Impaired Cleavage of Preproinsulin Signal Peptide Linked to Autosomal-Dominant Diabetes

Recently, missense mutations upstream of preproinsulin’s signal peptide (SP) cleavage site were reported to cause mutant INS gene-induced diabetes of youth (MIDY). Our objective was to understand the molecular pathogenesis using metabolic labeling and assays of proinsulin export and insulin and C-peptide production to examine the earliest events of insulin biosynthesis, highlighting molecular mechanisms underlying β-cell failure plus a novel strategy that might ameliorate the MIDY syndrome. We find that whereas preproinsulin-A(SP23)S is efficiently cleaved, producing authentic proinsulin and insulin, preproinsulin-A(SP24)D is inefficiently cleaved at an improper site, producing two subpopulations of molecules. Both show impaired oxidative folding and are retained in the endoplasmic reticulum (ER). Preproinsulin-A(SP24)D also blocks ER exit of coexpressed wild-type proinsulin, accounting for its dominant-negative behavior. Upon increased expression of ER–oxidoreductin-1, preproinsulin-A(SP24)D remains blocked but oxidative folding of wild-type proinsulin improves, accelerating its ER export and increasing wild-type insulin production. We conclude that the efficiency of SP cleavage is linked to the oxidation of (pre)proinsulin. In turn, impaired (pre)proinsulin oxidation affects ER export of the mutant as well as that of coexpressed wild-type proinsulin. Improving oxidative folding of wild-type proinsulin may provide a feasible way to rescue insulin production in patients with MIDY

Amaranth BRS Alegria : alternative for diversification of cropping systems

A diversificação do sistema produtivo depende de espécies com rápido crescimento, tolerância ao déficit hídrico, produção de biomassa, ciclagem de nutrientes e utilização humana e animal. As espécies Amaranthus caudatus, A. cruentus e A. hypochondriacus apresentam essas características e sementes claras, sem dormência. Distinguem-se das invasoras A. spinosus, A. hybridus, A. blitum e A. viridis, com sementes escuras e dormentes. Os grãos, com excelente qualidade protéica, atendem à demanda por dietas especiais, livres de glúten e podem ser usados na alimentação animal. O A. cruentus BRS Alegria, primeira recomendação ao cultivo granífero no Brasil, originou-se da variedade AM 5189, dos Estados Unidos, na qual realizou-se seleção massal. Em sucessão à soja, apresentou produção média de 2.359 kg ha-1 de grãos e 5.650 kg ha-1 de biomassa total em apenas 90 dias de ciclo.Diversification of production systems depends on rapid growth, tolerance to hydric stress, biomass production, nutrient cycling and human and animal utilization. The grain amaranth species Amaranthus caudatus, A. cruentus and A. hypochondriacus, with light seed colour and no dormancy, present these characteristics. They are distinguishable from the weeds A. spinosus, A. hybridus, A. blitum and A. viridis, with dark and dormant seeds. Their grains, with excellent protein quality, can be used in gluten-free special diets and livestock feed. The A. cruentus BRS Alegria, the first recommendation for grain production systems in Brazil, originated from mass selection in the variety AM 5189 of the United States. In double-cropping, after soybeans, it showed average yield of 2,359 kg ha-1 for grain and of 5,650 kg ha-1 for total biomass, in 90 days from emergence to maturity

Amaranto BRS Alegria: alternativa para diversificar os sistemas de produção

Diversification of production systems depends on rapid growth, tolerance to hydric stress, biomass production, nutrient cycling and human and animal utilization. The grain amaranth species Amaranthus caudatus, A. cruentus and A. hypochondriacus, with light seed colour and no dormancy, present these characteristics. They are distinguishable from the weeds A. spinosus, A. hybridus, A. blitum and A. viridis, with dark and dormant seeds. Their grains, with excellent protein quality, can be used in gluten-free special diets and livestock feed. The A. cruentus BRS Alegria, the first recommendation for grain production systems in Brazil, originated from mass selection in the variety AM 5189 of the United States. In double-cropping, after soybeans, it showed average yield of 2,359 kg ha-1 for grain and of 5,650 kg ha-1 for total biomass, in 90 days from emergence to maturity.A diversificação do sistema produtivo depende de espécies com rápido crescimento, tolerância ao déficit hídrico, produção de biomassa, ciclagem de nutrientes e utilização humana e animal. As espécies Amaranthus caudatus, A. cruentus e A. hypochondriacus apresentam essas características e sementes claras, sem dormência. Distinguem-se das invasoras A. spinosus, A. hybridus, A. blitum e A. viridis, com sementes escuras e dormentes. Os grãos, com excelente qualidade protéica, atendem à demanda por dietas especiais, livres de glúten e podem ser usados na alimentação animal. O A. cruentus BRS Alegria, primeira recomendação ao cultivo granífero no Brasil, originou-se da variedade AM 5189, dos Estados Unidos, na qual realizou-se seleção massal. Em sucessão à soja, apresentou produção média de 2.359 kg ha-1 de grãos e 5.650 kg ha-1 de biomassa total em apenas 90 dias de ciclo

Inefficient Translocation of Preproinsulin Contributes to Pancreatic β Cell Failure and Late-onset Diabetes

