Skeletal Muscle Mitochondrial Function/Dysfunction and Type 2 Diabetes

“Let food be your medicine and medicine be your food” stated Hippocrates, the father of Western medicine, in 400 B.C. This statement was based on the belief that food was able to influence disease, a concept that was revived several times in later years by painters, writers, scientists, and philosophers. One such philosopher, Ludwig Feuerbach, famously wrote in his 1863-4 essay “man is what he eats” introducing the idea that if we want to improve the spiritual conditions of people we must first improve their material conditions (Feuerbach, 2003). However, for years his warnings remained unheeded, at least in Western countries, in contrast to the teachings of Indian and Chinese medicine which for millennia have argued that a living organism has to assume a healthy diet. Like diet, physical activity has been also considered an important starting point for people's health. Hippocrates wrote in his book Regimen "if we could give every individual the right amount of nourishment and exercise, not too little and not too much, we would have found the safest way to health" (Hippocrates, 1955). Our knowledge about the links between diet, exercise, and disease has vastly increased since Hippocrates time. A healthy lifestyle based on diet and physical activity is now considered the keystone of disease prevention and the basis for a healthy aging. However, modern society has created conditions with virtually unrestricted access to food resources and reduced physical activity, resulting in a positive overall energy balance. This is far from the environment of our ”hunter-gathered ancestros” whose genes were modulated over thousands of years adapting our metabolism to survive when food was scarce and maximizing energy storage when food became available. In terms of evolution, this radical and sudden lifestyle change in modern society has led to a dramatic increase in the incidence of metabolic diseases including obesity and type 2 diabetes mellitus (T2DM). It seems clear that the development of T2DM has a genetic component that becomes obvious when individuals are exposed to western lifestyle. However, environment plays a critical role in the incidence of the disease being obesity the main etiological cause of T2DM. Thus, modest weight loss is enough for obese glucose intolerant subjects to prevent the development of T2DM (National Task Force on the Prevention and Treatment of Obesity, 2000)..

The protective effect of the Mediterranean diet on endothelial resistance to GLP-1 in type 2 diabetes: a preliminary report

In type 2 diabetes, acute hyperglycemia worsens endothelial function and inflammation,while resistance to GLP-1 action occurs. All these phenomena seem to be related to the generation of oxidative stress. A Mediterranean diet, supplemented with olive oil, increases plasma antioxidant capacity, suggesting that its implementation can have a favorable effect on the aforementioned phenomena. In the present study, we test the hypothesis that a Mediterranean diet using olive oil can counteract the effects of acute hyperglycemia and can improve the resistance of the endothelium to GLP-1 action

“Inflammaging” as a Druggable Target: A Senescence-Associated Secretory Phenotype—Centered View of Type 2 Diabetes

Aging is a complex phenomenon driven by a variety of molecular alterations. A relevant feature of aging is chronic low-grade inflammation, termed “inflammaging.” In type 2 diabetes mellitus (T2DM), many elements of aging appear earlier or are overrepresented, including consistent inflammaging. T2DM patients have an increased death rate, associated with an incremented inflammatory score. The source of this inflammation is debated. Recently, the senescence-associated secretory phenotype (SASP) has been proposed as the main origin of inflammaging in both aging and T2DM. Different pathogenic mechanisms linked to T2DM progression and complications development have been linked to senescence and SASP, that is, oxidative stress and endoplasmic reticulum (ER) stress. Here we review the latest data connecting oxidative and ER stress with the SASP in the context of aging and T2DM, with emphasis on endothelial cells (ECs) and endothelial dysfunction. Moreover, since current medical practice is insufficient to completely suppress the increased death rate of diabetic patients, we propose a SASP-centered view of T2DM as a futuristic therapeutic option, possibly opening new prospects by moving the attention from one-organ studies of diabetes complications to a wider targeting of the aging process

Dietary betaine supplementation increases Fgf21 levels to improve glucose homeostasis and reduce hepatic lipid accumulation in mice

