In the last decade, the ingestion of gluten, a heterogeneous complex of proteins present in wheat, rice, barley and probably in oats, has been associated with clinical disorders, such as celiac ...disease, wheat allergy and recently to non-celiac gluten sensitivity or wheat intolerance syndrome. Gluten-related disorders, which are becoming epidemiologically relevant with an estimated global prevalence of about 5%, require the exclusion of gluten from the diet. For the past 5 years, an important shift in the availability of gluten-free products, together with increased consumption in the general population, has been recorded and is estimated to be about 12-25%. Many people follow a self-prescribed gluten-free diet, despite the fact that the majority have not first been previously excluded, or confirmed, as having gluten disorders. They rely on claims that a gluten-free diet improves general health. In this review, we provide an overview of the clinical disorders related to gluten or wheat ingestion, pointing out the current certainties, open questions, possible answers and several doubts in the management of these conditions. KEY MESSAGE Incidence of gluten-related disorders is increased in the last decade and self-diagnosis is frequent with inappropriate starting of a gluten-free diet. Gluten and wheat are considered as the most important triggers to coeliac disease, wheat allergy and non-celiac gluten sensitivity. Pediatricians, allergologist and gastroenterologist are involved in the management of these conditions and appropriate diagnostic protocols are required.
Long-term glucocorticoid treatment is associated with numerous adverse outcomes, including weight gain, insulin resistance, and diabetes; however, the pathogenesis of these side effects remains ...obscure. Glucocorticoids also suppress osteoblast function, including osteocalcin synthesis. Osteocalcin is an osteoblast-specific peptide that is reported to be involved in normal murine fuel metabolism. We now demonstrate that osteoblasts play a pivotal role in the pathogenesis of glucocorticoid-induced dysmetabolism. Osteoblast-targeted disruption of glucocorticoid signaling significantly attenuated the suppression of osteocalcin synthesis and prevented the development of insulin resistance, glucose intolerance, and abnormal weight gain in corticosterone-treated mice. Nearly identical effects were observed in glucocorticoid-treated animals following heterotopic (hepatic) expression of both carboxylated and uncarboxylated osteocalcin through gene therapy, which additionally led to a reduction in hepatic lipid deposition and improved phosphorylation of the insulin receptor. These data suggest that the effects of exogenous high-dose glucocorticoids on insulin target tissues and systemic energy metabolism are mediated, at least in part, through the skeleton.
Increasing evidence suggests a role for excessive intake of fructose in the Western diet as a contributor to the current epidemics of metabolic syndrome and obesity. Hereditary fructose intolerance ...(HFI) is a difficult and potentially lethal orphan disease associated with impaired fructose metabolism. In HFI, the deficiency of aldolase B results in the accumulation of intracellular phosphorylated fructose, leading to phosphate sequestration and depletion, increased adenosine triphosphate (ATP) turnover, and a plethora of conditions that lead to clinical manifestations such as fatty liver, hyperuricemia, Fanconi syndrome, and severe hypoglycemia. Unfortunately, there is currently no treatment for HFI, and avoiding sugar and fructose has become challenging in our society. In this report, through use of genetically modified mice and pharmacological inhibitors, we demonstrate that the absence or inhibition of ketohexokinase (Khk), an enzyme upstream of aldolase B, is sufficient to prevent hypoglycemia and liver and intestinal injury associated with HFI. Herein we provide evidence for the first time to our knowledge of a potential therapeutic approach for HFI. Mechanistically, our studies suggest that it is the inhibition of the Khk C isoform, not the A isoform, that protects animals from HFI.
Serine hydrolases are a large family of multifunctional enzymes known to influence obesity. Here, we performed activity-based protein profiling to assess the functional level of serine hydrolases in ...liver biopsies from lean and obese humans in order to gain mechanistic insight into the pathophysiology of metabolic disease. We identified reduced hepatic activity of carboxylesterase 2 (CES2) and arylacetamide deacetylase (AADAC) in human obesity. In primary human hepatocytes, CES2 knockdown impaired glucose storage and lipid oxidation. In mice, obesity reduced CES2, whereas adenoviral delivery of human CES2 reversed hepatic steatosis, improved glucose tolerance, and decreased inflammation. Lipidomic analysis identified a network of CES2-regulated lipids altered in human and mouse obesity. CES2 possesses triglyceride and diacylglycerol lipase activities and displayed an inverse correlation with HOMA-IR and hepatic diacylglycerol concentrations in humans. Thus, decreased CES2 is a conserved feature of obesity and plays a causative role in the pathogenesis of obesity-related metabolic disturbances.
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•Obesity decreases hepatic activity of AADAC and CES2 in humans•CES2 depletion impairs lipid and glucose metabolism in primary human hepatocytes•Human CES2 expression reverses hepatic steatosis and glucose intolerance in mice•CES2 controls a hepatic lipid network dysregulated in human and mouse obesity
Ruby et al. utilize activity-based protein profiling to discover decreased arylacetamide deacetylase and carboxylesterase 2 activities in livers from obese humans. Carboxylesterase 2 controls a lipid network dysregulated in human obesity to reverse hepatic steatosis, glucose intolerance, and decrease inflammation in high-fat fed mice.
Resumen Introducción y objetivo: los trastornos gastrointestinales crónicos como la enfermedad celiaca y la intolerancia a la lactosa o fructosa en la edad adulta son cada vez más frecuentes y se ...suelen acompañar de sintomatología que repercute en las actividades diarias y limita en gran medida la dieta. El espectro de síntomas que manifiestan los afectados es heterogéneo y poco específico y, además, no existe un protocolo estandarizado y consensuado para el manejo dietético, lo que dificulta un correcto diagnóstico y un adecuado tratamiento. Los trastornos relacionados con malabsorción/intolerancia alimentaria pueden originarse por causas primarias (genéticas) o secundarias (parásitos, alergias, enfermedad inflamatoria intestinal, fármacos, etc.). El empleo de análisis genéticos permite descartar o confirmar causas primarias y, cuando sea necesario, centrar la búsqueda en las secundarias. El objetivo del enfoque algorítmico que proponemos es guiar el manejo dietético-nutricional del paciente con trastornos gastrointestinales crónicos para optimizar el proceso diagnóstico y el tratamiento nutricional. Material y métodos: tras realizar una revisión bibliográfica sobre las patologías más frecuentemente asociadas a estos trastornos, se proponen un algoritmo de pruebas y los sucesivos pasos a seguir en función de los resultados obtenidos, para concretar el diagnóstico y el tratamiento. Resultados: el algoritmo propuesto pretende ser una herramienta para el personal sanitario (gastroenterólogos, endocrinólogos, nutricionistas, etc.) que atiende a este tipo de paciente. Se busca guiar el flujo de pruebas diagnósticas en función de la información aportada por el paciente y la clínica al inicio, así como recomendar el tratamiento (dietético-nutricional y/o farmacológico) más adecuado. Conclusiones: el beneficio de utilizar un enfoque algorítmico es que este permite optimizar el proceso diagnóstico de causas primarias y secundarias y con ello, pautar un tratamiento nutricional personalizado considerando el origen del trastorno, a fin de paliar la intensidad y frecuencia de los síntomas con la menor cantidad de restricciones alimentarias posibles y minimizar la afección en la calidad de vida de los pacientes.
Rab1A is a small GTPase known for its role in vesicular trafficking. Recent evidence indicates that Rab1A is essential for amino acids (aas) sensing and signaling to regulate mTORC1 in normal and ...cancer cells. However, Rab1A’s in vivo function in mammals is not known. Here, we report the generation of tamoxifen (TAM)-induced whole body Rab1A knockout (Rab1A−/−) in adult mice. Rab1A−/− mice are viable but become hyperglycemic and glucose intolerant due to impaired insulin transcription and β-cell proliferation and maintenance. Mechanistically, Rab1A mediates AA-mTORC1 signaling, particularly branched chain amino acids (BCAA), to regulate the stability and localization of the insulin transcription factor Pdx1. Collectively, these results reveal a physiological role of aa-Rab1A-mTORC1 signaling in the control of whole-body glucose homeostasis in mammals. Intriguingly, Rab1A expression is reduced in β-cells of type 2 diabetes (T2D) patients, which is correlated with loss of insulin expression, suggesting that Rab1A downregulation contributes to T2D progression.
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•Rab1A regulates mTORC1 signaling in response to amino acids (aas) in beta-cells•Rab1A knockout mice are deficient of insulin expression and hyperglycemic•Branched chain aas regulate insulin transcription through mTORC1-Rab1A-PDX1 axis•Amino acids regulate beta-cell trans-differentiation through mTORC1-Rab1A-PDX1 axis
Zhang et al. generate and analyze inducible Rab1A knockout mice. The results reveal that Rab1A-mTORC1 mediates branched chain amino acids signaling and regulates PDX-dependent insulin transcription and beta-cell trans-differentiation to alpha-cells. This amino acid sensing and signaling mechanism controls whole-body glucose homeostasis in mice and men.
