Loss of postprandial insulin clearance control by Insulin-degrading enzyme drives dysmetabolism traits

• Type: Article in International Scientific Journal
• Date: 2021

Authors

Borges, DO (Author) Other; Patarrao, RS (Author) Other; Ribeiro, RT (Author) Other; de Oliveira, RM (Author) Other; Duarte, N (Author) Other; Belew, GD (Author) Other; Martins, M (Author) Other; Andrade, R (Author) Other; Costa, J (Author) Other; Correia, I (Author) Other; Boavida, JM (Author) Other; Duarte, R (Author) Other; Gardete Correia, L (Author) Other; Medina, JL (Author) Other; Raposo, JF (Author) Other; Jones, JG (Author) Other; Penha Goncalves, C (Author) Other; Macedo, MP (Author) Other

Journal

Title: Metabolism: Clinical and Experimental

Vol. 118

ISSN: 0026-0495

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 0 Citations

Scopus - 1 Citation

Other information

Authenticus ID: P-00T-KXN

DOI: 10.1016/j.metabol.2021.154735

Abstract (EN): Systemic insulin availability is determined by a balance between beta-cell secretion capacity and insulin clearance (IC). Insulin-degrading enzyme (IDE) is involved in the intracellular mechanisms underlying IC. The liver is a major player in IC control yet the role of hepatic IDE in glucose and lipid homeostasis remains unexplored. We hypothesized that IDE governs postprandial IC and hepatic IDE dysfunction amplifies dysmetabolic responses and prediabetes traits such as hepatic steatosis. In a European/Portuguese population-based cohort, IDE SNPs were strongly associated with postprandial IC in normoglycemic men but to a considerably lesser extent in women or in subjects with prediabetes. Liver-specific knockout-mice (LS-IDE KO) under normal chow diet (NCD), showed reduced postprandial IC with glucose intolerance and under high fat diet (HFD) were more susceptible to hepatic steatosis than control mice. This suggests that regulation of IC by IDE contributes to liver metabolic resilience. In agreement, LS-IDE KO hepatocytes revealed reduction of Glut2 expression levels with consequent impairment of glucose uptake and upregulation of CD36, a major hepatic free fatty acid transporter. Together these findings provide strong evidence that dysfunctional IC due to abnormal IDE regulation directly impairs postprandial hepatic glucose disposal and increases susceptibility to dysmetabolic conditions in the setting of Western diet/lifestyle.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 11