Sodium‑glucose cotransporter 2 inhibitors (SGLT2i): renal implications

Type 2 diabetes mellitus (DM2) is a chronic condition that affects more than 400 million individuals worldwide. In DM2 patients, an appropriate glycemic control slows the onset and delays the progression of all its micro and macrovascular complications. Even though there are several glucose-lowering drugs, only approximately half of patients achieve glycemic control, while undesirable adverse effects (e.g., low serum glucose) normally affect treatment. Therefore, there is a need for new types of treatments. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have just been developed for treating DM2. Renal hyperfiltration as a marker of increased intraglomerular pressure in diabetic patients, and the role of renin–angiotensin– aldosterone system (RAAS) in this phenomenon have been studied. Nevertheless, RAAS blockade does not completely reduce hyperfiltration or diabetic renal damage. In this sense, the contribution of renal tubular factors to the hyperfiltration state, including sodium–glucose cotransporter (SGLT), has been currently studied. SGLT2i reduce proximal tubular sodium reabsorption, therefore increasing distal sodium delivery to the macula densa, causing tubule-glomerular feedback activation, afferent vasoconstriction, and reduced hyperfiltration in animal models. In humans, SGLT2i was recently shown to reduce hyperfiltration in normotensive, normoalbuminuric patients suffering from type 1 diabetes mellitus. In DM2 clinical trials, SGLT2 is associated with significant hyperfiltration and albuminuria reduction. The aim of this article is to compile the information regarding SGLT2i drugs, emphasizing its mechanism of renal repercussion

Primeros ensayos ambulatorios de un páncreas artificial en Argentina

En el 2017, el grupo de trabajo realizó en Argentina el primer ensayo clínico piloto utilizando un Páncreas Artificial con un algoritmo no híbrido sin requerimiento de conteo de contenido de carbohidrato un nuevo algoritmo de origen argentino, denominado ARG (automatic regulation of glucose), en pacientes internados y muy controlados durante un período de 36 horas. En este trabajo se presenta un estudio realizado con dicho algoritmo ARG en marzo de 2021, en 5 pacientes con DMT1 no hospitalizados o ambulatorios y durante un mayor período de tiempo (6 s, en pacientes con DMT1 del Hospital Italiano de Buenos Aires (HIBA). Se evaluó eficacia y seguridad de días en total).Facultad de Ingenierí

Non-hybrid glycemic control of type 1 diabetes ambulatory patients

[EN] In this work, we present the experience of our research group with the glucose regulation in people with Type 1 Diabetes (insulin-dependent), known as artificial pancreas. Our research group has carried out three clinical trials in Argentina, which were the first ones in Latin America. The first two studies took place in 2016 and 2017, both in the Hospital Italiano de Buenos Aires (HIBA) with five adult subjects and a duration of 36 hours. The second trial evaluated the performance of a novel closed-loop controlalgorithm (without meal insulin boluses), called ARG Automatic Regulation of Glucose) and based on switched LQG control and a safety layer called SAFE (Safery Auxiliary Feedback Element), developed by researchers of our team. More recently and during COVID-19 pandemic, the first ambulatory trials took place, which were carried out in 2021 in a hotel with 5 subjects during 6 days. Additionally, for this third trial, the use of the artificial pancreas platform developed by the UNLP, called InsuMate, was incorporated. This platform connects a smartphone with the insulin pump and glucose monitor, houses the control algorithm, andallows the remote monitoring of multiple users. The results suggest that the ambulatory use of the ARG algorithm is feasible, safe and effective, compared to the usual reatment. In addition, the InsuMate platform was intuitive and easy to use for both healthcare staff and participants of the trial, achieving an over 95% of time in closed-loop.[ES] En este trabajo se presenta la experiencia argentina en el problema de regulación de los niveles de glucosa en sangre para pacientes con Diabetes Mellitus Tipo 1 (insulino-dependientes), denominado Páncreas Artificial. El grupo de trabajo ha realizado 3 pruebas clínicas, las primeras en Latinoamérica. Las dos primeras fueron concretadas en 2016 y 2017, ambas en el Hospital Italiano con 5 pacientes adultos durante 36 hs. En la segunda de ellas se utilizó un nuevo algoritmo de control de lazo cerrado puro (sin bolo prandial), llamado ARG (Automatic Regulation of Glucose) y basado en un control LQG conmutado en combinación con la capa de seguridad SAFE (Safety Auxiliary Feedback Element), desarrollado por investigadores de nuestro equipo. Este año se llevó a cabo la primera prueba ambulatoria, realizada en un hotel con 5 pacientes durante 6 días en marzo de 2021. En esta tercera prueba además, se utilizó una plataforma desarrollada por la Universidad Nacional de La Plata (UNLP), denominada InsuMate. Ésta conecta el celular con la bomba de insulina y el monitor de glucosa, aloja el algoritmo de control y permite el monitoreo remoto de múltiples pacientes. Los resultados obtenidos sugieren que el uso del algoritmo ARG en forma ambulatoria es factible, seguro y eficaz en comparación con la terapia usual. Asimismo, la plataforma InsuMate resultó ser intuitiva y sencilla para los usuarios, tanto médicos como pacientes participantes del ensayo, logrando un tiempo de funcionamiento del lazo cerrado superior al 95 %. Este trabajo ha sido realizado parcialmente gracias al apoyo de las Fundaciones Cellex (España) y Nuria (Argentina), y el financiamiento de los proyectos PICT2017-3211, PICT2019-2554, UNLP/I253, CONICET/PIP2595 y COVID Federal BS AS 28 del gobierno argentino.Garelli, F.; Fushimi, E.; Rosales, N.; Arambarri, D.; Serafini, MC.; De Battista, H.; Grosembacher, LA.... (2022). Control no-híbrido de glucemia ensayado en pacientes ambulatorios con Diabetes Tipo 1. Revista Iberoamericana de Automática e Informática industrial. 19(3):318-329. https://doi.org/10.4995/riai.2022.16652OJS31832919

