RESUMEN
ß cell failure in type 2 diabetes (T2D) is associated with hyperglycemia, but the mechanisms are not fully understood. Congenital hyperinsulinism caused by glucokinase mutations (GCK-CHI) is associated with ß cell replication and apoptosis. Here, we show that genetic activation of ß cell glucokinase, initially triggering replication, causes apoptosis associated with DNA double-strand breaks and activation of the tumor suppressor p53. ATP-sensitive potassium channels (KATP channels) and calcineurin mediate this toxic effect. Toxicity of long-term glucokinase overactivity was confirmed by finding late-onset diabetes in older members of a GCK-CHI family. Glucagon-like peptide-1 (GLP-1) mimetic treatment or p53 deletion rescues ß cells from glucokinase-induced death, but only GLP-1 analog rescues ß cell function. DNA damage and p53 activity in T2D suggest shared mechanisms of ß cell failure in hyperglycemia and CHI. Our results reveal membrane depolarization via KATP channels, calcineurin signaling, DNA breaks, and p53 as determinants of ß cell glucotoxicity and suggest pharmacological approaches to enhance ß cell survival in diabetes.
Asunto(s)
Hiperinsulinismo Congénito/complicaciones , Roturas del ADN de Doble Cadena , Diabetes Mellitus Tipo 2/complicaciones , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Proteína p53 Supresora de Tumor/metabolismo , Animales , Biomarcadores/metabolismo , Calcineurina/metabolismo , Muerte Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Hiperinsulinismo Congénito/enzimología , Hiperinsulinismo Congénito/patología , Roturas del ADN de Doble Cadena/efectos de los fármacos , Diabetes Mellitus Tipo 2/enzimología , Diabetes Mellitus Tipo 2/patología , Modelos Animales de Enfermedad , Activación Enzimática/efectos de los fármacos , Inducción Enzimática/efectos de los fármacos , Ayuno/metabolismo , Péptido 1 Similar al Glucagón/farmacología , Glucoquinasa/biosíntesis , Glucosa/toxicidad , Humanos , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/enzimología , Potenciales de la Membrana/efectos de los fármacos , Ratones , TransgenesRESUMEN
Recent studies revealed a surprising regenerative capacity of insulin-producing ß cells in mice, suggesting that regenerative therapy for human diabetes could in principle be achieved. Physiologic ß cell regeneration under stressed conditions relies on accelerated proliferation of surviving ß cells, but the factors that trigger and control this response remain unclear. Using islet transplantation experiments, we show that ß cell mass is controlled systemically rather than by local factors such as tissue damage. Chronic changes in ß cell glucose metabolism, rather than blood glucose levels per se, are the main positive regulator of basal and compensatory ß cell proliferation in vivo. Intracellularly, genetic and pharmacologic manipulations reveal that glucose induces ß cell replication via metabolism by glucokinase, the first step of glycolysis, followed by closure of K(ATP) channels and membrane depolarization. Our data provide a molecular mechanism for homeostatic control of ß cell mass by metabolic demand.