THU297 Metformin Treatment Of Juvenile Mice Alters Aging-Related Developmental And Metabolic Phenotypes In Sex-Dependent And -Independent Manners

Abstract

Abstract Disclosure: Y. Zhu: None. M. Engmann: None. D. Medina: None. A. Bartke: None. B.S. Ellsworth: None. R. Yuan: None. Metformin is a widely used drug for the treatment of type 2 diabetes that also has a strong potential for long-term effects which may extend healthspan and longevity. In the current study, C57BL/6J (B6) juvenile female and male mice were treated with metformin between the ages of 15 and 56 days. Saline was used as the control. The results show that early-life treatment with metformin has profound effects on developmental and metabolic traits. Body weight was significantly reduced by metformin treatment in both sexes (P<0.05, t test). At 10 weeks of age, mice were euthanized, and organ weights were recorded. In treated males, weights of epididymal, perirenal, and brown fat depots were significantly reduced (P<0.05, t test). Pancreas weight was significantly reduced in both sexes (P<0.05, t test). Hypothalamus weight was significantly reduced in the females, and whole brain weight was significantly reduced in the males. Tail length as well as age of sexual maturation were not significantly altered in either sex. No significant difference was found in circulating insulin-like growth factor 1 (IGF1) or adiponectin. Circulating insulin was significantly reduced by the treatment under fasting and non-fasting conditions in the male mice, while in the females no significant difference was detected. Insulin sensitivity, calculated by the quantitative insulin-sensitivity check index (QUICKI), was suggestively increased in the male mice (P=0.062, t test). Glucose tolerance test (GTT) did not show a significant difference in treated female mice; however, comparing the area under curve, metformin treatment significantly improved the glucose tolerance of male mice (P=0.014, t test). Insulin tolerance test (ITT) showed no significant difference in the male mice; but, unexpectedly, in female mice, metformin treatment significantly reduced insulin sensitivity. This study revealed that early-life metformin treatment alters development and metabolism of mice in both sex-specific and non-specific manners, which may have long-term impacts on metabolism in aging. Interestingly, comparing the results of this study with previous studies of metformin-treated heterogenous UM-HET3 mice, further analyses revealed that metformin effects on body weight, age of sexual maturation, body size, IGF1, adiponectin, insulin, GTT, and ITT, are genetically dependent. Funding: SIU collaborative grant to Rong Yuan and Buffy S. Ellsworth. SIU Geriatric foundation by Andrzej Bartke Presentation: Thursday, June 15, 2023