Remote Glucose Monitoring Platform for Multiple Simultaneous Patients at Coronavirus Disease 2019 Intensive Care Units: Case Report including Adults and Children

This work focuses on remote glucose monitoring at COVID-19 Intensive Care Units (ICU)in Argentina. We report the first cases using a new emergency platform for multi-centermulti-patient on-line remote glucose monitoring, which is accessible for everyone ondemand and which allows the integration of different glucose sensors. Five critical patientshave been monitored, two children and three adults, together with an ambulatory patient totest the platform versatility. All ICU patients have recovered or have been metabolicallycontrolled by the date of the submission of this report. Relevant lessons have been learnedfor the glucose management of critical patients, resulting in a new protocol in one of theparticipant hospitals.Fil: Garelli, Fabricio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones en Electrónica, Control y Procesamiento de Señales. Universidad Nacional de La Plata. Instituto de Investigaciones en Electrónica, Control y Procesamiento de Señales; ArgentinaFil: Rosales, Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones en Electrónica, Control y Procesamiento de Señales. Universidad Nacional de La Plata. Instituto de Investigaciones en Electrónica, Control y Procesamiento de Señales; ArgentinaFil: Fushimi, Emilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones en Electrónica, Control y Procesamiento de Señales. Universidad Nacional de La Plata. Instituto de Investigaciones en Electrónica, Control y Procesamiento de Señales; ArgentinaFil: Arambarri, Delfina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones en Electrónica, Control y Procesamiento de Señales. Universidad Nacional de La Plata. Instituto de Investigaciones en Electrónica, Control y Procesamiento de Señales; ArgentinaFil: Mendoza, Leandro Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones en Electrónica, Control y Procesamiento de Señales. Universidad Nacional de La Plata. Instituto de Investigaciones en Electrónica, Control y Procesamiento de Señales; ArgentinaFil: de Battista, Hernán. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones en Electrónica, Control y Procesamiento de Señales. Universidad Nacional de La Plata. Instituto de Investigaciones en Electrónica, Control y Procesamiento de Señales; ArgentinaFil: Sanchez Peña, Ricardo Salvador. Instituto Tecnológico de Buenos Aires. Departamento de Matemática. Centro de Sistemas y Control; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: García Arabehety, Julia. Hospital Italiano; ArgentinaFil: DIstefano, Sabrina. Hospital Italiano; ArgentinaFil: Barcala, Consuelo. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Giunta, Javier. Hospital Italiano; ArgentinaFil: Las Heras, Marcos. Hospital Italiano; ArgentinaFil: Martinez Mateu, Carolina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Prieto, Mariana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: San Román, Eduardo. Hospital Italiano; ArgentinaFil: Krochik, Andrea Gabriela. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Grosembacher, Luis. Hospital Italiano; Argentin

Artificial Pancreas: Clinical Study in Latin America Without Premeal Insulin Boluses

Background: Emerging therapies such as closed-loop (CL) glucose control, also known as artificial pancreas (AP) systems, have shown significant improvement in type 1 diabetes mellitus (T1DM) management. However, demanding patient intervention is still required, particularly at meal times. To reduce treatment burden, the automatic regulation of glucose (ARG) algorithm mitigates postprandial glucose excursions without feedforward insulin boluses. This work assesses feasibility of this new strategy in a clinical trial. Methods: A 36-hour pilot study was performed on five T1DM subjects to validate the ARG algorithm. Subjects wore a subcutaneous continuous glucose monitor (CGM) and an insulin pump. Insulin delivery was solely commanded by the ARG algorithm, without premeal insulin boluses. This was the first clinical trial in Latin America to validate an AP controller. Results: For the total 36-hour period, results were as follows: average time of CGM readings in range 70-250 mg/dl: 88.6%, in range 70-180 mg/dl: 74.7%, <70 mg/dl: 5.8%, and <50 mg/dl: 0.8%. Results improved analyzing the final 15-hour period of this trial. In that case, the time spent in range was 70-250 mg/dl: 94.7%, in range 70-180 mg/dl: 82.6%, <70 mg/dl: 4.1%, and <50 mg/dl: 0.2%. During the last night the time spent in range was 70-250 mg/dl: 95%, in range 70-180 mg/dl: 87.7%, <70 mg/dl: 5.0%, and <50 mg/dl: 0.0%. No severe hypoglycemia occurred. No serious adverse events were reported. Conclusions: The ARG algorithm was successfully validated in a pilot clinical trial, encouraging further tests with a larger number of patients and in outpatient settings.Facultad de Ingenierí