Identifying markers of human insulin resistance may permit development of new approaches for treatment and prevention of type 2 diabetes. To this end, we analyzed the fasting plasma metabolome in metabolically characterized human volunteers across a spectrum of insulin resistance. We demonstrate that plasma betaine levels are reduced in insulin-resistant humans and correlate closely with insulin sensitivity. Moreover, betaine administration to mice with diet-induced obesity prevents the development of impaired glucose homeostasis, reduces hepatic lipid accumulation, increases white adipose oxidative capacity, and enhances whole-body energy expenditure. In parallel with these beneficial metabolic effects, betaine supplementation robustly increased hepatic and circulating fibroblast growth factor (Fgf)21 levels. Betaine administration failed to improve glucose homeostasis and liver fat content in Fgf21(-/-) mice, demonstrating that Fgf21 is necessary for betaine's beneficial effects. Together, these data indicate that dietary betaine increases Fgf21 levels to improve metabolic health in mice and suggest that betaine supplementation merits further investigation as a supplement for treatment or prevention of type 2 diabetes in humans

Synergistic roles of climate warming and human occupation in Patagonian megafaunal extinctions during the Last Deglaciation

The causes of Late Pleistocene megafaunal extinctions (60,000 to 11,650 years ago, hereafter 60 to 11.65 ka) remain contentious, with major phases coinciding with both human arrival and climate change around the world. The Americas provide a unique opportunity to disentangle these factors as human colonization took place over a narrow time frame (~15 to 14.6 ka) but during contrasting temperature trends across each continent. Unfortunately, limited data sets in South America have so far precluded detailed comparison. We analyze genetic and radiocarbon data from 89 and 71 Patagonian megafaunal bones, respectively, more than doubling the high-quality Pleistocene megafaunal radiocarbon data sets from the region.We identify a narrowmegafaunal extinction phase 12,280 ± 110 years ago, some 1 to 3 thousand years after initial human presence in the area. Although humans arrived immediately prior to a cold phase, the Antarctic Cold Reversal stadial, megafaunal extinctions did not occur until the stadial finished and the subsequent warming phase commenced some 1 to 3 thousand years later. The increased resolution provided by the Patagonian material reveals that the sequence of climate and extinction events in North and South America were temporally inverted, but in both cases, megafaunal extinctions did not occur until human presence and climate warming coincided. Overall, metapopulation processes involving subpopulation connectivity on a continental scale appear to have been critical for megafaunal species survival of both climate change and human impacts.Fil: Metcalf, Jessica L.. University of Adelaide; Australia. State University of Colorado Boulder; Estados UnidosFil: Turney, Chris. University of New South Wales; AustraliaFil: Barnett, Ross. University of Oxford; Reino Unido. Universidad de Copenhagen; DinamarcaFil: Martin, Fabiana. Universidad de Magallanes. Instituto de la Patagonia. Centro de Estudios del Hombre Austral; ChileFil: Bray, Sarah C.. University of Adelaide; Australia. University of South