Impact of the SGLT-2-AMPK/SIRT1 Pathway on Glucose, Lipid Metabolism, and Autophagy in Gestational Diabetes Progression

Abstract

Background: Gestational diabetes mellitus (GDM) is a prevalent pregnancy-related metabolic disorder marked by impaired glucose tolerance. We investigated the expression of sodium-dependent glucose transporters 2 (SGLT-2) and their impact on glucose and lipid metabolism and autophagy in GDM mice. We used inhibition of SGLT-2 in GDM mice to observe the effects of Amp-activated protein kinase (AMPK) and sirtuin 1 (SIRT1). The goal of this experiment was to explore the relationship between SGLT-2 and AMPK/SIRT1. Methods: GDM model (Model group) and control group were established in pregnant mice. Mice in the Model group were treated daily with dagliflozin (Dapagliflozin), AMPK inhibitor, Dorsomorphin (BML-275) and AMPK activator, Acadesine (AICAR). After completion, a blood sample was drawn to test the fasting plasma glucose (FPG) and fasting insulin (FINS) values to calculate the homeostatic model assessment of insulin resistance (HOMA-IR). The expression of SGLT-2 and AMPK/SIRT1 was measured by Quantitative Real-time polymerase chain reaction (qRT-PCR), and the levels of glucose and lipid metabolism-related indexes were measured by the biochemistry instrument. Hematoxylin-Eosin (HE) staining was used to observe histopathological changes in placental tissue. Results: The Model group exhibited higher levels of FPG, HOMA-IR, and FINS compared to the control group. AMPK/SIRT1 expression was downregulated, while SGLT-2 expression was upregulated (p < 0.05). Histopathological examination revealed severe placental tissue damage in the Model group. Inhibiting SGLT-2 led to increased expression of AMPK/SIRT1 (p < 0.05). Activation of AMPK decreased the expression level of SGLT-2, significantly ameliorating placental tissue damage in GDM mice, reducing FPG, FINS, HOMA-IR, and lipid metabolism (p < 0.05). Inhibition of AMPK had the opposite effects. Conclusion: Elevated expression of SGLT-2 in GDM contributes to the accelerated pathological progression of the disease. Targeted molecular therapy focused on reducing SGLT-2 presents a promising avenue for future GDM treatment.