Among the defects in the early events of insulin biosynthesis, proinsulin misfolding and endoplasmic reticulum (ER) stress have drawn increasing attention as causes of β cell failure. However, no studies have yet addressed potential defects at the cytosolic entry point of preproinsulin into the secretory pathway. Here, we provide the first evidence that inefficient translocation of preproinsulin (caused by loss of a positive charge in the n region of its signal sequence) contributes to β cell failure and diabetes. Specifically, we find that, after targeting to the ER membrane, preproinsulin signal peptide (SP) mutants associated with autosomal dominant late-onset diabetes fail to be fully translocated across the ER membrane. The newly synthesized, untranslocated preproinsulin remains strongly associated with the ER membrane, exposing its proinsulin moiety to the cytosol. Rather than accumulating in the ER and inducing ER stress, untranslocated preproinsulin accumulates in a juxtanuclear compartment distinct from the Golgi complex, induces the expression of heat shock protein 70 (HSP70), and promotes β cell death. Restoring an N-terminal positive charge to the mutant preproinsulin SP significantly improves the translocation defect. These findings not only reveal a novel molecular pathogenesis of β cell failure and diabetes but also provide the first evidence of the physiological and pathological significance of the SP n region positive charge of secretory proteins

Genome-environment Interaction in type 2 Diabetes Mellitus

Introduction: type 2 diabetes mellitus is the predominant form of diabetes worldwide. It is a heterogeneous syndrome of multifactorial etiology that combines genetic and environmental factors and it is increasingly important due to its morbidity, mortality and disabling effects, which affect the quality of life of those who suffer from it and of their relatives, and due to the use of medical services. Objective: to identify the contribution of the genome-environment interaction in the genesis of type 2 diabetes mellitus in patients of the Puentes Grandes Polyclinic. Methods: an analytical study of population-based case-control was conducted from February 2015 to March 2016 at the Puentes Grandes Polyclinic. Information was obtained from a written questionnaire and the review of individual medical records. We conducted a study that included 60 cases and 120 controls. Results: the existence of familial aggregation in type 2 diabetes mellitus was confirmed, the risk of suffering the disease was 3.6 times higher when a first degree relative was affected and 3.02 times higher when the risk factor of obesity was present and the risk of becoming ill was 14.12 times higher when genetic and environmental factors were overlapped. Conclusions: Type 2 diabetes mellitus is more likely to appear when genetic and environmental factors coincide because it is a multifactorial disease in which the presence of genetic factors is not enough, but the action of a predisposing environment is required to appear.Introducción: la diabetes mellitus tipo 2 presenta una alta prevalencia a nivel mundial. Es un síndrome heterogéneo de etiología multifactorial que combina factores genéticos y ambientales y que cada vez cobra mayor importancia por su morbilidad, su mortalidad y sus efectos incapacitantes, que afectan la calidad de vida de quienes la padecen y de sus familiares, y por el uso de los servicios médicos. Objetivo: identificar la contribución de la interacción genoma-ambiente en la génesis de la diabetes mellitus tipo 2 en pacientes del Policlínico Puentes Grandes. Métodos: se realizó un estudio analítico de casos y controles con base poblacional desde febrero de 2015 a marzo de 2016 en el Policlínico Puentes Grandes. La información se obtuvo por un cuestionario escrito y la revisión de historias clínicas individuales. Se estudiaron 60 casos y 120 controles. Resultados: se constató la presencia de agregación familiar en la diabetes mellitus tipo 2, el riesgo de padecer la enfermedad fue 3,6 veces mayor cuando se tiene un familiar de primer grado afectado y 3,02 veces mayor cuando estuvo presente el factor de riesgo obesidad y el riesgo de enfermar cuando se imbricaban los factores genéticos y ambientales fue 14,12 veces mayor. Conclusiones: existe mayor probabilidad de presentar diabetes mellitus tipo 2 cuando coinciden los factores genéticos y ambientales porque es una enfermedad multifactorial en la que no es suficiente la presencia de factores genéticos, sino que se necesita la acción de un ambiente predisponente para expresarla

Electroestimulación interósea en un modelo de elongación con fijación externa

Antecedentes: La reparación de una fractura implica procesos celulares complejos. Sin embargo, a pesar de un tratamiento óptimo, algunas fracturas curan lentamente o, simplemente, no se reparan. Estas complicaciones apoyan la necesidad de terapias innovadoras. La estimulación electromagnética es una tecnología no invasiva que pudiera tener un impacto directo sobre muchas vías celulares. Objetivo: Demostrar la eficacia de la electroestimulación por corriente alterna, aplicada durante una elongación ósea para acelerar el proceso de consolidación, por 30 días en un modelo animal. Materiales y métodos: Se disenó˜ un dispositivo de circuito cerrado y voltaje graduado, que se mantuvo en contacto con el fijador externo. El grupo A fue elongado sin electroestimulación y el grupo B fue electroestimulado desde el inicio de la distracción. Se tomaron radiografías a los 15 y 30 días posquirúrgicos, se realizaron tinciones de hematoxilina y eosina, y de tricrómico de Masson

Isotermas de adsorción en harina de maíz (Zea mays L.)

El objetivo de este trabajo fue determinar las isotermas de adsorción de humedad de harina de maíz a tres temperaturas (7, 22 y 45 °C) para el rango de a w entre 0,10 y 0,95. Las isotermas se modelaron utilizando siete ecuaciones comúnmente aplicadas en alimentos. La calidad de ajuste se evaluó con el coeficiente de regresión (r²) y el porcentaje de error medio relativo (% E), en función de los cuales se observó que los modelos propuestos por GAB, Oswin y Halsey ajustaron de mejor manera los datos experimentales. La humedad de la monocapa (Xm) y la humedad de seguridad (X S) presentaron dependencia con la temperatura con valores de Ea de 13,6 y 3,3 kJ/mol, respectivamente. Se cálculo el calor isostérico de adsorción (Q S) usando la ecuación de Clausius-Clapeyron, obteniéndose un máximo de 21 kJ/mol, para una humedad de 0,075 g agua/g m.s., este parámetro se modeló utilizando la ecuación propuesta por Tsami