Yamaguchi Yuko, Kuwata Hitoshi, Imura Masahiro, Moyama Shota, Usui Ryota, Matsushiro Mari, Hamamoto Yoshiyuki, Yamada Yuichiro, Seino Yutaka, Yamazaki Yuji
Center for Diabetes, Endocrinology and Metabolism, Kansai Electric Power Hospital, Osaka, Japan.
Yutaka Seino Distinguished Center for Diabetes Research, Kansai Electric Power Medical Research Institute, Kyoto, Japan.
Diabetologia. 2025 Jul 22. doi: 10.1007/s00125-025-06493-5.
AIMS/HYPOTHESIS: This study investigated insulin sensitivity using the hyperinsulinaemic-euglycaemic clamp technique in individuals with obesity and type 2 diabetes treated with tirzepatide at the low dose of 5 mg over a 12-week treatment period.
This prospective, single-arm, open-label, single-centre study was conducted in obese individuals with type 2 diabetes. Participants received tirzepatide 2.5 mg once weekly for 4 weeks; the dose was then increased to 5 mg for the remaining 8 weeks. The primary outcome was change in the glucose infusion rate. Secondary outcomes were changes in HbA, body weight, body composition, lipid profile, glucagon level, the HOMA2-IR and HOMA2-%β indices, and the association of these variables with the glucose infusion rate (GIR).
Sixteen participants completed the study. The GIR increased from 3.21 to 5.16 mg min kg (p<0.001). HbA decreased from 63.4 to 43.6 mmol/mol (7.95% to 6.14%, p<0.001) and body weight decreased by 4.9 kg (5.0%, p<0.001). Muscle mass, fat mass and fat percentage significantly decreased by 1.8%, 9.1% and 4.5%, respectively. Glucagon decreased significantly from 28.8 pg/ml to 20.8 pg/ml. However, simple linear regression analysis revealed no significant relationship between changes in GIR and other clinical variables.
CONCLUSIONS/INTERPRETATION: Tirzepatide significantly improves insulin sensitivity within 12 weeks, indicating an early metabolic effect that is not solely attributable to weight loss.
UMIN registration number: UMIN000056862.
目的/假设：本研究采用高胰岛素-正葡萄糖钳夹技术，对肥胖且患有2型糖尿病的个体在12周治疗期内使用低剂量5毫克替尔泊肽进行治疗，以调查胰岛素敏感性。
本前瞻性、单臂、开放标签、单中心研究在肥胖的2型糖尿病个体中进行。参与者每周一次接受2.5毫克替尔泊肽治疗，持续4周；之后剂量增加至5毫克，持续剩余的8周。主要结局为葡萄糖输注率的变化。次要结局包括糖化血红蛋白（HbA）、体重、身体成分、血脂谱、胰高血糖素水平、HOMA2-IR和HOMA2-%β指数的变化，以及这些变量与葡萄糖输注率（GIR）的关联。
16名参与者完成了研究。葡萄糖输注率从3.21增加至5.16毫克·分钟·千克（p<0.001）。糖化血红蛋白从63.4降至43.6毫摩尔/摩尔（7.95%至6.14%，p<0.001），体重下降了4.9千克（5.0%，p<0.001）。肌肉量、脂肪量和脂肪百分比分别显著下降了1.8%、9.1%和4.5%。胰高血糖素从28.8皮克/毫升显著降至20.8皮克/毫升。然而，简单线性回归分析显示葡萄糖输注率变化与其他临床变量之间无显著关系。
结论/解读：替尔泊肽在12周内显著改善胰岛素敏感性，表明存在一种早期代谢效应，并非仅归因于体重减轻。
UMIN注册号：UMIN000056862。
