans with those of 13,234 consecutive patients (age range 20-80 yr) presenting at the hospital for abdominal/biliary ultrasound during the same time interval. Associations between GH and IGF-I levels and GBP in acromegaly were also examined. RESULTS: There was a higher prevalence of GBP in patients with acromegaly compared with controls (29.03 vs 4.62%, P = 0.000008); relative risk was 6.29 (95% confidence interval 3.61-10.96). Eight of nine patients with acromegaly and GBP were older than 50 yr of age. GH levels were higher in those with GBP (median 30.8 µg/liter, interquartile range 10.9-39.1) than those without (8.2 µg/liter, interquartile range 6.0-16.0), but IGF-I levels were comparable. CONCLUSIONS: This is the first study to demonstrate an increased prevalence of GBP in patients with newly diagnosed acromegaly. Further studies are required to determine whether these patients are at increased risk of developing gallbladder carcinoma and to define the role, if any, of biliary ultrasound surveillance.
Asunto(s)
Acromegalia/epidemiología , Enfermedades de la Vesícula Biliar/epidemiología , Pólipos/epidemiología , Acromegalia/sangre , Acromegalia/diagnóstico , Acromegalia/etiología , Adenoma/complicaciones , Adulto , Factores de Edad , Anciano , Femenino , Enfermedades de la Vesícula Biliar/sangre , Hormona de Crecimiento Humana/sangre , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Persona de Mediana Edad , Neoplasias Hipofisarias/complicaciones , Pólipos/sangre , PrevalenciaRESUMEN
There is evidence that the oral contraceptive pill (OCP) and smoking contribute independently to risk of circulatory disease. There is mixed evidence that the combined risk may be greater than the sum of these factors operating in isolation. Little is known about how the general population views the risks from OCP use, singly and in combination with smoking. Previous attempts at assessing whether the public views risks as operating synergistically have generally found evidence for subadditive models, where the combined risk is less than the sum of factors operating in isolation. However, concerns have been expressed over the validity of the measures of risk perception used. Therefore, this study used three distinct methods of measurement to assess the extent to which 241 undergraduate students perceive the risks of smoking and the OCP separately and combined, for circulatory disease. For all three methods, respondents read each of four vignettes describing information about a woman's risk factors (with high and low levels of both OCP and smoking), and then estimated risk of circulatory disease using one of the three risk measures. The three measures produced similar ratings. Consistent with the epidemiological evidence, information about smoking had more impact on estimates of overall risk than did information about the OCP For all three measures, responses were consistent with an additive model of risk from smoking and the OCP. This convergence of results from different methods suggests that all three methods of measurement employed, which all had a large number of response options, may be valid.