RESUMEN
Sotagliflozin (trade name INFEPA) is a novel dual sodium-glucose cotransporter-1 and -2 (SGLT-1/2) inhibitor that was developed by Lexicon Pharmaceuticals. It has emerged as a promising therapy for managing heart failure and other cardiovascular complications associated with type 2 diabetes mellitus (T2DM). Its dual inhibition of SGLT-1 and SGLT-2 receptors uniquely decreases glucose absorption in the intestine in addition to decreasing renal glucose reabsorption, leading to improved glycemic control and cardio-reno protection. Clinical trials have demonstrated its efficacy in reducing cardiovascular death, heart failure hospitalizations, and urgent visits, particularly in T2DM patients with chronic kidney disease (CKD). The drug was approved in 2023 by the Food and Drug Administration for reducing cardiovascular death and heart failure in T2DM patients with CKD and those with heart failure, irrespective of diabetic status or ejection fraction. However, despite its considerable therapeutic potential, sotagliflozin does pose notable adverse effects, including diabetic ketoacidosis, genital infections, and diarrhea. As a result, it has faced regulatory challenges in certain regions, notably the United States. The Food and Drug Administration has so far withheld approval for sotagliflozin in the treatment of type 1 diabetes due to concerns about its safety profile, specifically the risk of diabetic ketoacidosis, although Lexicon Pharmaceuticals plans to submit another new drug application for this use in 2024. Further investigation and clinical trials are warranted to fully elucidate sotagliflozin's impact on diabetes and CKD.
RESUMEN
Stem-cell-derived tissues offer platforms to study organ development, model physiology during health and disease, and test novel therapies. We describe methods to isolate cells at successive stages during in vitro differentiation of human stem cells into the pancreatic endocrine lineage. Using flow cytometry, we purify live lineage intermediates in numbers not available by fetal biopsy. These include pancreatic and endocrine progenitors, isolated based on known surface markers. We further report a strategy that leverages intracellular zinc content and DPP4/CD26 expression to separate monohormonal insulin+ ß cells from polyhormonal counterparts. These methods enable comprehensive molecular profiling during human islet lineage progression. © 2020 Wiley Periodicals LLC. Basic Protocol: In vitro isolation of human islet developmental intermediates.
Asunto(s)
Citometría de Flujo/métodos , Células Secretoras de Insulina/citología , Biomarcadores/metabolismo , Diferenciación Celular , Humanos , Células MadreRESUMEN
Stem-cell-derived tissues could transform disease research and therapy, yet most methods generate functionally immature products. We investigate how human pluripotent stem cells (hPSCs) differentiate into pancreatic islets in vitro by profiling DNA methylation, chromatin accessibility, and histone modification changes. We find that enhancer potential is reset upon lineage commitment and show how pervasive epigenetic priming steers endocrine cell fates. Modeling islet differentiation and maturation regulatory circuits reveals genes critical for generating endocrine cells and identifies circadian control as limiting for in vitro islet function. Entrainment to circadian feeding/fasting cycles triggers islet metabolic maturation by inducing cyclic synthesis of energy metabolism and insulin secretion effectors, including antiphasic insulin and glucagon pulses. Following entrainment, hPSC-derived islets gain persistent chromatin changes and rhythmic insulin responses with a raised glucose threshold, a hallmark of functional maturity, and function within days of transplantation. Thus, hPSC-derived tissues are amenable to functional improvement by circadian modulation.