Sex-specific differences in glucose metabolism and pancreatic function in streptozotocin-induced diabetic mice: The protective role of estrogen.

Sex differences significantly influence the pathophysiology of diabetes mellitus, with estrogen playing a protective role in glucose metabolism, insulin sensitivity, and beta-cell function. This study investigated sex-specific differences in glucose homeostasis, lipid metabolism, and pancreatic function in a streptozotocin (STZ)-induced diabetic mouse model. Eight-week-old male, female, and ovariectomized female C57BL/6J mice received STZ (40 mg/kg) for five consecutive days. Biochemical assessments, including fasting blood glucose (FBG), hemoglobin A1c (HbA1c), and oral glucose tolerance tests (OGTT), were conducted at 4 and 8 weeks post-STZ treatment. Plasma insulin levels, beta-cell function (%B), and insulin sensitivity (%S) were assessed using the HOMA2 calculator. Pancreatic tissues were analyzed via histology and immunofluorescence, while hepatic gene expression was evaluated using microarray analysis. Male and ovariectomized female mice showed significantly higher FBG and HbA1c levels and impaired glucose tolerance compared to female mice, indicating estrogen's protective role in glucose regulation. Histological analysis revealed severe pancreatic islet atrophy and reduced beta-cell mass in male and ovariectomized females, while intact females maintained better insulin-glucagon balance. Transcriptomic analysis identified sex-specific alterations in key metabolic pathways, including insulin signaling and lipid metabolism, which were more disrupted in males and ovariectomized females. Significant sex-specific metabolic and molecular differences exist in STZ-induced diabetes. Estrogen's protective effects highlight its therapeutic potential for preserving beta-cell function and metabolic stability, especially in postmenopausal women.