The Roles of Incretin Hormones GIP and GLP-1 in Metabolic and Cardiovascular Health - A Comprehensive Review

Sep 30, 2026

Uploaded by James

Incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) regulate metabolic and cardiovascular homeostasis through coordinated incretin-axis signaling. GLP-1 receptor agonists are established for type 2 diabetes and obesity, reflecting insulinotropic actions, weight reduction, and proven cardiovascular benefits. Historically, GIP was overlooked due to impaired β-cell responsiveness in type 2 diabetes, but dual GIP/GLP-1 receptor agonists such as tirzepatide have reframed this view. This review synthesizes key physiology, pathophysiology, receptor distribution, secretion patterns, therapeutic evidence, and cardiovascular protective mechanisms.

LanguageEnglish

CategoryHealthcare

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Pages16

Reading Time40 min

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Abstract

Introduction

The Evolving Story of Incretins

Keywords

Publication Details

Review The Roles of Incretin Hormones GIP and GLP-1 in Metabolic and Cardiovascular Health: A Comprehensive Review Dai Yamanouchi 1,2 1 Division of Vascular Surgery, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; [yamano@surgery.wisc.edu or dai.yamanouchi@fujita-hu.ac.jp](yamano@surgery.wisc.edu or dai.yamanouchi@fujita-hu.ac.jp) [2](2 Department of Vascular Surgery)[ Department of Vascular Surgery](2 Department of Vascular Surgery), [Fujita Health University](Fujita Health University), [Toyoake 470-1192](Toyoake 470-1192), [Japan](Japan) Abstract The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagonlike peptide-1 (GLP-1) play central roles in metabolic and cardiovascular regulation. GLP-1 receptor agonists (GLP-1RAs) are established therapies for type 2 diabetes mellitus (T2DM) and obesity because of their insulinotropic effects, weight reduction, and proven cardiovascular benefit in trial level. In contrast, GIP was historically overlooked due to reduced β-cell responsiveness in T2DM. The development of dual GIP/GLP-1 receptor agonists has reshaped this view. Tirzepatide, the first-in-class co-agonist, an antidiabetic medication to treat type 2 diabetes and for weight loss, provides superior glycemic control and weight loss compared with selective GLP-1RAs in clinical trials, demonstrating synergistic actions between the two incretin pathways. This review summarizes key physiology, pathophysiology, and therapeutic evidence in incretin biology. We describe secretion patterns, receptor distributions, and distinct actions of GIP and GLP-1, as well as alterations in incretin signaling in T2DM and obesity. Cardiovascular protective mechanisms are outlined, including improvements in lipid metabolism, reductions in blood pressure, enhanced endothelial nitric oxide activity, suppression of macrophage inflammation, decreased foam-cell formation, and stabilization of atherosclerotic plaques. At the therapeutic level, emerging directions—such as dual and triple agonists—and unresolved questions regarding longterm vascular effects of GIP and the potential for genotype-guided incretin therapy are also discussed. Collectively, these findings highlight an emerging shift toward integrated incretin-axis modulation as a therapeutic strategy for metabolic and cardiovascular disease. Keywords: incretin hormones; GLP-1 receptor agonists; GIP signaling; tirzepatide; dual agonists; insulin secretion; atherosclerosis; cardiovascular protection; metabolic disease; obesity treatment Academic Editor: ConsolatoM. Sergi Received: 18 November 2025 Revised: 17 December 2025 Accepted: 18 December 2025 Published: 19 December 2025 Copyright: © 2025 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. 1. Introduction 1.1. The Evolving Story of Incretins Incretins are gut-derived peptide hormones secreted in response to nutrient intake that enhance glucose-dependent insulin secretion and thereby reduce postprandial blood glucose levels. The two principal incretin hormones in humans are glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) . The term incretin effect refers to the phenomenon whereby oral glucose administration elicits a greater insulin response than intravenous glucose delivery, reflecting the physiological contribution of incretin hormones to postprandial glucose homeostasis. Incretin biology has become increasingly central to modern metabolic therapeutics, reshaping not only how glucose regulation is understood but also how obesity, cardiovascular disease, and multisystem metabolic dysfunction are treated. The two primary incretin hormones—glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1)—are secreted from enteroendocri

FAQs

What roles do GIP and GLP-1 play in metabolic and cardiovascular health?

GIP and GLP-1 are incretin hormones that coordinate metabolic and cardiovascular regulation, enhancing glucose-dependent insulin secretion and influencing disease-related cardiovascular pathways.

Why were GIP therapies historically overlooked in type 2 diabetes?

GIP was historically considered less effective because β-cell responsiveness was reduced in type 2 diabetes, limiting its insulinotropic contribution.

What does tirzepatide change in the incretin treatment landscape?

As a dual GIP/GLP-1 receptor co-agonist, tirzepatide has shown superior glycemic control and weight loss in clinical trials versus selective GLP-1 receptor agonists, indicating synergistic actions across incretin pathways.

Sep 30, 2026

Uploaded by James