RESUMEN
We aimed to evaluate the effect of acetylsalicylic acid (ASA) treatment on diabetes-induced erectile dysfunction. Adult male Sprague-Dawley rats were divided into four groups as follows: (i) control (C), (ii) diabetic (D), (iii) ASA-treated control (C+ASA) and (iv) ASA-treated diabetic (D+ASA) groups. In groups 2 and 4, diabetes was induced by injection of 35 mg kg(-1) streptozotocin. ASA (100 mg kg(-1) day(-1) , orally) was administrated to rats in groups 3 and 4 for 8 weeks. Both intracavernosal pressure (ICP) and mean arterial blood pressure (MAP) were measured in in vivo studies. In organ bath, the relaxation responses to acetylcholine (ACh), electrical field stimulation (EFS) and sodium nitroprusside were tested in corpus cavernosum (CC) strips. The mRNA expression for neuronal nitric oxide synthase (nNOS) was calculated using reverse transcription polymerase chain reaction technique. In in vivo experiments, diabetic rats displayed reduced ICP/MAP values, which were normalised with ASA treatment. The relaxant response to high-dose ACh and EFS at low frequencies (1-8 Hz) in CC strips from the D+ASA group were significantly higher when compared to the D group. Treatment with ASA normalised the raised mRNA expressions of nNOS in diabetic penile tissues. ASA may be involved in mRNA of protein synthesis of NO released from nonadrenergic and noncholinergic cavernosal nerve in diabetes.
Asunto(s)
Aspirina/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/fisiopatología , Erección Peniana/efectos de los fármacos , Acetilcolina/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Complicaciones de la Diabetes/genética , Complicaciones de la Diabetes/fisiopatología , Complicaciones de la Diabetes/prevención & control , Diabetes Mellitus Experimental/genética , Estimulación Eléctrica , Disfunción Eréctil/genética , Disfunción Eréctil/fisiopatología , Disfunción Eréctil/prevención & control , Masculino , Óxido Nítrico Sintasa de Tipo I/genética , Nitroprusiato/farmacología , Erección Peniana/genética , Erección Peniana/fisiología , Pene/irrigación sanguínea , Pene/efectos de los fármacos , Pene/fisiopatología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Thyroid hormone deficiency has been reported to decrease expression and function of both beta(1)- and beta(2)-adrenoceptor in different tissues including heart. The purpose of this study was to examine the possible contribution of beta(3)-adrenoceptors to cardiac dysfunction in hypothyroidism. In addition, effect of this pathology on beta(1)- and beta(2)-adrenoceptor was investigated. Hypothyroidism was induced by adding methimazole (300 mg/l) to drinking water of rats for 8 weeks. Cardiac hemodynamic parameters were measured in anesthetised rats in vivo. Responses to beta-adrenoceptor agonists were examined in rat papillary muscle in vitro. We also studied the effect of hypotyroidism on mRNA expression of beta-adrenoceptors, Gialpha, GRK, and eNOS in rat heart. All of the hemodynamic parameters (systolic, diastolic and mean arterial pressure, left ventricular pressure, heart rate, +dp/dt, and -dp/dt) were significantly reduced by the methimazole treatment. The negative inotropic effect elicited by BRL 37344 (a beta(3)-adrenoceptor preferential agonist) and positive inotropic effects produced by isoprenaline and noradrenaline, respectively, were significantly decreased in papillary muscle of hypothyroid rats as compared to those of controls. On the other hand, hypothyroidism resulted in increased cardiac beta(2)- and beta(3)-adrenoceptor, Gialpha(2), Gialpha(3), GRK3, and eNOS mRNA expressions. However, beta(1)-adrenoceptor and GRK2 mRNA expressions were not changed significantly in this pathology. These results show that mRNA expression of beta(3)-adrenoceptors as well as the signalling pathway components mediated through beta(3)-adrenoceptors are significantly increased in hypothyroid rat heart. Since we could not correlate these alternates with the decreased negative inotropic response mediated by this receptor subtype, it is not clear whether these changes are important for hypothyroid induced reduction in cardiac function.
