High glucose exposure of preimplantation embryos causes glucose intolerance and insulin resistance in F1 and F2 male offspring

Although studies suggest that maternal high glucose (HG) increases offspring susceptibility to type 2 diabetes mellitus (T2DM), the underlying mechanisms are largely unclear. We studied whether glucose levels in oviducts are elevated when pregestational diabetic females get pregnant and whether the oviductal HG (OVHG) would act directly on embryos to increase offspring's T2DM susceptibility. We established an in vivo model of OVHG by injecting female mice with streptozotocin (STZ) during the preimplantation period and an in vitro model of embryo culture with HG (ECHG) by culturing preimplantation embryos with HG, before examining glucose tolerance and insulin resistance (IR) in F1 and F2 offspring. Injection of female mice with STZ induced a lasting significant glucose elevation in blood and oviduct fluid during the preimplantation period. The glucose tolerance test showed that both the STZ-induced OVHG and the ECHG caused glucose intolerance in F1 male and F1-sired F2 male offspring but had no effect on female offspring. Insulin tolerance test and the analysis for IR-related gene expression and glycogen contents in liver and muscle revealed significant IR in these male offspring. This study provided evidence that HG can act directly on preimplantation embryos to increase offspring's T2DM susceptibility suggesting that the preimplantation period is a critical stage for transmission of mother's diabetes to offspring. This study was supported by grants from the China National Natural Science Foundation (Nos. 31772599, 32072738, 31702114, and 31902160), and the Natural Science Foundation of Shandong Province (Nos. ZR2022MC036, ZR2017BC025 and ZR2020QC102).