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Persistent organelle stress in chronic disease impairs these pathways, driving systemic hormone resistance and metabolic failure. A paradigm shifts in glucagon-like peptide-1 receptor (GLP-1R) signaling from diffuse events to spatiotemporally organized signalosomes offer insightful mechanisms into these conditions. The localization of internalized GLP-1Rs at the Mitochondria-ER interface supports a contactomics framework for understanding bioenergetic restoration. 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