Acute effects of dietary glycemic index on antioxidant capacity in a nutrient-controlled feeding study.

Oxidative stress, caused by an imbalance between antioxidant capacity and reactive oxygen species, may be an early event in a metabolic cascade elicited by a high glycemic index (GI) diet, ultimately increasing the risk for cardiovascular disease and diabetes. We conducted a feeding study to evaluate the acute effects of low-GI compared with high-GI diets on oxidative stress and cardiovascular disease risk factors. The crossover study comprised two 10-day in-patient admissions to a clinical research center. For the admissions, 12 overweight or obese (BMI: 27-45 kg/m(2)) male subjects aged 18-35 years consumed low-GI or high-GI diets controlled for potentially confounding nutrients. On day 7, after an overnight fast and then during a 5-h postprandial period, we assessed total antioxidant capacity (total and perchloric acid (PCA) protein-precipitated plasma oxygen radical absorbance capacity (ORAC) assay) and oxidative stress status (urinary F(2alpha)-isoprostanes (F(2)IP)). On day 10, we measured cardiovascular disease risk factors. Under fasting conditions, total antioxidant capacity was significantly higher during the low-GI vs. high-GI diet based on total ORAC (11,736 +/- 668 vs. 10,381 +/- 612 micromol Trolox equivalents/l, P = 0.002) and PCA-ORAC (1,276 +/- 96 vs. 1,210 +/- 96 micromol Trolox equivalents/l, P = 0.02). Area under the postprandial response curve also differed significantly between the two diets for total ORAC and PCA-ORAC. No diet effects were observed for the other variables. Enhancement in plasma total antioxidant capacity occurs within 1 week on a low-GI diet, before changes in other risk factors, raising the possibility that this phenomenon may mediate, at least in part, the previously reported effects of GI on health.

Management of maturity-onset diabetes of the young (MODY)

La diabetes de tipo MODY (maturity-onset diabetes of the young) afecta entre 1 y 5% de los pacientes con diabetes en los Estados Unidos y otras naciones industrializadas. Las tres características más importantes de esta entidad son: desarrollo de diabetes antes de la edad de 25 a 30 años en ausencia de autoanticuerpos pancreáticos, transmisión genética autosómica dominante y evidencia de secreción residual de insulina. Existen seis subtipos de MODY de los cuales, el tipo 2 (mutación de la glucoquinasa-GKS) y el tipo 3 (mutación del factor nuclear hepático 1 alfa (HNF-1-alfa) son los más prevalentes (70% de todos los casos de diabetes de tipo MODY). Las sulfonilureas son la medicación de primera línea tanto en los niños como en los adultos, cuando la terapia dietética no es suficiente para normalizar la glicemia. Aunque los pacientes con subtipos 1, 3, y 4 usualmente responden bien a la terapia oral con sulfonilureas, un porcentaje significativo de pacientes con los subtipos 1 y 3 necesitan terapia con insulina debido a un deterioro progresivo de las células beta del páncreas. El mantenimiento de un estilo de vida activo y un peso normal, son recomendaciones esenciales en todos los pacientes con diabetes de tipo MODY.

Maturity-Onset Diabetes of the Young (MODY) affects 1-5% of people with diabetes in the USA and other industrialized countries. The three main features of MODY include: Development of diabetes before the age of 25 to 30 in absence of pancreatic antibodies, autosomal dominant inheritance, and evidence of residual insulin secretion. There are six subtypes of MODY of which, MODY2 (GCK mutation) and MODY3 (HNF1-alphaƒnmutation) are the most prevalent, accounting for more than 70% of cases. Sulfonylureas (SUs) remain the medication of first choice in children and adults when dietary therapy is insufficient to maintain normoglycemia. Although patients with MODY1, 3, and 4 usually respond very well to oral SUs, due to progressive beta-cell failure, a significant proportion of MODY1 and MODY3 patients may eventually require insulin therapy. Leading an active lifestyle and maintaining a normal weight are essential recommendations for all MODY patients.

Diabetes mellitus in children and adolescents.

