What question did this study set out to answer?

The study aimed to investigate the combined effects of tirzepatide and pioglitazone on insulin sensitivity and adipose tissue remodeling.

June 9, 2026

1266-OR: Tirzepatide and Pioglitazone Combination Therapy Synergistically Improves Insulin Sensitivity and Adipose Tissue Remodeling

Key Points

The study aimed to investigate the combined effects of tirzepatide and pioglitazone on insulin sensitivity and adipose tissue remodeling.
32 male Sprague Dawley rats were used, fed a high-fat diet for 12 weeks, followed by treatment for 8 weeks with placebo, pioglitazone, tirzepatide, or both.
Body weight, fasting blood glucose, and calorie intake were monitored weekly alongside oral glucose tolerance tests and insulin tolerance tests at the end of the treatment.
Single-nucleus RNA sequencing analysis was performed on adipose tissue to evaluate cellular changes.
The combination group had a significant reduction in glucose area under the curve compared to tirzepatide alone (p<0.05).
Brown adipose tissue weight significantly increased with pioglitazone treatment alone or in combination, compared to tirzepatide alone.
RNA sequencing revealed a shift in adipocyte transcriptional profiles towards a more metabolically healthy phenotype when using both drugs.

Abstract

Introduction and Objective: Tirzepatide, a dual GLP-1 and GIP receptor agonist, enhances glucose-stimulated insulin secretion, significantly reduces HbA1c, and promotes weight loss. Tirzepatide use leads to improvements in insulin sensitivity, both via weight loss-dependent and independent mechanisms. Pioglitazone, a PPARγ activator, enhances insulin sensitivity via distinct pathways. We hypothesized that combining Tirzepatide and pioglitazone would result in additive benefits for insulin action and adipose tissue remodeling. Methods: 32 male Sprague Dawley rats (6-8 weeks old) were fed high-fat diet for 12 weeks, then were treated with placebo, pioglitazone (10 mg/kg), Tirzepatide (100 nmol/kg), or their combination, for 8weeks. Body weight, fasting blood glucose (FBG), and calorie intake were monitored weekly. Oral glucose tolerance tests (OGTT) and insulin tolerance tests (ITT) were conducted at study end, and liver, adipose, muscle, and pancreatic tissues were collected. White adipose tissue single-nucleus RNASeq was performed to assess changes in the cellular makeup of the tissue. Results: Final body weights were 671.3 ± 26.2 g (placebo), 689.1 ± 23.4 g (pioglitazone), 532.3 ± 17.8 g(Tirzepatide), and 534.1 ± 18.6 g (combination). The combination group showed significant additive reductions in glucose area under the curve (AUC) compared to Tirzepatide alone (p-Value 0.05). Brown adipose tissue weight increased significantly with pioglitazone, alone or in combination, compared to Tirzepatide alone. Single-nucleus RNASeq analysis revealed a shift in adipocytic transcriptional profile from a more metabolically stressed to a metabolically healthy phenotype with the use of the drugs. Conclusion: Tirzepatide mitigated pioglitazone-induced weight gain, while their combination provided synergistic improvements in insulin sensitivity and adipocyte physiology. Disclosure M. Abu-Farha: None. D. Vatner: None. M. Qaddoumi: None. M. Abdul-Ghani: None. J. Golla: None. I. Al Khairi: None. A. Al Madhoun: None. Y. Al Sanae: None. F. Al-Mulla: None. N. Abukhalaf: None. J.A. Abubaker: None. Funding Kuwait Foundation for the Advancement of Sciences (KFAS). RA AM2023-029

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Cite This Study

ABU-FARHA et al. (Sun,) studied this question.

synapsesocial.com/papers/6a27ad83a963992e16267afb https://doi.org/https://doi.org/10.2337/db26-1266-or

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