Binding kinetics, bias, receptor internalization and effects on insulin secretion in vitro and in vivo of a novel GLP-1R/GIPR dual agonist, HISHS-2001.

ABSTRACT:

Aims

The use of incretin analogues has emerged as an effective approach to achieve both enhanced insulin secretion and weight loss in Type 2 diabetes (T2D) patients. Agonists which bind and stimulate multiple receptors have shown particular promise. However, off-target effects remain a complication of using these agents, and modified versions with optimised pharmacological profiles and/or biased signalling are sought.

Materials and methods

Ligand synthesis was achieved using standard solid-phase techniques. Assessments of GLP-1R-binding kinetics, G protein recruitment and receptor internalisation were performed using biochemical and imaging approaches. Insulin secretion was measured in purified mouse and human islets, and drug efficacy was assessed in hyperglycaemic db/db mi

SUBMITTER: Manchanda Y 

PROVIDER: S-EPMC12409219 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature