This review by Qiyuan Keith Liu explores the mechanisms of action and therapeutic applications of glucagon-like peptide-1 (GLP-1) and dual GIP/GLP-1 receptor agonists. GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) are naturally occurring hormonal peptides produced in the gastrointestinal tract, collectively known as incretins. The concept of the incretin effect, which involves the regulation of insulin secretion in response to glucose intake, was first proposed in the 1970s. GLP-1 and GIP play crucial roles in glucose and lipid metabolism, insulin secretion, and satiety regulation. GLP-1 and GIP are released from enteroendocrine cells in the gastrointestinal tract and bind to their respective receptors (GLP-1Rs and GIPRs) in various tissues, including the pancreas, brain, and adipose tissue. These receptors belong to the class B family of 7-transmembrane G protein-coupled receptors (GPCRs). The binding of these hormones to their receptors triggers downstream signaling pathways, leading to increased insulin secretion and reduced glucagon secretion. The review highlights the therapeutic potential of GLP-1 and GIP in treating type 2 diabetes mellitus (T2DM) and obesity. GLP-1 receptor antagonists (GLP-1RAs) and dual GIP/GLP-1 receptor agonists have shown promise in improving glycemic control and reducing body weight. FDA-approved GLP-1RAs, such as exenatide, lixisenatide, albiglutide, dulaglutide, liraglutide, and semaglutide, have been developed to extend the half-life and enhance the efficacy of GLP-1. Dual GIP/GLP-1 receptor agonists, such as tirzepatide and NNC0090-2746, offer a more physiological approach by targeting both receptors simultaneously. The review also discusses the pharmacokinetic and pharmacodynamic properties of these agents, including their mechanisms of action, clinical efficacy, and safety profiles. GLP-1 and GIP have pleiotropic effects, including enhancing insulin secretion, modulating glucagon release, regulating satiety, slowing gastric emptying, and reducing systemic blood pressure. The review emphasizes the importance of understanding the complex interactions between these hormones and their receptors in the context of various metabolic disorders. Overall, the review provides a comprehensive overview of the current understanding of GLP-1 and GIP, their therapeutic applications, and the ongoing research efforts to develop more effective and safe treatments for T2DM and obesity.This review by Qiyuan Keith Liu explores the mechanisms of action and therapeutic applications of glucagon-like peptide-1 (GLP-1) and dual GIP/GLP-1 receptor agonists. GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) are naturally occurring hormonal peptides produced in the gastrointestinal tract, collectively known as incretins. The concept of the incretin effect, which involves the regulation of insulin secretion in response to glucose intake, was first proposed in the 1970s. GLP-1 and GIP play crucial roles in glucose and lipid metabolism, insulin secretion, and satiety regulation. GLP-1 and GIP are released from enteroendocrine cells in the gastrointestinal tract and bind to their respective receptors (GLP-1Rs and GIPRs) in various tissues, including the pancreas, brain, and adipose tissue. These receptors belong to the class B family of 7-transmembrane G protein-coupled receptors (GPCRs). The binding of these hormones to their receptors triggers downstream signaling pathways, leading to increased insulin secretion and reduced glucagon secretion. The review highlights the therapeutic potential of GLP-1 and GIP in treating type 2 diabetes mellitus (T2DM) and obesity. GLP-1 receptor antagonists (GLP-1RAs) and dual GIP/GLP-1 receptor agonists have shown promise in improving glycemic control and reducing body weight. FDA-approved GLP-1RAs, such as exenatide, lixisenatide, albiglutide, dulaglutide, liraglutide, and semaglutide, have been developed to extend the half-life and enhance the efficacy of GLP-1. Dual GIP/GLP-1 receptor agonists, such as tirzepatide and NNC0090-2746, offer a more physiological approach by targeting both receptors simultaneously. The review also discusses the pharmacokinetic and pharmacodynamic properties of these agents, including their mechanisms of action, clinical efficacy, and safety profiles. GLP-1 and GIP have pleiotropic effects, including enhancing insulin secretion, modulating glucagon release, regulating satiety, slowing gastric emptying, and reducing systemic blood pressure. The review emphasizes the importance of understanding the complex interactions between these hormones and their receptors in the context of various metabolic disorders. Overall, the review provides a comprehensive overview of the current understanding of GLP-1 and GIP, their therapeutic applications, and the ongoing research efforts to develop more effective and safe treatments for T2DM and obesity.