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Background: Estrogen and progesterone are closely related to the occurrence of diabetes, and the progestogenic and estrogenic effects in the development of diabetes are related to their blood levels and the organism state, and it is not clear what effect their combination will be. The present study was to investigate the interaction between estrogen and progesterone in the development of diabetes mellitus.

Methods: A model of type 1 diabetes mellitus（T1DM）was established in ovariectomized (OVX) mice by intraperitoneal injection of streptozotocin (STZ), and the levels of plasma glucose, insulin, C-peptide, progesterone, and estradiol, the changes of islet cells, the expressions of glucose transporter 4 (GLUT4), Glucokinase (Gck), Glucose-6-phosphatase (G-6-P) and phosphoenolpyruvate carboxylase (PCK) were detected after chronically injected different doses of progesterone and 17β-estradiol subcutaneously for 4 weeks.

Results: Progesterone and 17β-estradiol could delay the occurrence of T1DM induced by STZ in ovariectomized mice, but there was no dose-response relationship; progesterone (2mg/kg) and 17β-estradiol (0.1mg/kg) injected separately or jointly could make the plasma concentration of estradiol and progesterone reaches the physiological dose range, which markedly inhibited the increase of the blood glucose induced by STZ, improved the glucose tolerance, protected islet cells, promoted C-peptide and insulin secretion, up-regulated skeletal muscle GLUT4 and liver Gck expressions, but significantly down-regulated the expressions of liver PCK and G-6-P mRNA.

Conclusions: The physiological dose of progesterone combined with estradiol has certain synergistic effects in delaying the occurrence of diabetes, the mechanisms are probably related to the protection of islet cells, the promotion of insulin release, skeletal muscle glucose transport, and liver glucose metabolism.