How May GIP Enhance the Therapeutic Efficacy of GLP-1?

• Published in: Trends in endocrinology and metabolism Vol. 31; no. 6; pp. 410 - 421
• Main Authors: Samms, Ricardo J., Coghlan, Matthew P., Sloop, Kyle W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 01.06.2020
• Subjects: glucagon-like peptide-1; glucose-dependent insulinotropic polypeptide; LY3298176; NNC00902746; tirzepatide; type 2 diabetes mellitus; type 2 diabetes mellitus; LY3298176; NNC00902746; tirzepatide; glucose-dependent insulinotropic polypeptide; glucagon-like peptide-1
• ISSN: 1043-2760; 1879-3061; 1879-3061
• DOI: 10.1016/j.tem.2020.02.006

Glucagon-like peptide-1 (GLP-1) receptor agonists improve glucose homeostasis, reduce bodyweight, and over time benefit cardiovascular health in type 2 diabetes mellitus (T2DM). However, dose-related gastrointestinal effects limit efficacy, and therefore agents possessing GLP-1 pharmacology that can also target alternative pathways may expand the therapeutic index. One approach is to engineer GLP-1 activity into the sequence of glucose-dependent insulinotropic polypeptide (GIP). Although the therapeutic implications of the lipogenic actions of GIP are debated, its ability to improve lipid and glucose metabolism is especially evident when paired with the anorexigenic mechanism of GLP-1. We review the complexity of GIP in regulating adipose tissue function and energy balance in the context of recent findings in T2DM showing that dual GIP/GLP-1 receptor agonist therapy produces profound weight loss, glycemic control, and lipid lowering. Novel ligands possessing agonist activity at both GIP and GLP-1 receptors are being investigated for the treatment of T2DM.The GIP component of dual GIP/GLP-1 receptor agonism is hypothesized to act centrally to enhance GLP-1-induced weight loss.The ability of GIP to target white adipose tissue (WAT) and improve its lipid buffering capacity is proposed to protect from ‘spillover’ of dietary lipids.Pairing the anorexigenic effects of GIP/GLP-1 receptor agonism with the peripheral actions of GIP to promote lipid storage in WAT may be advantageous over the mechanisms of current treatments for T2DM.