Oral insulin-mimetic compounds that act independently of insulin

The hallmarks of insulin action are the stimulation and suppression of anabolic and catabolic responses, respectively. These responses are orchestrated by the insulin pathway and are initiated by the binding of insulin to the insulin receptor, which leads to activation of the receptor's intrinsic tyrosine kinase. Severe defects in the insulin pathway, such as in types A and B and advanced type 1 and 2 diabetes lead to severe insulin resistance, resulting in a partial or complete absence of response to exogenous insulin and other known classes of antidiabetes therapies. We have characterized a novel class of arylalkylamine vanadium salts that exert potent insulin-mimetic effects downstream of the insulin receptor in adipocytes. These compounds trigger insulin signaling, which is characterized by rapid activation of insulin receptor substrate-1, Akt, and glycogen synthase kinase-3 independent of insulin receptor phosphorylation. Administration of these compounds to animal models of diabetes lowered glycemia and normalized the plasma lipid profile. Arylalkylamine vanadium compounds also showed antidiabetic effects in severely diabetic rats with undetectable circulating insulin. These results demonstrate the feasibility of insulin-like regulation in the complete absence of insulin and downstream of the insulin receptor. This represents a novel therapeutic approach for diabetic patients with severe insulin resistance

The imidazoline SL 84.0418 shows stereoselectivity in blocking alpha 2-adrenoceptors but not ATP-sensitive K+ channels in pancreatic B-cells.

The novel alpha 2-adrenoceptor antagonist SL 84.0418 (2-(4,5-dihydro-1H-imidazol-2-yl)-1,2,4,5-tetrahydro-2-propyl-pyrrolo[3, 2,1- hi]-indole hydrochloride) is a racemic mixture of a (-) enantiomer (SL 86.0714) and a (+) enantiomer (SL 86.0715 or deriglidole). It was recently reported to inhibit alpha 2-adrenoceptors and ATP-sensitive K+ channels in mouse pancreatic B-cells, and to increase insulin release. We have now studied the stereospecificity of these responses with isolated mouse islets. Both enantiomers were equipotent in potentiating insulin release induced by 15 mM glucose alone. SL 86.0714 and deriglidole were also equally effective in inhibiting 86Rb efflux from islets perifused with a low-glucose medium, and in reversing the inhibition of glucose-induced insulin release caused by the opening of ATP-sensitive K+ channels with diazoxide. In contrast, deriglidole was approximately 100-fold more potent than SL 86.0714 in reversing the inhibition of insulin release caused by the activation of alpha 2-adrenoceptors with clonidine. The effects of SL 84.0418 are thus stereoselective on alpha 2-adrenoceptors, but not on ATP-sensitive K+ channels of pancreatic B-cells

Sulphonylureas do not increase insulin secretion by a mechanism other than a rise in cytoplasmic Ca2+ in pancreatic B-cells

The following sequence of events is thought to underlie the stimulation of insulin release by hypoglycaemic sulphonylureas. Interaction of the drugs with a high-affinity binding site (sulphonylurea receptor) in the B-cell membrane leads to closure of ATP-sensitive K+ channels, depolarization, opening of voltage-dependent Ca2+ channels, Ca2+ influx and rise in cytoplasmic [Ca2+]i. Recent experiments using permeabilized islet cells or measuring changes in B-cell membrane capacitance have suggested that sulphonylureas can increase insulin release by a mechanism independent of a change in [Ca2+]i. This provocative hypothesis was tested here with intact mouse islets. When B-cells were strongly depolarized by 60 mM K+, [Ca2+]i was increased and insulin secretion stimulated. Under these conditions, tolbutamide did not further increase [Ca2+]i or insulin release, whether it was applied before or after high K+, and whether the concentration of glucose was 3 or 15 mM. This contrasts with the ability of forskolin and phorbol 12-myristate 13-acetate (PMA) to increase release in the presence of high K+. Tolbutamide also failed to increase insulin release from islets depolarized with barium (substituted for extracellular Ca2+) or with arginine in the presence of high glucose. Glibenclamide and its non-sulphonylurea moiety meglitinide were also without effect on insulin release from already depolarized B-cells. In the absence of extracellular Ca2+, acetylcholine induced monophasic peaks of [Ca2+]i and insulin secretion which were both unaffected by tolbutamide. Insulin release from permeabilized islet cells was stimulated by raising free Ca2+ (between 0.1 and 23 microM). This effect was not affected by tolbutamide and inconsistently increased by glibenclamide. In conclusion, the present study does not support the proposal that hypoglycaemic sulphonylureas can increase insulin release even when they do not also raise [Ca2+]i in B-cells

No evidence for a role of reverse Na(+)-Ca2+ exchange in insulin release from mouse pancreatic islets

