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The role of GLP-1 and GIP receptor agonists in the treatment of diabetes and obesity
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DOI：10.1016/j.phrs.2026.108365.png)
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Abstract
En 中文
Owing to the therapeutic success of glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) agonists in the management of diabetes and obesity, the pharmacology of these drugs and their receptors has engendered considerable interest. GLP-1 and GIP are incretin hormones so named owing to their ability to increase insulin secretion. Currently FDA-approved GLP-1 peptide receptor agonists used for the management of diabetes include liraglutide, semaglutide, and injectable dulaglutide. Agonists approved for the management of obesity include liraglutide and semaglutide, which have injectable and oral formulations. Tirzepatide is a combined GLP-1 and GIP receptor peptide agonist given by injections that is FDA-approved for the management of type 2 diabetes, obesity, and obese patients with a weight-related comorbidity such as obstructive sleep apnea. Orforglipron is a small molecule orally bioavailable medicine that is approved for the treatment of obesity. Retatrutide is an injectable peptide agonist of GLP-1R, GIPR, and the glucagon receptor that is undergoing clinical trials for the management of obesity and diabetes. The peptides per se undergo rapid degradation in the body. To overcome the need for frequent injections, molecular engineering strategies were used to prolong circulating half-lives. Peptide fatty acid acylation represents one strategy for extending the half-life of peptides by co-opting the role of albumin as a fatty acid transporter thereby retaining peptides in the systemic circulation. A universal side effect of all GLP-1 receptor agonists includes nausea and vomiting. Consequently, the dosage is escalated sequentially over a period of weeks to mitigate these side effects.
Keywords:
Dulaglutide (PubMed CID: 171042928)
Insulin degludec (PubMed CID: 118984462)
Insulin Glargine (PubMed CID: 118984454)
Liraglutide (PubMed CID: 16134956)
Lixisenatide (PubMed CID: 90472060)
Metformin (PubMed CID: 4091)
Orforglipron (PubMed CID: 137319706)
Retatrutide (PubMed CID: 178245957)
Semaglutide (PubMed CID: 56843331)
Tirzepatide (PubMed CID: 166567236)
7TM
seven transmembrane
BBB
blood-brain barrier
CNS
central nervous system
DAG
diacylglycerol
DPP-4
dipeptidyl peptidase-4
ECD
extracellular domain
ECL
extracellular loop
FDA
United States Food and Drug Administration
FPG
fasting plasma glucose
GCG
glucagon
GCGR
glucagon receptor
GPCR
G-protein coupled receptor
GIP
glucose-dependent insulinotropic polypeptide
GLP-1R
glucagon-like peptide-1 receptor
GLP-1RA
Glucagon-like peptide-receptor agonist
ICD
intracellular domain
ICL
intracellular loop
IP1
intervening peptide-1
IP3
inositol tris phosphate
MGF
major proglucagon fragment
NTS
nucleus tractus solitarius
PAM
Peptidylglycine α-amidating monooxygenase
PO
per os (by mouth)
SQ
subcutaneous
T2D
type 2 diabetes
PC
prohormone convertase
Fasting plasma glucose
G-protein coupled receptors
Hemoglobin A1C
Incretin
Peptide-GLP-1 receptor interaction
Prescription drug expenditures
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