ArticleThe Journal of clinical investigation2021
GIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese mice.
Article in The Journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 126 papers, 2 of them syntheses that pooled it.
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Who cites it
126 citing papers in PubMed, 2 syntheses or guidelines pooled it, 209 citations in OpenAlex.
- Optimal dose of tirzepatide for type 2 diabetes mellitus: A meta-analysis and trial sequential analysis.Frontiers in cardiovascular medicine · 2022Pooled it
- Basal insulin intensification with GLP-1RA and dual GIP and GLP-1RA in patients with uncontrolled type 2 diabetes mellitus: A rapid review of randomized controlled trials and meta-analysis.Frontiers in endocrinology · 2022Pooled it
- Retatrutide-Associated Improvements in Cardiovascular Risk Biomarkers in Adults With Obesity With or Without Type 2 Diabetes.Diabetes, obesity & metabolism · 2026Trial
- Insulin Sensitivity and Beta Cell Function With Macupatide Alone or With Dulaglutide in Type 2 Diabetes: A Phase 1b, Randomised Controlled Trial.Diabetes, obesity & metabolism · 2026Trial
- ARD-101, a gut-restricted TAS2R agonist, reduces hunger in adults and promotes weight loss in DIO mice with DPP-4 inhibition.Molecular metabolism · 2026Trial
- Long-acting GIPR agonist LY3537021 reduces body weight and fasting blood glucose in patients with T2D: Preclinical development and phase 1 randomized ascending dose studies.Molecular metabolism · 2026Trial
- Early induction of insulin sensitisation treated by tirzepatide: a prospective, single-arm, open-label study in Japanese individuals with obesity and type 2 diabetes.Diabetologia · 2025Trial
- Association of bodyweight loss with changes in lipids, blood pressure, and fasting serum glucose following tirzepatide treatment in Japanese participants with type 2 diabetes: A post hoc analysis of the SURPASS J-mono trial.Journal of diabetes investigation · 2025Trial
- Improved HbA1c and Body Weight in GADA-Positive Individuals Treated With Tirzepatide: A Post Hoc Analysis of SURPASS.The Journal of clinical endocrinology and metabolism · 2025Trial
- Change in pharmacodynamic variables following once-weekly tirzepatide treatment versus dulaglutide in Japanese patients with type 2 diabetes (SURPASS J-mono substudy).Diabetes, obesity & metabolism · 2023Trial
- GLP-1 Receptor Agonist and GIP/GLP-1 Receptor Dual Agonist Therapeutics at the Intersection of Alcohol Use Disorder, Obesity, and Cardiometabolic Dysfunction.Biological psychiatry global open science · 2026Review
- Lipid sensing and brain hormone receptors in food intake and glucose regulation.Nature reviews. Endocrinology · 2026Review
- Adipose Tissue Remodeling Beyond Weight Loss: New Insights Into Incretin-Based Therapies and Bariatric Surgery.Current obesity reports · 2026Review
- Glycemic and bodyweight effects ofScience advances · 2026Article
- The evolving landscape of obesity pharmacotherapy.Nature reviews. Drug discovery · 2026Review
- Clinical Potential of GIP in Type 2 Diabetes and Obesity.Diabetes care · 2026Review
- GIP in Cardiovascular and Kidney Disease: From Physiology to Pharmacology.Diabetes, obesity & metabolism · 2026Review
- Genetically proxied glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptor pathway modulation is associated with favorable aging phenotypes: a drug-target Mendelian randomization study.Cardiovascular diabetology · 2026Article
- Tirzepatide Attenuates Wire Injury-Induced Arterial Remodeling in Non-Diabetic and Diabetic Mice: Comparison with Semaglutide.Biomedicines · 2026Article
- Insulin Resistance as a Systemic Metabolic Risk State for Cancer: Mechanisms, Biomarkers, and Prevention.International journal of molecular sciences · 2026Review
66 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
28 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Tirzepatide (LY3298176), a dual GIP and GLP-1 receptor (GLP-1R) agonist, delivered superior glycemic control and weight loss compared with GLP-1R agonism in patients with type 2 diabetes. However, the mechanism by which tirzepatide improves efficacy and how GIP receptor (GIPR) agonism contributes is not fully understood. Here, we show that tirzepatide is an effective insulin sensitizer, improving insulin sensitivity in obese mice to a greater extent than GLP-1R agonism. To determine whether GIPR agonism contributes, we compared the effect of tirzepatide in obese WT and Glp-1r-null mice. In the absence of GLP-1R-induced weight loss, tirzepatide improved insulin sensitivity by enhancing glucose disposal in white adipose tissue (WAT). In support of this, a long-acting GIPR agonist (LAGIPRA) was found to enhance insulin sensitivity by augmenting glucose disposal in WAT. Interestingly, the effect of tirzepatide and LAGIPRA on insulin sensitivity was associated with reduced branched-chain amino acids (BCAAs) and ketoacids in the circulation. Insulin sensitization was associated with upregulation of genes associated with the catabolism of glucose, lipid, and BCAAs in brown adipose tissue. Together, our studies show that tirzepatide improved insulin sensitivity in a weight-dependent and -independent manner. These results highlight how GIPR agonism contributes to the therapeutic profile of dual-receptor agonism, offering mechanistic insights into the clinical efficacy of tirzepatide.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.