We studied whether reverse Na(+)-Ca2+ exchange can increase cytoplasmic Ca2+ ([Ca2+]i) in mouse islets and contribute to insulin release. The exchange was stimulated by replacing Na+ with choline, sucrose, or lithium in a medium containing 15 mM glucose. Na+ omission increased electrical activity in B cells, [Ca2+]i, and insulin release. When voltage-dependent Ca2+ channels were blocked by nimodipine or closed by holding the membrane polarized with diazoxide, Na+ omission caused a slight hyperpolarization, a small rise in [Ca2+]i, and a marginal increase in insulin release (the latter only with choline). This small rise in [Ca2+]i was dependent on extracellular Ca2+ but was hardly augmented when intracellular Na+ was raised with alanine. When B cells were depolarized by 30 mM K+, Na+ omission did not affect the membrane potential but increased [Ca2+]i and insulin release. If Ca2+ channels were blocked by nimodipine, only marginal increases in Ca2+ and insulin release persisted, which were not different from those observed when the cells were not depolarized. This indicates that Ca2+ influx through voltage-dependent Ca2+ channels rather than via reverse Na(+)-Ca2+ exchange underlies the rise in [Ca2+]i and in insulin release produced by Na+ removal. No decisive support for Ca2+ influx by reverse Na(+)-Ca2+ exchange could be found

Inhibition of protein synthesis sequentially impairs distinct steps of stimulus-secretion coupling in pancreatic beta cells

Proteins with a short half-life are potential sites of pancreatic ss cell dysfunction under pathophysiological conditions. In this study, mouse islets were used to establish which step in the regulation of insulin secretion is most sensitive to inhibition of protein synthesis by 10 microM cycloheximide (CHX). Although islet protein synthesis was inhibited approximately 95% after 1 h, the inhibition of insulin secretion was delayed and progressive. After long (18-20 h) CHX-treatment, the strong (80%) inhibition of glucose-, tolbutamide-, and K(+)-induced insulin secretion was not due to lower insulin stores, to any marked impairment of glucose metabolism or to altered function of K(+)-ATP channels (total K(+)-ATP currents were however decreased). It was partly caused by a decreased Ca(2+) influx (whole-cell Ca(2+) current) resulting in a smaller rise in cytosolic Ca(2+) ([Ca(2+)](i)). The situation was very different after short (2-5 h) CHX-treatment. Insulin secretion was 50-60% inhibited although islet glucose metabolism was unaffected and stimulus-induced [Ca(2+)](i) rise was not (2 h) or only marginally (5 h) decreased. The efficiency of Ca(2+) on secretion was thus impaired. The inhibition of insulin secretion by 15 h of CHX treatment was more slowly reversible (>4 h) than that of protein synthesis. This reversibility of secretion was largely attributable to recovery of a normal Ca(2+) efficiency. In conclusion, inhibition of protein synthesis in islets inhibits insulin secretion in two stages: a rapid decrease in the efficiency of Ca(2+) on exocytosis, followed by a decrease in the Ca(2+) signal mediated by a slower loss of functional Ca(2+) channels. Glucose metabolism and the regulation of K(+)-ATP channels are more resistant. Proteins with a short half-life appear to be important to ensure optimal Ca(2+) effects on exocytosis, and are the potential Achille's heel of stimulus-secretion coupling

Synergistic impact of innate immunity hyper-activation and endothelial dysfunction on the magnitude of organ failure in the infection-sepsis continuum

Biomarkers; Infection; SynergyBiomarcadors; Infecció; SinergiaBiomarcadores; Infección; SinergiaObjectives Identifying host response biomarkers implicated in the emergence of organ failure during infection is key to improving the early detection of this complication. Methods Twenty biomarkers of innate immunity, T-cell response, endothelial dysfunction, coagulation, and immunosuppression were profiled in 180 surgical patients with infections of diverse severity (IDS) and 53 with no infection (nIDS). Those better differentiating IDS/nIDS in the area under the curve were combined to test their association with the sequential organ failure assessment score by linear regression analysis in IDS. Results were validated in another IDS cohort of 174 patients. Results C-reactive protein, procalcitonin, pentraxin-3, lipocalin-2 (LCN2), tumoral necrosis factor-α, angiopoietin-2, triggering receptor expressed on myeloid cells-1 (TREM-1) and interleukin (IL)-15 yielded an area under the curve ≥0.75 to differentiate IDS from nIDS. The combination of LCN2, IL-15, TREM-1, angiopoietin-2 (Dys-4) showed the strongest association with sequential organ failure assessment score in IDS (adjusted regression coefficient; standard error; P): Dys-4 (3.55;0.44; <0.001), LCN2 (2.24; 0.28; <0.001), angiopoietin-2 (1.92; 0.33; <0.001), IL-15 (1.78; 0.40; <0.001), TREM-1(1.74; 0.46; <0.001), tumoral necrosis factor-α (1.60; 0.31; <0.001), pentraxin-3 (1.12; 0.18; <0.001), procalcitonin (0.85; 0.12; <0.001). Dys-4 provided similar results in the validation cohort. Conclusions There is a synergistic impact of innate immunity hyper-activation (LCN2, IL-15, TREM-1) and endothelial dysfunction (angiopoietin-2) on the magnitude of organ failure during infection.This work was supported by the Instituto de Salud Carlos III (ISCIII) and co-funded by European Regional Development Fund/European Social Fund “A way to make Europe“/”Investing in your future” [Project “PI19/00590” (JFBM), Project “PI22/00968” (JFBM), Sara Borrell program “CD018/0123” (APT) and PFIS program “FI20/00278” (AdlF)]. The funding sources did not play any role in the design of the study and collection, analysis, interpretation of data, or writing the manuscript