Sayın Editör, Çölyak hastalığı, her yaşta ortaya çıkabilen ve toplumun yaklaşık %1’ini etkileyen glutene karşı duyarlılık ile karakterize, asemptomatik durumdan malabsorbsiyondan kadar farklı ...klinikle (Gastrointestinal ve ekstraintestinal) seyreden, glutensiz diyetle iyileşebilen otoimmun familyal bir enteropatidir.1,2 Tanı konmamış çölyak hastalarının bilinen çölyak hastalarının 10 katına kadar çıkabildiği düşünülmektedir.1,2 Bu yüksek oran, tipik hastalık bulguların yanısıra, özellikle tedaviye dirençli ve/veya sürekli replasman tedavisine ihtiyaç duyan hastalarda (Demir, folat, B12, B1, vitamin D ve kalsiyum eksikliği ve ilişkili hastalıklarda) çölyak hastalığının tanıda düşünülmesini gerektiğini göstermektedir.1,3 Beslenme alışkanlıklarının değişmesiyle ile birlikte daha fazla gluten ile karşılaşmaktayız. Buğday, arpa, çavdar ve yulafta bulunan gliadin immunpatogenezden sorumlu tutulmaktadır.1,4 Bu tahıllardan yapılan ekmek dünyada bilinen en eski temel besin kaynağıdır. Gluten ekmek yapımında viskoelastik hamur oluşumu ile ilişkilidir.5 Yapılan çalışmalar ekşi hamur yöntemi ile üretilen ürünlerin gluteni yıktığını ve mineral biyoyaralanımını arttırdığını göstermekte hatta çölyak hastalarında kullanılabileceğini düşündürmektedir.6,7 Ekşi hamur yönteminde, normal kültür mayaları ile birlikte yabani mayalar, laktik, asetik ve sitrik asit bakterilerin laktik asit fermantasyonuna uğrayan hamur parçası, sonraki hamurda maya olarak kullanmaktır.8 Ekmek yapımında ekşi hamur tozu ikame oran arttıkça gluten miktarının azaldığı görülmüştür.9 Mayalı ekmek ile ekşi mayalı ekmeğin karşılaştırıldığı bir çalışmada, ekşi hamur ekmeği ile beslenen farelerde hemoglobin, hematokrit, ferritin ve demir düzeyleri anlamlı derecede yüksek, vücuttan atılan demir düzeylerinde ise önemli bir azalma belirlenmiştir.7,10 30-40 yıl öncesine kadar geleneksel doğal bir fermente ürün olan ekşi mayalı ekmekler tüketilirken günümüzde bu oran çok düşmüştür. Ekşi mayalı ekmeklerin tüketiminin artırılması ile değişik seviyelerdeki saptanmamış enteropatilerin ilerlemeden engellenmesi/iyileşmesi mümkün görünmektedir. Ancak ekşi hamur fermantasyonunda biyoaktif bileşen düzeylerindeki bu değişimin mekanizması hala tam olarak açıklanamamıştır. Hem bu hususta hem de kullanılabilirlik konusunda geniş çalışmalara ihtiyaç vardır.
In 1570 the Spanish Crown decided to create, in the overseas spaces, the Holy Office of the Inquisition in order to control, effectively, the religious manifestations of the people and their social ...behaviors, bringing intolerance towards those who had different practices. However, initially it had only two district courts installed in the viceroyalties capitals of Mexico and Peru. The other places, captaincies and governorates, were controlled by commissioners dependent on Mexico or Lima, as appropriate. In the case of the Government of Chile, several police stations were deployed between the two dioceses. However, they were not efficient enough to achieve the objectives proposed in the inquisitorial ideology, on the one hand because of precarious material, and on the other hand because of the lack of ad-hoc officials to fill the positions. This led to the Chilean Governorate experience a more laxed control than other imperial territories. However, the climate of fear and prejudice among the inhabitants permeated the society generating intolerance and discrimination through other perspectives and through other social control devices, which survived in the republic and allow to understand —partway— the intolerance and discrimination in the current Chile. The present article will make a tour of the installation of the Holy Office in America, the historiographic status of the studies related to the Inquisition in Chile, the possible lines of investigation and the hypotheses to be tested.
En 1570, la Corona española determinó crear, en los espacios de ultramar, el Santo Oficio de la Inquisición, con la finalidad de controlar eficazmente las manifestaciones religiosas de la población y sus comportamientos sociales, lo que acarreó la intolerancia hacia quienes tenían prácticas diversas. No obstante, en un comienzo contó con solo dos tribunales de distrito instalados en las capitales virreinales de México y el Perú. Los demás espacios, capitanías y gobernaciones, fueron controlados por comisarías dependientes de México o Lima, según correspondiera. En el caso de la Gobernación de Chile, una serie de comisarías se desplegaron entre sus dos diócesis. Sin embargo, ellas no fueron lo suficientemente eficientes para lograr los objetivos propuestos en el ideario inquisitorial, tanto por la precariedad material como por la falta de funcionarios ad-hoc para llenar los cargos. Lo anterior conllevó a que la Gobernación de Chile experimentara un control más laxo en comparación con otros territorios imperiales. No obstante, el clima de miedo y prejuicios entre los habitantes permeó a la sociedad, y generó intolerancia y discriminación desde otras perspectivas y mediante otros dispositivos de control social que pervivieron en la república y que permiten entender —en parte— la intolerancia y discriminación en el Chile actual. El presente artículo realizará un recorrido por la instalación del Santo Oficio en América, el estado historiográfico de los estudios relativos a la Inquisición en Chile, las posibles líneas de investigación y las hipótesis por probar.
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