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.
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.
Kuwait Foundation for the Advancement of Sciences (KFAS). RA AM2023-029
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