Metformin has attracted increasing interest for its potential benefits in extending healthspan and longevity. This study examined the effects of early-life metformin treatment on the development and metabolism of C57BL/6 J (B6) mice, with metformin administered to juvenile mice from 15 to 56 days of age. Metformin treatment led to decreased body weight in both sexes (P < 0.05, t-test). At 9 weeks of age, mice were euthanized and organ weights were recorded. The relative weight of retroperitoneal fat was decreased in females, while relative weights of perigonadal and retroperitoneal fat were decreased, and relative liver weight was increased in males (P < 0.05, t-test). Glucose and insulin tolerance tests (GTT and ITT) were conducted at the age of 7 weeks. ANOVA revealed a significant impairment in insulin sensitivity by the treatment, and a significantly interactive effect on glucose tolerance between sex and treatment, underscoring a disparity in GTT between sexes in response to the treatment. Metformin treatment reduced circulating insulin levels in fasting and non-fasting conditions for male mice, with no significant alterations observed in female mice. qRT-PCR analysis of glucose metabolism-related genes (Akt2, Glut2, Glut4, Irs1, Nrip1, Pi3k, Pi3kca, Pkca) in the liver and skeletal muscle reveals metformin-induced sex- and organ-specific effects on gene expression. Comparison with previous studies in heterogeneous UM-HET3 mice receiving the same treatment suggests that genetic differences may contribute to variability in the effects of metformin treatment on development and metabolism. These findings indicate that early-life metformin treatment affects development and metabolism in both sex- and genetics-dependent manners.

二甲双胍因其在延长健康寿命和寿命方面的潜在益处而引起了越来越多的兴趣。本研究检查了生命早期二甲双胍治疗对 C57BL/6 J (B6) 小鼠发育和代谢的影响，对 15 至 56 天龄的幼年小鼠施用二甲双胍。二甲双胍治疗导致男女体重下降（P  < 0.05，t检验）。9周龄时，对小鼠实施安乐死并记录器官重量。女性腹膜后脂肪相对重量减少，男性性腺周围脂肪和腹膜后脂肪相对重量减少，肝脏相对重量增加（P  < 0.05，t检验）。7周龄时进行血糖和胰岛素耐量测试（GTT和ITT）。方差分析显示治疗对胰岛素敏感性有显着损害，并且性别和治疗之间对葡萄糖耐量有显着的交互作用，强调了性别之间 GTT 对治疗的反应存在差异。二甲双胍治疗降低了雄性小鼠在禁食和非禁食条件下的循环胰岛素水平，而在雌性小鼠中没有观察到显着的变化。对肝脏和骨骼肌中葡萄糖代谢相关基因（Akt2、Glut2、Glut4、Irs1、Nrip1、Pi3k、Pi3kca、Pkca ）的 qRT-PCR 分析揭示了二甲双胍诱导的性别和器官特异性对基因表达的影响。与之前对接受相同治疗的异质 UM-HET3 小鼠的研究进行比较表明，遗传差异可能导致二甲双胍治疗对发育和代谢的影响存在差异。这些发现表明，生命早期二甲双胍治疗会以性别和遗传依赖性方式影响发育和代谢。