Australia; AustraliaFil: Vilstrup, Julia T.. Universidad de Copenhagen; DinamarcaFil: Orlando, Ludovic. Universidad de Copenhagen; DinamarcaFil: Salas-Gismondi, Rodolfo. Université de Montpellier. Institut des Sciences de l’Evolution; Francia. Universidad Nacional Mayor de San Marcos; PerúFil: Loponte, Daniel Marcelo. Secretaría de Cultura de la Nación. Dirección Nacional de Cultura y Museos. Instituto Nacional de Antropología y Pensamiento Latinoamericano; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Medina, Matias Eduardo. Centro de Estudios Históricos ; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: de Nigris, Mariana Eleonor. Secretaría de Cultura de la Nación. Dirección Nacional de Cultura y Museos. Instituto Nacional de Antropología y Pensamiento Latinoamericano; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Civalero, Maria Teresa. Secretaría de Cultura de la Nación. Dirección Nacional de Cultura y Museos. Instituto Nacional de Antropología y Pensamiento Latinoamericano; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Fernández, Pablo Marcelo. Secretaría de Cultura de la Nación. Dirección Nacional de Cultura y Museos. Instituto Nacional de Antropología y Pensamiento Latinoamericano; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gasco, Alejandra Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Exactas y Naturales. Laboratorio de Paleoecología Humana; ArgentinaFil: Duran, Victor Alberto. Universidad Nacional de Cuyo. Facultad de Ciencias Exactas y Naturales. Laboratorio de Paleoecología Humana; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Seymour, Kevin L.. Royal Ontario Museum. Department of Natural History; CanadáFil: Otaola, Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Saavedra 15. Instituto Multidisciplinario de Historia y Ciencias Humanas; ArgentinaFil: Gil, Adolfo Fabian. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Museo de Historia Natural de San Rafael - Ianigla | Provincia de Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Museo de Historia Natural de San Rafael - Ianigla | Universidad Nacional de Cuyo. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Museo de Historia Natural de San Rafael - Ianigla; ArgentinaFil: Paunero, Rafael. Universidad Nacional de La Plata; ArgentinaFil: Prevosti, Francisco Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Regional de Investigaciones Científicas y Transferencia Tecnológica de La Rioja. - Universidad Nacional de La Rioja. Centro Regional de Investigaciones Científicas y Transferencia Tecnológica de La Rioja. - Universidad Nacional de Catamarca. Centro Regional de Investigaciones Científicas y Transferencia Tecnológica de La Rioja. - Secretaría de Industria y Minería. Servicio Geológico Minero Argentino. Centro Regional de Investigaciones Científicas y Transferencia Tecnológica de La Rioja. - Provincia de La Rioja. Centro Regional de Investigaciones Científicas y Transferencia Tecnológica de La Rioja; ArgentinaFil: Bradshaw, Corey J. A.. University of Adelaide; AustraliaFil: Wheeler, Jane C.. Instituto de Investigación y Desarrollo de Camélidos Sudamericanos; PerúFil: Borrero, Luis Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Saavedra 15. Instituto Multidisciplinario de Historia y Ciencias Humanas; ArgentinaFil: Austin, Jeremy J.. University of Adelaide; AustraliaFil: Cooper, Alan. University of Adelaide; Australia. University of Oxford; Reino Unid

