Dual GIP and GLP-1 receptor agonist tirzepatide improves beta-cell function and insulin sensitivity in type 2 diabetes

Context: Novel dual GIP and GLP-1 receptor agonist (RA) tirzepatide
demonstrated substantially greater glucose control and weight loss (WL)
compared with selective GLP-1RA dulaglutide. Objective: Explore mechanisms
of glucose control by tirzepatide. Design: Post-hoc analyses of fasting
biomarkers and multiple linear regression analysis. Setting: 47 sites in 4
countries. Patients or Other Participants: 316 subjects with Type 2
diabetes. Interventions: Tirzepatide (1, 5, 10, 15 mg), dulaglutide (1.5
mg), placebo. Main Outcome Measures: Analyze biomarkers of beta-cell
function and insulin resistance (IR) and evaluate WL contributions to IR
improvements at 26 weeks. Results: HOMA2-B significantly increased with
dulaglutide and tirzepatide 5, 10, and 15 mg compared with placebo
(p<0.02). Proinsulin/insulin  and proinsulin/C-peptide
ratios significantly decreased with tirzepatide 10 and 15 mg compared with
placebo and dulaglutide (p<0.007). Tirzepatide 10 and 15 mg
significantly decreased fasting insulin (p<0.033) and tirzepatide
10 mg significantly decreased HOMA2-IR (p=0.004) compared with placebo and
dulaglutide. Markers of improved insulin sensitivity (IS) adiponectin,
IGFBP-1, and IGFBP-2 significantly increased by one or more doses of
tirzepatide (p<0.05). To determine whether improvements in IR were
directly attributable to WL, multiple linear regression analysis with
potential confounding variables age, sex, metformin, triglycerides, and
HbA1c was conducted. WL significantly (p<0.028) explained only 13%
and 21% of improvement in HOMA2-IR with tirzepatide 10 and 15 mg,
respectively. Conclusions: Tirzepatide improved markers of IS and
beta-cell function to a greater extent than dulaglutide. IS effects of
tirzepatide were only partly attributable to WL, suggesting dual receptor
agonism confers distinct mechanisms of glycemic control.

研究背景：新型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（RA）替尔泊肽（tirzepatide），相较于选择性GLP-1受体激动剂度拉糖肽（dulaglutide），在血糖控制与体重减轻（WL）方面展现出更为显著的效果。
研究目的：探究替尔泊肽调控血糖的作用机制。
研究设计：空腹生物标志物事后分析与多元线性回归分析。
研究场景：覆盖4个国家的47家研究中心。
研究对象：316名2型糖尿病患者。
干预措施：替尔泊肽（1mg、5mg、10mg、15mg）、度拉糖肽（1.5mg）以及安慰剂。
主要结局指标：分析β细胞功能与胰岛素抵抗（IR）相关生物标志物，并评估26周时体重减轻对胰岛素抵抗改善的贡献程度。
研究结果：与安慰剂组相比，度拉糖肽组以及替尔泊肽5mg、10mg、15mg组的稳态模型评估2-β细胞功能指数（HOMA2-B）均显著升高（p<0.02）。与安慰剂组和度拉糖肽组相比，替尔泊肽10mg、15mg组的胰岛素原/胰岛素比值以及胰岛素原/C肽比值均显著降低（p<0.007）。与安慰剂组和度拉糖肽组相比，替尔泊肽10mg、15mg组的空腹胰岛素水平显著降低（p<0.033），且替尔泊肽10mg组的稳态模型评估2-胰岛素抵抗指数（HOMA2-IR）显著降低（p=0.004）。替尔泊肽各剂量组均可使胰岛素敏感性（IS）相关改善标志物脂联素（adiponectin）、胰岛素样生长因子结合蛋白1（IGFBP-1）以及胰岛素样生长因子结合蛋白2（IGFBP-2）水平显著升高（p<0.05）。为明确胰岛素抵抗的改善是否直接源于体重减轻，本研究纳入年龄、性别、二甲双胍使用情况、甘油三酯水平以及糖化血红蛋白（HbA1c）作为潜在混杂变量，开展多元线性回归分析。结果显示，体重减轻仅分别解释了替尔泊肽10mg、15mg组HOMA2-IR改善情况的13%与21%，且差异具有统计学意义（p<0.028）。
研究结论：相较于度拉糖肽，替尔泊肽可更为显著地改善胰岛素敏感性与β细胞功能相关标志物水平；替尔泊肽的胰岛素敏感性改善作用仅部分源于体重减轻，提示双重受体激动作用可赋予替尔泊肽独特的血糖调控机制。