Asunto(s)
Hipotiroidismo/metabolismo , Miocardio/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Agonistas Adrenérgicos beta/farmacología , Animales , Hipotiroidismo/genética , Masculino , Modelos Animales , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Adrenérgicos beta/metabolismo , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/metabolismo , Receptores Adrenérgicos beta 3/genéticaAsunto(s)
Acantosis Nigricans/diagnóstico , Acantosis Nigricans/sangre , Niño , Femenino , Humanos , Insulina/sangreAsunto(s)
Alopecia/inducido químicamente , Fármacos Anti-VIH/efectos adversos , Enfermedad de Graves/inducido químicamente , Infecciones por VIH/complicaciones , Inhibidores de la Proteasa del VIH/efectos adversos , Inhibidores de la Transcriptasa Inversa/efectos adversos , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Adulto , Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Inhibidores de la Proteasa del VIH/uso terapéutico , Humanos , Masculino , Inhibidores de la Transcriptasa Inversa/uso terapéuticoRESUMEN
The lipoatrophy syndromes are a heterogeneous group of syndromes characterized by a paucity of adipose tissue. Severe lipoatrophy is associated with insulin-resistant diabetes mellitus (DM). The loss of adipose tissue can have a genetic, immune, or infectious/drug-associated etiology. Causative mutations have been identified in patients for one form of partial lipoatrophy--Dunnigan-type familial partial lipodystrophy. Experiments using lipoatrophic mice demonstrate that the diabetes results from the lack of fat and that leptin deficiency is a contributing factor. Thiazolidinedione therapy improves metabolic control in lipoatrophic patients; the efficacy of leptin treatment is currently being investigated.
Asunto(s)
Tejido Adiposo/fisiopatología , Diabetes Mellitus Lipoatrófica/fisiopatología , Tejido Adiposo/patología , Animales , Diabetes Mellitus Lipoatrófica/genética , Humanos , RatonesRESUMEN
There is uncertainty about the site(s) of action of the antidiabetic thiazolidinediones (TZDs). These drugs are agonist ligands of the transcription factor PPAR gamma, which is abundant in adipose tissue but is normally present at very low levels in liver and muscle. We have studied the effects of TZDs in A-ZIP/F-1 mice, which lack white adipose tissue. The A-ZIP/F-1 phenotype strikingly resembles that of humans with severe lipoatrophic diabetes, including the lack of fat, marked insulin resistance and hyperglycemia, hyperlipidemia, and fatty liver. Rosiglitazone or troglitazone treatment did not reduce glucose or insulin levels, suggesting that white adipose tissue is required for the antidiabetic effects of TZDs. However, TZD treatment was effective in lowering circulating triglycerides and increasing whole body fatty acid oxidation in the A-ZIP/F-1 mice, indicating that this effect occurs via targets other than white adipose tissue. A-ZIP/F-1 mice have markedly increased liver PPAR gamma mRNA levels, which may be a general property of fatty livers. Rosiglitazone treatment increased the triglyceride content of the steatotic livers of A-ZIP/F-1 and ob/ob mice, but not the "lean" livers of fat-transplanted A-ZIP/F-1 mice. In light of this evidence that rosiglitazone acts differently in steatotic livers, the effects of rosiglitazone, particularly on hepatic triglyceride levels, should be examined in humans with hepatic steatosis.
Asunto(s)
Tejido Adiposo/fisiología , Cromanos/uso terapéutico , Diabetes Mellitus Lipoatrófica/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Tiazoles/uso terapéutico , Tiazolidinedionas , Triglicéridos/metabolismo , Animales , Glucemia , Diabetes Mellitus Lipoatrófica/metabolismo , Modelos Animales de Enfermedad , Femenino , Insulina/metabolismo , Ligandos , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptores Citoplasmáticos y Nucleares/genética , Pruebas de Función Respiratoria , Rosiglitazona , Factores de Transcripción/genética , TroglitazonaAsunto(s)
Diabetes Mellitus/patología , Hipoglucemia/patología , Insulinoma/patología , Neoplasias Pancreáticas/patología , Proinsulina/metabolismo , Glucemia/metabolismo , Diabetes Mellitus/etiología , Humanos , Hipoglucemia/etiología , Insulina/sangre , Insulinoma/complicaciones , Insulinoma/metabolismo , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/complicaciones , Neoplasias Pancreáticas/metabolismoRESUMEN
