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Dysregulated LIF-STAT3 pathway is responsible for impaired embryo implantation in a Streptozotocin-induced diabetic
Tong-Song Wang1, Fei Gao1, Qian-Rong Qi1
1School of Science, Shantou University, Shantou 515063, China.
Abstract:
The prevalence of diabetes is increasing worldwide with the trend of patients being young and creating a significant burden on health systems, including reproductive problems, but the effects of diabetes on embryo implantation are still poorly understood. Our study was to examine effects of diabetes on mouse embryo implantation, providing experimental basis for treating diabetes and its complications. Streptozotocin (STZ) was applied to induce type 1 diabetes from day 2 of pregnancy or pseudopregnancy in mice. Embryo transfer was used to analyze effects of uterine environment on embryo implantation. Our results revealed that the implantation rate is significantly reduced in diabetic mice compared to controls, and the change of uterine environment is the main reason leading to the decreased implantation rate. Compared to control, the levels of LIF and p-STAT3 are significantly decreased in diabetic mice on day 4 of pregnancy, and serum estrogen level is significantly higher. Estrogen stimulates LIF expression under physiological level, but the excessive estrogen inhibits LIF expression. LIF, progesterone or insulin supplement can rescue embryo implantation in diabetic mice. Our data indicated that the dysregulated LIF-STAT3 pathway caused by the high level of estrogen results in the impaired implantation in diabetic mice, which can be rescued by LIF, progesterone or insulin supplement.
Insights
Diabetes impairs embryo implantation by altering the uterine environment, primarily through a dysregulated LIF-STAT3 pathway. Supplementation with LIF, progesterone, or insulin can restore implantation rates in diabetic mice.
Area of Science:
- Reproductive biology
- Endocrinology
- Metabolic disorders
Background:
- Diabetes prevalence is rising globally, affecting younger populations and straining healthcare systems.
- Reproductive complications are a significant concern in diabetes, yet its impact on embryo implantation remains unclear.
- Understanding diabetes' effects on early pregnancy is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the impact of diabetes on mouse embryo implantation.
- To identify the underlying mechanisms responsible for implantation failure in diabetic conditions.
- To provide an experimental foundation for managing diabetes-related reproductive issues.
Main Methods:
- Type 1 diabetes was induced in mice using streptozotocin (STZ) on day 2 of pregnancy.
- Embryo transfer experiments were conducted to assess the uterine environment's role.
- Levels of Leukemia Inhibitory Factor (LIF), phosphorylated STAT3 (p-STAT3), and serum estrogen were measured.
Main Results:
- Diabetic mice exhibited significantly reduced embryo implantation rates compared to controls.
- The uterine environment was identified as the primary factor contributing to decreased implantation.
- LIF and p-STAT3 levels were decreased, while serum estrogen levels were elevated in diabetic mice.
- Supplementation with LIF, progesterone, or insulin successfully rescued embryo implantation.
Conclusions:
- High estrogen levels in diabetes disrupt the LIF-STAT3 pathway, impairing embryo implantation.
- The dysregulated LIF-STAT3 pathway is a key mechanism underlying implantation failure in diabetic mice.
- LIF, progesterone, or insulin supplementation offers potential therapeutic strategies for improving fertility in diabetic individuals.
