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Aging is characterized by a functional decline in the physiological functions and organic systems, causing frailty, illness, and death. Ferroptosis is an iron- (Fe-) dependent regulated cell death, which has been implicated in the pathogenesis of several disorders, such as cardiovascular and neurological diseases. The present study investigated behavioral and oxidative stress parameters over the aging of Drosophila melanogaster that, together with augmented Fe levels, indicate the occurrence of ferroptosis. Our work demonstrated that older flies (30-day-old) of both sexes presented impaired locomotion and balance when compared with younger flies (5-day-old). Older flies also produced higher reactive oxygen species (ROS) levels, decreased glutathione levels (GSH), and increased lipid peroxidation. In parallel, Fe levels were augmented in the fly’s hemolymph. The GSH depletion with diethyl maleate potentiated the behavioral damage associated with age. Our data demonstrated biochemical effects that characterize the occurrence of ferroptosis over the age of D. melanogaster and reports the involvement of GSH in the age-associated damages, which could be in part attributed to the augmented levels of Fe.

Supplemental Digital Content is available in the text., Background: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without previous cardiovascular disease (primary prevention). Methods: In CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), 4401 participants with type 2 diabetes mellitus and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care. Results: Primary prevention participants (n=2181, 49.6%) were younger (61 versus 65 years), were more often female (37% versus 31%), and had shorter duration of diabetes mellitus (15 years versus 16 years) compared with secondary prevention participants (n=2220, 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80 [95% CI, 0.67–0.95]; P=0.01), with consistent reductions in both the primary (HR, 0.68 [95% CI, 0.49–0.94]) and secondary (HR, 0.85 [95% CI, 0.69–1.06]) prevention groups (P for interaction=0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78 [95% CI, 0.61–1.00]), nonfatal myocardial infarction (HR, 0.81 [95% CI, 0.59–1.10]), and nonfatal stroke (HR, 0.80 [95% CI, 0.56–1.15]). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P for interaction >0.5 for each outcome). Conclusions: Canagliflozin significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, including in participants who did not have previous cardiovascular disease. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02065791.

La célula ß no sólo es capaz de fabricar y secretar la insulina, sino además, hace que dicha secreción sea en el momento justo y en la cantidad adecuada. Las elevaciones postprandiales de glucosa generan una respuesta secretora aguda en la célula ß, pero en ciertas patologías como la diabética, el escenario cambia radicalmente, resultando en una disfunción caracterizada por un proceso secretor alterado y múltiples cambios fenotípicos. En estos, los nutrientes, glucosa y ácidos grasos, están elevados de forma crónica, convirtiéndose en sustancias tóxicas que pueden llevar a la muerte de la propia célula ß. Por lo tanto, cualquier aproximación terapéutica a la cura de esta enfermedad debe afrontar la necesidad de reemplazar o evitar esta disminución celular, siendo imperativo mencionar el papel de los hipoglucemiantes orales como los inhibidores de la DPP-4 y los análogos de la GLP-1 en la protección contra el fracaso de la masa de células ß. The beta cell is not only able to produce and secrete insulin, but also makes this secretion is at the right time and in the right amount. Postprandial glucose elevations produce an acute secretory response in the beta cell, but in certain diseases such as diabetes mellitus, the scene changes dramatically, resulting in dysfunction, characterized by an altered secretion process and multiple phenotypic changes. In these, nutrients like glucose and fatty acids are chronically elevated, becoming toxic substances that can lead to death of the beta cell itself. Therefore, any therapeutic approach to cure this disease must face the need to replace or avoid this cell decline, it is imperative to mention the role of oral hypoglycemic agents as inhibitors of DPP-4 and analogs of the GLP-1 in protection against failure of the ß cell mass. 5-15 storino1974@gmail.com, marcelo.storino@merck.com Cuatrimestral

