Targeting Insulin-Degrading Enzyme in Insulin Clearance

Abstract

© 2021 by the authors.Hepatic insulin clearance, a physiological process that in response to nutritional cues clears ~50–80% of circulating insulin, is emerging as an important factor in our understanding of the pathogenesis of type 2 diabetes mellitus (T2DM). Insulin-degrading enzyme (IDE) is a highly conserved Zn2+-metalloprotease that degrades insulin and several other intermediate-size peptides. Both, insulin clearance and IDE activity are reduced in diabetic patients, albeit the cause-effect relationship in humans remains unproven. Because historically IDE has been proposed as the main enzyme involved in insulin degradation, efforts in the development of IDE inhibitors as therapeutics in diabetic patients has attracted attention during the last decades. In this review, we retrace the path from Mirsky’s seminal discovery of IDE to the present, highlighting the pros and cons of the development of IDE inhibitors as a pharmacological approach to treating diabetic patients.This research was funded by the Ministerio de Economía, Industria y Competitividad, grant number SAF2016-77871-C2-2-R to G.P.; Ministerio de Ciencia e Innovación PID2019-110496RB-C22 to G.P.; European Foundation for the Study of Diabetes (European Diabetes Research Programme on New Targets for Type 2 Diabetes supported by MSD-2017) to G.P.; European Foundation for the Study of Diabetes (EFSD) -Novo Nordisk to B.M.; and the US National Institutes of Health (GM115617) to M.A.L. The project leading to these results has received funding from “La Caixa” Foundation, under agreement LCF/PR/PR18/51130007 to G.P. C.M.G.-C. was supported by a fellowship from the Junta de Castilla y León and the European Social Fund (ORDER EDU/574/2018). B.M. was supported by a “Rising Star” fellowship (EFSD-Novo Nordisk)