The possible link between high glucose-induced PKCβ expression and the appearance of GLP-1 resistance in endothelial cells

[eng] INTRODUCTION. It has been demonstrated that Glucagon-like peptide-1 (GPL-1) has a protective effect on endothelial cells. GLP-1 improves endothelial function in diabetes, however the mechanisms underlying the GLP-1 protective effects have not yet been fully elucidated. Additionally, it has been proposed that GLP-1 could restore high glucose - endoplasmic reticulum (ER) stress induction. Recent evidences claim a resistance of GLP-1 action that has been shown in pancreatic 13-cells of diabetic patients. A proposed mechanism to explain this resistance to the GLP-1 action in diabetes is the activation of PKCI3, induced by hyperglycaemia, which is able to reduce the expression of GLP-1 receptor. AIM. The aim of this thesis project was to decipher if GLP-1 acute treatment is able to counteract chronic high glucose-induced damage in Human umbilical Vein Endothelial cells (HUVECs). METHODS. In this study HUVECs were cultured for 21 days under normal glucose (5mmol/L, NG) or high glucose (25mmol/L glucose, HG) concentrations. GLP-1 and Ruboxistaurin were added alone or in combination, 1 hour before cell harvesting. Analysis of GLP-1 receptor protein levels as well as of gene expression of different ER stress-related genes, proliferation markers, antioxidant cell response-related genes and PKA subunits was performed. ROS production was also measured in HUVECs exposed to mentioned treatments. RESULTS. GLP-1 receptor expression was reduced in HUVECs exposed to chronic high glucose concentrations and it was partially restored after treatment with the chemical PKCI3 specific inhibitor, Ruboxistaurin. GLP-1, added as an acute treatment in endothelial cells, had the capacity to induce the expression of detoxifying enzymes Nrf2 targets, to increase transcript levels of scavenger genes, to attenuate the high glucose-induced PKA subunits expression, ER stress and also the apoptotic phenotype of HUVECs only when high glucose-induced PKCI3 overexpression was reduced by Ruboxistaurin. In the same direction, ROS production induced by high glucose was reduced by GLP-1 in the presence of PKCI3 inhibitor. CONCLUSIONS. This study suggests that PKCI3 increase, induced by high glucose, could have a role in endothelial GLP-1 resistance, reducing GLP-1 receptor levels and disrupting GLP-1 canonical pathway.[spa] INTRODUCCIÓN. Se ha demostrado que el Glucagon-like peptide-1 (GLP-1) tiene un efecto protector sobre las células endoteliales. GLP-1 mejora la función endotelial en la diabetes, sin embargo los mecanismos subyacentes a los efectos protectores de GLP-1 aún no han sido completamente aclarada. Además, se ha propuesto que el GLP-1 podría restaurar la función del retículo endoplasmático (ER), cuyo estés es inducido en condiciones de alta glucosa. Evidencias recientes afirman que existe una resistencia a las propiedades beneficiosas del GLP-1. Esto se ha demostrado en las células beta del páncreas de pacientes diabéticos. Un mecanismo propuesto para explicar esta resistencia a la acción de GLP-1 en la diabetes es la activación de PKCβ, inducida por la hiperglucemia, que se ha visto está involucrada en la reducción de la expresión del receptor del GLP-1 en el endotelio glomerular de modelos animales de diabetes. OBJETIVO. El objetivo de este proyecto de tesis fue descifrar si el tratamiento agudo con GLP-1 puede contrarrestar el daño inducido por condiciones de alta glucosa crónica en las células endoteliales humanas de la vena umbilical (HUVECs) y también corroborar los efectos de dicha molécula en caso de que se inhiba la activación de PKCI3 inducida por las altas concentraciones de glucosa. MÉTODOS. En este estudio las células HUVEC se cultivaron durante 21 días bajo las dos condiciones de glucosa normal (5 mmol/L, NG) o alta glucosa (25 mmol/L, HG). Se añadieron GLP-1 y Ruboxistaurin, el inhibidor específico de PKCI3, solos o en combinación, 1 hora antes de la recolección de células. Se realizó un análisis de los niveles de proteína del receptor del GLP-1, así como de la expresión génica de diferentes relacionados con el estrés del ER, la proliferación, el proceso de apoptosis, y también los genes relacionados con la respuesta antioxidante. La producción de ROS fue además medida en las HUVECs expuestas a los diferentes tratamientos mencionados. RESULTADOS. La expresión del receptor del GLP-1 fue reducida en las HUVECs expuestas a concentraciones de alta glucosa crónica y fue parcialmente restaurada después del tratamiento con el inhibidor específico de PKCI3, Ruboxistaurin. GLP-1, añadido como un tratamiento agudo en las células endoteliales, tuvo la capacidad de inducir la expresión de enzimas desintoxicantes que son dianas de Nrf2, el regulador más importante de la respuesta antioxidante en las células. Además, el GLP-1 aumentó los niveles de transcriptos de los marcadores de estrés de ER inducido por la alta glucosa y los marcadores de proliferación en las HUVECs sólo cuando la sobreexpresión PKCβ inducida por la alta glucosa se redujo en presecia de su inhibidor. En la misma dirección, la producción de ROS inducida por la alta glucosa disminuyó cuando las HUVECs se trataron con GLP-1 en presencia del inhibidor de PKCI3. CONCLUSIONES. Este estudio sugiere que el aumento de PKCβ, inducido por la alta glucosa, podría tener un papel en la resistencia a las acciones protectoras del GLP-1 a nivel endotelial, reduciendo los niveles del receptor del GLP-1 e interrumpiendo su vía canónica