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Título: | Unraveling the role of the insulin-degrading enzyme (IDE) on hepatic insulin and glucagon signaling |
Autor: | González Casimiro, Carlos M.; Merino, Beatriz CSIC ORCID CVN; Balsinde, Jesús CSIC ORCID ; Cózar-Castellano, Irene CSIC ORCID CVN; Perdomo, Germán CSIC ORCID CVN | Fecha de publicación: | 3-may-2020 | Citación: | 11th Ciberdem Annual Meeting (2020) | Resumen: | IDE is a protease that degrades insulin and glucagon. Genetic Ide polymorphisms are linked to increased risk of developing T2DM. Reduced IDE levels associates with lower insulin clearance in T2DM patients. However, molecular mechanisms linking IDE with the pathophysiology of T2DM are poorly defined. To investigate the role of IDE on T2DM, we fed mice with a standard diet (SD) or high-fat diet (HFD) and examined the impact of loss- versus -gain of IDE function on insulin and glucagon action in hepatocytes. L-IDE-KO mice fed a SD exhibited insulin resistance and glucose intolerance with no change in hepatic insulin clearance. Insulin resistance was associated with increased FoxO1 activation, reduced insulin receptor (IR) protein levels, and reduced phosphorylation of CEACAM1, which promotes receptor-mediated insulin uptake to be degraded. L-IDE-KO mice exacerbates hyperinsulinemia and insulin resistance in the setting of HFD-induced obesity, in parallel to an increase in pancreatic beta-cell function without altering insulin clearance. Insulin resistance was associated with increased FoxO1 activation and ~2-fold increase of GLUT2 protein levels. Conversely, gain of IDE function (adenoviral delivery) improves glucose tolerance and insulin sensitivity, in parallel to a reciprocal ~2-fold reduction in hepatic GLUT2 protein levels. Furthermore, in response to insulin, IDE co-immunoprecipitates with the IR. On the other hand, hepatic IDE depletion did not alter circulating glucagon levels in mice fed SD or HFD. Interestingly, L-IDE-KO mice showed reduced CREB protein levels. Likewise, depletion of Ide in AML12 cells significantly reduced CREB protein levels, in parallel with increased glycogen synthase protein levels. In conclusion, loss of IDE function aggravates insulin resistance and glucose intolerance, whereas gain of IDE function exerts beneficial effects on glucose tolerance and insulin sensitivity in the setting of obesity, providing a strong rationale for developing pharmacological compounds targeting IDE activation for T2DM treatment. | Descripción: | Trabajo presentado en el 11th Ciberdem Annual Meeting celebrado en modalidad online, del 3 al 5 de noviembre de 2020. | URI: | http://hdl.handle.net/10261/223983 |
Aparece en las colecciones: | (IBGM) Comunicaciones congresos |
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