Science advancesAug 26, 2026

Designing long-lasting and brain-stable GLP-1 receptor drugs based on how IDE breaks down GLP-1

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗

Updated Aug 29, 2026

Abstract

Insulin-degrading enzyme (IDE) is identified as a previously unknown protease that degrades glucagon-like peptide-1 (GLP-1).

IDE has two cleavage sites that specifically degrade GLP-1 but not insulin.
The degradation of GLP-1 by IDE is a major mechanism regulating glucose control.
GLP-1 and Semaglutide were engineered with D-amino acid substitutions to resist IDE degradation.
Modified peptides demonstrate enhanced stability in various biological fluids, including plasma and the central nervous system.
D-Ser¹⁸-Semaglutide shows prolonged plasma retention and sustained glucose-lowering effects in mice.
Knockdown of IDE and intracerebral injection of D-Ser¹⁸-Semaglutide support IDE's role in GLP-1 degradation, especially in the central nervous system.

Simplified

Glucagon-like peptide-1 (GLP-1) is a key incretin hormone rapidly degraded by circulating proteases such as DPP-4. The metabolism of GLP-1 by other proteases, particularly tissue-resident proteases, remains largely unexplored. Here, we identify insulin-degrading enzyme (IDE) as a previously unknown GLP-1-degrading protease with two cleavage sites. We show that IDE-mediated degradation of GLP-1, but not insulin, represents a major mechanism regulating glucose control. To resist IDE, we engineered GLP-1 and Semaglutide with D-amino acid substitutions at these sites. These peptides exhibit enhanced stability in plasma, liver and intestinal secretomes, peritoneal fluid, and central nervous system (CNS). D-Ser¹⁸-Semaglutide shows prolonged plasma retention and sustained glucose-lowering effects in mice. Moreover, IDE knockdown and intracerebral injection of D-Ser¹⁸-Semaglutide confirm IDE's physiological role in GLP-1 degradation, particularly in the CNS. These findings reveal a previously unidentified regulatory mechanism of GLP-1 metabolism and provide a strategy for designing long-acting agonists with improved metabolic and CNS therapeutic potential.