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

Diego O. Borges, Rita S. Patarrão, Rogério T. Ribeiro, Rita Machado de Oliveira, Nádia Duarte, Getachew Debas Belew, Madalena Martins, Rita Andrade, João Costa, Isabel Correia, José Manuel Boavida, Rui Duarte, Luís Gardete-Correia, José Luís Medina, João F. Raposo, John G. Jones, Carlos Penha-Gonçalves, M. Paula Macedo

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number154735
JournalMetabolism: Clinical and Experimental
Volume118
DOIs
Publication statusPublished - May 2021

Keywords

  • Genetic susceptibility
  • Hepatic steatosis
  • Hyperinsulinemia
  • Insulin clearance
  • Insulin-degrading enzyme
  • Prediabetes

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