Implementation of a University Guidance Service (SOU) in the Faculty of Biological Sciences: Comprehensive Student Support and Monitoring Program

El acompañamiento y el seguimiento académico de los estudiantes son tareas de gran importancia, necesarias para garantizar el éxito de su carrera profesional durante su vida universitaria, y después de ésta. Estos procesos no comienzan necesariamente con el ingreso de los estudiantes en la Universidad, sino que se extienden a los estudiantes de último curso de educación secundaria y bachillerato. Existe por tanto la necesidad de incluir dentro de las acciones que realizamos en la facultad (información, formación, inclusión) a los estudiantes de bachillerato, dándoles a conocer nuestro entorno de cara a su incorporación en la facultad. Por otro lado, la experiencia del equipo que trabajará en este proyecto, nos ha llevado a ser conscientes de los innumerables problemas que tienen los estudiantes de nuestra facultad para obtener información, formación, acompañamiento, seguimiento o inclusión en cuestiones que pueden afectar de una forma directa en sus actividades académica cotidianas y en su formación integral que reciben en nuestra facultad. La falta de una unidad o servicio centralizado para satisfacer estas necesidades ha sido aún más patente desde la pandemia. En la Facultad de Ciencias Biológicas se realizan multitud de actividades relacionadas con estas iniciativas y que son desconocidas por gran parte de la comunidad universitaria. Las acciones que se vienen realizando desde la facultad de Ciencias Biológicas estas dispersas entre distintos servicios y vicedecanatos (Vicedecanato de Calidad, Innovación y Sostenibilidad, Vicedecanato de Estudiantes, Practicas Externas y Movilidad, Vicedecanato de Estudios, Coordinadora de Grado, Oficina Erasmus, Vicedecanato de Investigación, Secretaría Académica, Delegación de Estudiantes, Oficina de Diversidad, etc.). En este sentido, con este proyecto pretendemos potenciar, sincronizar, coordinar y dar visibilidad a todas estas, mostrando la inmensa utilidad que suponen para nuestros estudiantes, cómo influyen en la mejora de sus actividades académicas curriculares y extracurriculares y su proyección hacia el mundo laboral. Analizaremos cómo cada una de estas actividades influyen positivamente generando una retroalimentación entre los distintos grupos de participantes del proyecto: Estudiantes, Profesores y Personal de Administración y Servicios. Todo ello, será evaluado cualitativa y cuantitativamente mediante la elaboración de encuestas a cada uno de los sectores y los comentarios y evaluaciones que el programa Docentia nos pueda aportar. La finalidad, por tanto, de este proyecto es crear de forma integrativa un Servicio de Orientación Universitario (SOU) para los estudiantes de nuestra facultad, donde se engloben todas las actividades de acompañamiento y seguimiento que venimos realizando, junto con otras que puedan surgir. Todo ello permitirá mejorar la integración y el desenvolvimiento de nuestros estudiantes en el centro mediante su participación en distintas acciones que, a su vez, redundarán en un mejor aprovechamiento de los recursos del centro, una mejora curricular y, en último término, facilitarán su proyección laboral. Este proyecto, también tiene por objetivo solventar la necesidad existente de dar visibilidad a las actividades de acompañamiento y seguimiento de estudiantes que los distintos colectivos de la facultad realizan, con la finalidad de mejorar su aprovechamiento y su optimización a través un análisis de fortalezas y debilidades, lo que nos permitirá generar futuras nuevas acciones que se integrarán en el SOU de la Facultad de Ciencias Biológicas.UCMDecanatoDepto. de Genética, Fisiología y MicrobiologíaFac. de Ciencias BiológicasFALSEsubmitte