Until recently, diabetes in children was virtually synonymous with type 1 diabetes mellitus, whereas type 2 diabetes was a disease of middle age and the elderly. Over the past 10-20 years, an alarming increase in the prevalence of type 2 diabetes has been reported from pediatric diabetes centers in North America and elsewhere in the world. Lifestyle factors responsible for the worldwide epidemic of overweight and obesity are responsible for the increase in the prevalence of type 2 diabetes in adults and children. This article briefly discusses the diagnosis and major types of diabetes in children but focuses on aspects of type 2 diabetes in children and adolescents, including demographics, pathophysiology, clinical presentation, screening, prevention and treatment. The identification of children at risk for type 2 diabetes and the implementation of community-wide preventive programs will be essential to reverse the tide. The availability of calorie dense "fast foods," candy, and sugared soft drinks must be restricted in schools and other venues frequented by children. Parents must limit the amount of time their children spend watching television and playing computer games. After-school programs that promote physical activity should be a priority of local and central governmental agencies. Prevention will only succeed if governments and local communities recognize that childhood obesity is an important public health problem and provide an environment that promotes changes in lifestyle that prevent and reverse obesity.

Enhanced repression by HESX1 as a cause of hypopituitarism and septooptic dysplasia.

HESX1 is a paired-like homeodomain transcription factor that functions as a repressor of PROP1-mediated gene stimulation. Mutations in HESX1 have been implicated in cases of septooptic dysplasia and congenital hypopituitarism. All mutations in HESX1 identified to date have resulted in impaired DNA binding and defective HESX1 action. We have identified a novel HESX1 mutation in genomic nucleotide position 1684 (g.1684delG), which results in a mutant protein with increased DNA binding. In turn, this mutation causes increased repression of PROP1-dependent gene activity. These data suggest that enhancement of transcriptional repression during pituitary organogenesis is a novel mechanism for the development of congenital pituitary disorders.

Human type 3 iodothyronine selenodeiodinase is located in the plasma membrane and undergoes rapid internalization to endosomes.

The type 3 iodothyronine selenodeiodinase (D3) is an integral membrane protein that inactivates thyroid hormones. By using immunofluorescence cytochemistry confocal microscopy of live or fixed cells transiently expressing FLAG-tagged human D3 or monkey hepatocarcinoma cells expressing endogenous D3, we identified D3 in the plasma membrane. It co-localizes with Na,K-ATPase alpha, with the early endosomal marker EEA-1 and clathrin, but not with two endoplasmic reticulum resident proteins. Most of the D3 molecule is extracellular and can be biotinylated with a cell-impermeant probe. There is constant internalization of D3 that is blocked by sucrose or methyl-beta-cyclodextrin-containing medium. Exposing cells to a weak base such as primaquine increases the pool of internalized D3, suggesting that D3 is recycled between plasma membrane and early endosomes. Such recycling could account for the much longer half-life of D3 (12 h) than the thyroxine activating members of the selenodeiodinase family, type 1 (D1; 8 h) or type 2 (D2; 2 h) deiodinase. The extracellular location of D3 gives ready access to circulating thyroid hormones, explaining its capacity for rapid inactivation of circulating thyroxine and triiodothyronine in patients with hemangiomas and its blockade of the access of maternal thyroid hormones to the human fetus.

Ubc6p and ubc7p are required for normal and substrate-induced endoplasmic reticulum-associated degradation of the human selenoprotein type 2 iodothyronine monodeiodinase.

The type 2 monodeiodinase (D2) is an endoplasmic reticulum-resident membrane selenoprotein responsible for catalyzing the first step in thyroid hormone action, T(4) deiodination to T(3). Its short half-life is due to ubiquitination and proteolysis by proteasomes, a mechanism that is accelerated by D2 interaction with T(4). To identify proteins involved in D2 ubiquitination, a FLAG-tagged selenocystine133-to-Cys mutation of the human D2 (CysD2) was created and expressed in Saccharomyces cerevisiae using the GAL1 gene promoter. CysD2 activity was detected in the microsomes, indistinguishable from transiently expressed CysD2 in vertebrate cells. Treatment with 100 mg/ml cycloheximide or 30 micro M T(4) caused rapid loss of CysD2 (t(1/2) = approximately 30 min). Clasto-lactacystin beta-lactone not only increased galactose-inducible CysD2 but also stabilized CysD2 in the presence of cycloheximide or T(4). Immunoprecipitation with anti-FLAG antibody combined with Western analysis with antiubiquitin revealed that CysD2 is heavily ubiquitinated. Expression of CysD2 in yeast strains that lack the ubiquitin conjugases Ubc6p or Ubc7p stabilized CysD2 half-life by markedly reducing CysD2 ubiquitination, whereas no difference was detected in Ubc1p-deficient mutants. Similarly, expression of CysD2 in UBC6 and UBC7 mutants also impaired the substrate-induced loss of CysD2 activity and protein. In conclusion, Ubc6p and Ubc7p are required for normal and substrate-induced ubiquitination and proteolysis of D2.