CRISPR-on system for the activation of the endogenous human INS gene

Advances in the field of epigenetics have allowed the design of new therapeutic strategies to address complex diseases such as type 1 diabetes (T1D). Clustered regularly interspaced short palindromic repeats (CRISPR)-on is a novel and powerful RNA-guided transcriptional activator system that can turn on specific gene expression; however, it remains unclear whether this system can be widely used or whether its use will be restricted depending on cell types, methylation promoter statuses or the capacity to modulate chromatin state. Our results revealed that the CRISPR-on system fused with transcriptional activators (dCas9-VP160) activated endogenous human INS, which is a silenced gene with a fully methylated promoter. Similarly, we observed a synergistic effect on gene activation when multiple single guide RNAs were used, and the transcriptional activation was maintained until day 21. Regarding the epigenetic profile, the targeted promoter gene did not exhibit alteration in its methylation status but rather exhibited altered levels of H3K9ac following treatment. Importantly, we showed that dCas9-VP160 acts on patients' cells in vitro, particularly the fibroblasts of patients with T1D.Fil: Giménez, Carla Alejandra. Hospital Italiano; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ielpi, Marcelo. Hospital Italiano; ArgentinaFil: Mutto, Adrián Angel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; ArgentinaFil: Grosembacher, Luis. Hospital Italiano; ArgentinaFil: Argibay, Pablo. Hospital Italiano; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Pereyra Bonnet, Federico Alberto. Hospital Italiano; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Artificial Pancreas: Clinical Study in Latin America Without Premeal Insulin Boluses

Background: Emerging therapies such as closed-loop (CL) glucose control, also known as artificial pancreas (AP) systems, have shown significant improvement in type 1 diabetes mellitus (T1DM) management. However, demanding patient intervention is still required, particularly at meal times. To reduce treatment burden, the automatic regulation of glucose (ARG) algorithm mitigates postprandial glucose excursions without feedforward insulin boluses. This work assesses feasibility of this new strategy in a clinical trial. Methods: A 36-hour pilot study was performed on five T1DM subjects to validate the ARG algorithm. Subjects wore a subcutaneous continuous glucose monitor (CGM) and an insulin pump. Insulin delivery was solely commanded by the ARG algorithm, without premeal insulin boluses. This was the first clinical trial in Latin America to validate an AP controller. Results: For the total 36-hour period, results were as follows: average time of CGM readings in range 70-250 mg/dl: 88.6%, in range 70-180 mg/dl: 74.7%, <70 mg/dl: 5.8%, and <50 mg/dl: 0.8%. Results improved analyzing the final 15-hour period of this trial. In that case, the time spent in range was 70-250 mg/dl: 94.7%, in range 70-180 mg/dl: 82.6%, <70 mg/dl: 4.1%, and <50 mg/dl: 0.2%. During the last night the time spent in range was 70-250 mg/dl: 95%, in range 70-180 mg/dl: 87.7%, <70 mg/dl: 5.0%, and <50 mg/dl: 0.0%. No severe hypoglycemia occurred. No serious adverse events were reported. Conclusions: The ARG algorithm was successfully validated in a pilot clinical trial, encouraging further tests with a larger number of patients and in outpatient settings.Fil: Sanchez Peña, Ricardo Salvador. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Tecnológico de Buenos Aires; ArgentinaFil: Colmegna, Patricio Hernán. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; Argentina. University of Virginia; Estados UnidosFil: Garelli, Fabricio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de La Plata; ArgentinaFil: de Battista, Hernán. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de La Plata; ArgentinaFil: García Violini, Diego Demián. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Tecnológico de Buenos Aires; ArgentinaFil: Moscoso Vásquez, Hilda Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Tecnológico de Buenos Aires; ArgentinaFil: Rosales, Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de La Plata; ArgentinaFil: Fushimi, Emilia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de La Plata; ArgentinaFil: Campos-Náñez, Enrique. Typezero Technologies; Estados UnidosFil: Breton, Marc. University of Virginia; Estados UnidosFil: Beruto, Valeria. Hospital Italiano; ArgentinaFil: Scibona, Paula. Hospital Italiano; ArgentinaFil: Rodriguez, Cintia. Hospital Italiano; ArgentinaFil: Giunta, Javier. Hospital Italiano; ArgentinaFil: Simonovich, Ventura. Hospital Italiano; ArgentinaFil: Belloso, Waldo Horacio. Hospital Italiano; ArgentinaFil: Cherñavvsky, Daniel. Hospital Italiano; ArgentinaFil: Grosembacher, Luis. Hospital Italiano; Argentin