Chronic GIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese insulin resistant mice

Tirzepatide (LY3298176), a dual GIP and GLP-1 receptor agonist, has been shown to deliver enhanced glycemic control and superior weight loss compared to a selective GLP-1 receptor (GLP-1R) agonist in patients with type 2 diabetes mellitus. However, the mechanism by which tirzepatide improves efficacy and how GIP receptor (GIPR) agonism contributes to the therapy is not fully understood. Here, hyperinsulinemic-euglycemic clamp studies were used to show that tirzepatide is a highly effective insulin sensitizer, improving insulin sensitivity in obese mice to a greater extent than GLP-1R agonism. To determine if GIPR agonism contributes to the insulin sensitization, we compared the effect of tirzepatide in obese wild-type and Glp-1r null mice. In the absence of GLP-1R induced weight loss, tirzepatide improved systemic insulin sensitivity by enhancing glucose disposal in WAT. To corroborate these results, chronic treatment with a long-acting GIPR agonist (LAGIPRA) was also found to enhance insulin sensitivity by increasing insulin stimulated glucose uptake in WAT. Interestingly, the effect of tirzepatide and LAGIPRA on insulin sensitivity was associated with reduced branched chain amino and keto acids in the circulation. Whole-body insulin sensitization was associated with pronounced 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 GIP and GLP-1 receptor agonism, offering mechanistic insights into the clinical efficacy of tirzepatide. Overall design: 24 total samples. Treatments include Vehicle, LAGIPRA, TZP, PairFed groups. N = 6 for each treatment group.

替尔泊肽（Tirzepatide，LY3298176）是一种双重葡萄糖依赖性促胰岛素多肽（GIP）与胰高血糖素样肽-1（GLP-1）受体激动剂。研究显示，相较于选择性GLP-1受体（GLP-1R）激动剂，该药物可改善2型糖尿病患者的血糖控制水平，并带来更显著的体重减轻效果。然而，替尔泊肽提升治疗效能的具体分子机制，以及GIP受体（GIPR）激动在该疗法中的作用贡献，尚未完全阐明。本研究采用高胰岛素-正常血糖钳夹实验（hyperinsulinemic-euglycemic clamp）证实，替尔泊肽是一种高效胰岛素增敏剂，相较于GLP-1R激动剂，其对肥胖小鼠的胰岛素敏感性提升效果更为显著。为明确GIPR激动是否参与胰岛素增敏过程，我们分别在肥胖野生型小鼠与GLP-1受体敲除（Glp-1r null）小鼠中对比了替尔泊肽的作用效应。在不存在GLP-1R介导的体重减轻的情况下，替尔泊肽通过增强白色脂肪组织（WAT）的葡萄糖摄取能力，改善全身胰岛素敏感性。为验证上述实验结果，我们还发现，对小鼠施以长效GIPR激动剂（LAGIPRA）的慢性给药，可通过提升胰岛素刺激下白色脂肪组织的葡萄糖摄取量，增强胰岛素敏感性。值得注意的是，替尔泊肽与LAGIPRA对胰岛素敏感性的调控作用，与循环中支链氨基酸与酮酸水平降低密切相关。全身胰岛素增敏效应与棕色脂肪组织（BAT）中葡萄糖、脂质及支链氨基酸分解代谢相关基因的显著上调表达密切相关。综上，本研究证实替尔泊肽可通过体重依赖与非体重依赖两种方式改善胰岛素敏感性。上述结果阐明了GIPR激动在双重GIP与GLP-1受体激动疗法中的治疗贡献，为替尔泊肽的临床疗效提供了机制层面的科学见解。总体实验设计：共计24个样本。处理组包括溶剂对照组（Vehicle）、长效GIPR激动剂组、替尔泊肽组与配对喂养组，每组样本量n=6。