La célula β no sólo es capaz de fabricar y secretar la insulina, sino además, hace que dicha secreción sea en el momento justo y en la cantidad adecuada. Las elevaciones postprandiales de glucosa generan una respuesta secretora aguda en la célula β, pero en ciertas patologías como la diabética, el escenario cambia radicalmente, resultando en una disfunción caracterizada por un proceso secretor alterado y múltiples cambios fenotípicos. En estos, los nutrientes, glucosa y ácidos grasos, están elevados de forma crónica, convirtiéndose en sustancias tóxicas que pueden llevar a la muerte de la propia célula β. Por lo tanto, cualquier aproximación terapéutica a la cura de esta enfermedad debe afrontar la necesidad de reemplazar o evitar esta disminución celular, siendo imperativo mencionar el papel de los hipoglucemiantes orales como los inhibidores de la DPP-4 y los análogos de la GLP-1 en la protección contra el fracaso de la masa de células β. The beta cell is not only able to produce and secrete insulin, but also makes this secretion is at the right time and in the right amount. Postprandial glucose elevations produce an acute secretory response in the beta cell, but in certain diseases such as diabetes mellitus, the scene changes dramatically, resulting in dysfunction, characterized by an altered secretion process and multiple phenotypic changes. In these, nutrients like glucose and fatty acids are chronically elevated, becoming toxic substances that can lead to death of the beta cell itself. Therefore, any therapeutic approach to cure this disease must face the need to replace or avoid this cell decline, it is imperative to mention the role of oral hypoglycemic agents as inhibitors of DPP-4 and analogs of the GLP-1 in protection against failure of the β cell mass.

Trabajo presentado en el 9th Congress of Toxicology in Developing Countries and XIX Brazilian Congress of Toxicology, celebrado en Natal, Brasil, del 7 al 10 de noviembre de 2015

Fue hace 30 años cuando la relación entre hipertrigliceridemia y la enfermedad de la arteria coronaria se postuló por primera vez y luego se confirmó en muchos artículos, así como en el estudio PROCAM. La condición de resistencia a la insulina tiene un perfil lipídico y la capacidad intestinal para producir quilomicrones postprandiales distintiva, que cada vez es más relevante. La absorción de colesterol es regulada por un portador (NPC1L1) cuya expresión está aumentada en los pacientes diabéticos y con resistencia a la insulina, que desempeña un papel importante en el origen de la dislipidemia postprandial, que es una respuesta fisiológica durante todo el día siempre que la ingesta oral-grasa supera la necesidad. Un gran número de estudios han demostrado que la dislipidemia postprandial contribuye al desarrollo de la aterosclerosis y la enfermedad de la arteria coronaria (CAD). Los pacientes obesos y diabéticos, así como aquellos con síndrome metabólico a menudo tienen dislipidemia postprandial. El paciente diabético se caracteriza esencialmente por tener niveles elevados de colesterol no-HDL en lugar de los altos niveles de LDL. Este no- HDL cuenta con acciones para muchas partículas aterogénicas, denominándose "riesgo residual" y que no está cubierto por el uso de las estatinas. Debido a todas estas pruebas, creemos que la normalización de la medición de los niveles de triglicéridos postprandiales debe ser pertinente con el fin de utilizar este parámetro como un factor de riesgo directamente relacionado con la patogénesis de la aterosclerosis y los eventos cardiovasculares. It was 30 years ago when the relationship between hypertriglyceridemia and coronary artery disease was first postulated and then it was confirmed in many articles as well as in the PROCAM study. The insulin-resistance condition has a distinctive lipid profile and the intestinal ability to produce postprandial chylomicrons it´s becoming more relevant. Cholesterol absorption is regulated by a carrier (NPC1L1) whose expression is increased in diabetic and insulin-resistance patients and it plays an important role originating postprandial dyslipidemia, which is a physiological response throughout the day whenever the fatty oral intake exceeds the need of it. A large number of studies have shown that postprandial dyslipidemia contributes to developing atherosclerosis and coronary artery disease (CAD). Obese and diabetic patients as well as those with metabolic syndrome often have postprandial dyslipidemia. The diabetic patient is essentially characterized for having elevated levels of Non-HDL cholesterol rather than high levels of LDL. This Non-HDL share accounts for many atherogenic particles, it is called “Residual Risk” and it is not covered by the use of statins. Due to all these evidence we believe the standardization of measuring postprandial triglycerides levels to be pertinent in order to use this parameter as a risk factor directly related with the pathogenesis of atherosclerosis and cardiovascular events.