BACKGROUND: Troglitazone promotes adipocyte differentiation in vitro and increases insulin sensitivity in vivo. Therefore, troglitazone may have therapeutic benefit in lipoatrophic diabetes. OBJECTIVE: To determine whether troglitazone ameliorates hyperglycemia and hypertriglyceridemia or increases fat mass in lipoatrophic patients. DESIGN: Open-labeled prospective study. SETTING: United States and Canada. PATIENTS: 20 patients with various syndromes associated with lipoatrophy or lipodystrophy. INTERVENTION: 6 months of therapy with troglitazone, 200 to 600 mg/d. MEASUREMENTS: Levels of hemoglobin A1c triglycerides, free fatty acids, and insulin; respiratory quotient; percentage of body fat; liver volume; and regional fat mass. RESULTS: In the 13 patients with diabetes who completed 6 months of troglitazone therapy, hemoglobin A1c levels decreased by a mean of 2.8% (95% CI, 1.9% to 3.7%; P < 0.001). In all 19 study patients, fasting triglyceride levels decreased by 2.6 mmol/L (230 mg/dL) (CI, 0.7 to 4.5 mmol/L [62 to 398 mg/dL]; P = 0.019) and free fatty acid levels decreased by 325 micromol/L (CI, 135 to 515 micromol/L; P = 0.035). The respiratory quotient decreased by a mean of 0.12 (CI, 0.08 to 0.16; P < 0.001), suggesting that troglitazone promoted oxidation of fat. Body fat increased by a mean of 2.4 percentage points (CI, 1.3 to 4.5 percentage points; P = 0.044). Magnetic resonance imaging showed an increase in subcutaneous adipose tissue but not in visceral fat. In one patient, the serum alanine aminotransferase level increased eightfold during the 10th months of troglitazone treatment but normalized 3 months after discontinuation of treatment Liver biopsy revealed an eosinophilic infiltrate, suggesting hypersensitivity reaction as a cause of hepatotoxicity. CONCLUSION: Troglitazone therapy improved metabolic control and increased body fat in patients with lipoatrophic diabetes. The substantial benefits of troglitazone must be balanced against the risk for hepatotoxicity, which can occur relatively late in the treatment course.
Asunto(s)
Cromanos/uso terapéutico , Hipoglucemiantes/uso terapéutico , Lipodistrofia/tratamiento farmacológico , Tiazoles/uso terapéutico , Tiazolidinedionas , Tejido Adiposo/anatomía & histología , Tejido Adiposo/efectos de los fármacos , Adulto , Anciano , Composición Corporal/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Niño , Cromanos/efectos adversos , Esquema de Medicación , Ácidos Grasos no Esterificados/sangre , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Hipoglucemiantes/efectos adversos , Insulina/sangre , Resistencia a la Insulina/fisiología , Lipodistrofia/sangre , Lipodistrofia/fisiopatología , Hígado/anatomía & histología , Hígado/efectos de los fármacos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Pruebas de Función Respiratoria , Estadísticas no Paramétricas , Síndrome , Tiazoles/efectos adversos , Triglicéridos/sangre , TroglitazonaRESUMEN
Familial partial lipodystrophy (FPLD), Dunnigan variety, is an autosomal dominant disorder characterized by marked loss of subcutaneous adipose tissue from the extremities and trunk but by excess fat deposition in the head and neck. The disease is frequently associated with profound insulin resistance, dyslipidemia, and diabetes. We have localized a gene for FPLD to chromosome 1q21-q23, and it has recently been proposed that nuclear lamin A/C is altered in FPLD, on the basis of a novel missense mutation (R482Q) in five Canadian probands. This gene had previously been shown to be altered in autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD-AD) and in dilated cardiomyopathy and conduction-system disease. We examined 15 families with FPLD for mutations in lamin A/C. Five families harbored the R482Q alteration that segregated with the disease phenotype. Seven families harbored an R482W alteration, and one family harbored a G465D alteration. All these mutations lie within exon 8 of the lamin A/C gene-an exon that has also been shown to harbor different missense mutations that are responsible for EDMD-AD. Mutations could not be detected in lamin A/C in one FPLD family in which there was linkage to chromosome 1q21-q23. One family with atypical FPLD harbored an R582H alteration in exon 11 of lamin A. This exon does not comprise part of the lamin C coding region. All mutations in FPLD affect the globular C-terminal domain of the lamin A/C protein. In contrast, mutations responsible for dilated cardiomyopathy and conduction-system disease are observed in the rod domain of the protein. The FPLD mutations R482Q and R482W occurred on different haplotypes, indicating that they are likely to have arisen more than once.
Asunto(s)
Sustitución de Aminoácidos/genética , Haplotipos/genética , Lipodistrofia/genética , Mutación Missense/genética , Proteínas Nucleares/genética , Alelos , Secuencia de Aminoácidos , Cromosomas Humanos Par 1/genética , Estudios de Cohortes , Análisis Mutacional de ADN , Exones/genética , Femenino , Humanos , Lamina Tipo A , Laminas , Lipodistrofia/fisiopatología , Masculino , Repeticiones de Microsatélite/genética , Datos de Secuencia Molecular , Proteínas Nucleares/química , Linaje , Polimorfismo Genético/genética , Estructura Terciaria de Proteína , Alineación de SecuenciaRESUMEN
Congenital generalized lipodystrophy (CGL, Berardinelli-Seip Syndrome, OMIM # 269700) is a rare autosomal recessive disorder characterized by near complete absence of adipose tissue from birth. Affected individuals have marked insulin resistance, hypertriglyceridemia and acanthosis nigricans, and develop diabetes mellitus during teenage years. The genetic defect for CGL is unknown. A semi-automated genome-wide scan with a set of highly polymorphic short tandem repeats (STR) was carried out in 17 well-characterized pedigrees and identified a locus for CGL to chromosome 9q34. The maximum two-point lod score obtained was 3.6 at D9S1818 (theta(max) = 0.05). There was evidence for genetic heterogeneity (alpha = 0.73) and 2 of the pedigrees were unlinked. Multipoint linkage analysis excluding the 2 unlinked families yielded a peak lod score of 5.4 between loci D9S1818 and D9S1826. The CGL1 critical region harbors a plausible candidate gene encoding the retinoid X receptor alpha (RXRA) that plays a central role in adipocyte differentiation. Identification of the CGL gene(s) will contribute to our understanding of the adipocyte differentiation and elucidation of the mechanisms of insulin resistance in disorders of adipose tissue.
Asunto(s)
Mapeo Cromosómico , Cromosomas Humanos Par 9 , Lipodistrofia/congénito , Lipodistrofia/genética , Acantosis Nigricans/genética , Adipocitos , Adolescente , Diferenciación Celular , Consanguinidad , Diabetes Mellitus/genética , Femenino , Genotipo , Humanos , Hipertrigliceridemia/genética , Resistencia a la Insulina/genética , Escala de Lod , Masculino , Linaje , Receptores de Ácido Retinoico/genética , Receptores X Retinoide , Factores de Transcripción/genéticaAsunto(s)
Síndrome de ACTH Ectópico/complicaciones , Hormona Adrenocorticotrópica/metabolismo , Síndrome de Cushing/etiología , Neoplasias Pulmonares/metabolismo , Síndrome de ACTH Ectópico/patología , Síndrome de ACTH Ectópico/cirugía , Adrenalectomía , Niño , Síndrome de Cushing/cirugía , Femenino , Humanos , Pulmón/patología , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugía , NeumonectomíaAsunto(s)
Acantosis Nigricans/genética , Resistencia a la Insulina/genética , Fosfoproteínas/genética , Receptor de Insulina/genética , Animales , Diabetes Mellitus Tipo 2/genética , Femenino , Humanos , Hiperandrogenismo/genética , Proteínas Sustrato del Receptor de Insulina , Masculino , Ratones , Fosfoproteínas/fisiología , Fosforilación , Mutación Puntual , Polimorfismo Genético , Receptor de Insulina/fisiologíaRESUMEN
This prospective pilot study was undertaken to test the efficacy of oral methyl-prednisolone (MP) therapy at spontaneous remission phase of type 1 diabetes in intervening the course of the disease. Twenty-five type 1 diabetic patients who were classified as having a spontaneous remission (honeymoon) were divided into treatment and non-treatment groups on voluntary basis. Fifteen patients thus making up the treatment group (13 males and 2 females, mean age 23.8 +/- 6.2 years) received 0.7-1.0 mg/kg/day of MP p.o. for 2 weeks. The dose of the drug was then gradually diminished every week until 5 mg/day (approx. 0.1 mg/kg/day) and discontinued at 10 +/- 2 weeks. In case of hyperglycemia occurring in 12 of 15 patients due to the administration of steroid, insulin was used to normalize blood glucose levels (average 0.47 +/- 0.21 IU/kg/day). The non-treatment group (8 males and 2 females, mean age 21.8 +/- 8.9) did not receive any special medication or placebo except for insulin whenever necessary to regulate glycemia. Upon completion of protocol, all patients in treatment group displayed clinical remission with 10 still in non-insulin requiring remission for follow-up periods ranging between 16 and 91 months. The remaining 5 patients relapsed within 3-15 months of therapy. Other metabolic (including basal and stimulated C-peptide levels) and immunological indices that have spontaneously ameliorated with the occurrence of honeymoon were also maintained within normal range in the NIR patients. Meanwhile, natural remission in the non-MP-treated group terminated at 3.4 +/- 0.6 months with deterioration of all metabolic and immunological markers as well as increasing requirements for insulin. In conclusion, the spontaneous remission of the patients could be prolonged significantly by MP therapy as opposed to no therapy (P < 0.001). These results suggest that the spontaneous remission phase may be a crucial point of intervention in immunotherapy of type 1 diabetes and that randomized trials with MP at this particular phase would be worthwhile.