Metformin improves d-galactose induced premature ovarian insufficiency through PI3K-Akt-FOXO3a pathway.

PURPOSE: Metformin (MET), a first-line treatment for type 2 diabetes mellitus, restores ovarian function in women with polycystic ovary syndrome. MET has been shown to increase the rate of success for in vitro fertilization when utilized in assisted reproductive technologies. This study was designed to examine the impact of MET on ovarian function and fertility in a mouse model of galactose-induced premature ovarian insufficiency (POI). We further investigated the underlying mechanisms. MATERIALS AND METHODS: Female mice were divided into 4 groups: saline, d-galactose, d-galactose â€‹+ â€‹MET, and MET. Body weight, ovarian index, and fertility were assessed. The hormonal profile was done. Advanced glycation end products (AGEPs), receptor for advanced glycation end products (RAGE), phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), forkhead box O3a (FOXO3a) expression were measured. Ovarian follicle counting and morphology were analyzed. Immunohistochemistry of cleaved caspase-3 expression was performed. RESULTS: Our findings demonstrated that MET reversed irregularities in the estrus cycle, enhanced the ovarian index, and improved the abnormal levels of hormones and AGEs induced by d-galactose. Furthermore, the expression levels of PI3K, Akt, FOXO3a, and RAGE were upregulated with d-galactose. However, MET attenuated their expression levels. The primordial follicles ratio was improved, whereas atretic follicles and apoptotic-related cleaved caspase-3 expression were decreased in the d-galactose â€‹+ â€‹MET group compared to the d-galactose group. CONCLUSION: This study demonstrates that MET partially rescued ovarian dysfunction and apoptosis induced by d-galactose via a mechanism involving PI3K-Akt-FOXO3a pathway. Our finding proposed that MET may be a promising alternative treatment for POI.

Atypical antipsychotics such as risperidone, but not paliperidone, worsen vascular endothelial function via upregulation of adhesion molecules VCAM-1, ICAM-1, and E-selectin in diabetic rats.

Schizophrenia doubles the odds of diabetes, and atypical antipsychotics (AAPs) also increase risk of diabetes. Indeed, little is known about the effects of AAPs on vascular dysfunctions associated with diabetes. This study aimed to determine the effects of risperidone (RISP) and paliperidone (PALI) on the vascular function of diabetic rats. Diabetes was induced by feeding with a high-fat diet followed by the administration of streptozotocin (35 mg·(kg body mass)(-1), by intraperitoneal injection). Rats received RISP or PALI (1.25 mg·kg(-1)·d(-1), per os) for 3 weeks. Endothelium-dependent relaxation, systolic blood pressure, lipid profile, insulin resistance, and adhesion molecules, vascular cell-adhesion-molecule-1 (VCAM-1), intracellular-adhesion-molecule-1 (ICAM-1), and E-selectin were investigated. RISP significantly worsened the impaired endothelium-dependent relaxation of diabetic aortic rings with upregulation of the adhesion molecules VCAM-1, ICAM-1, and E-selectin, and proinflammatory cytokines MPC-1 and TNF-α. RISP augmented the metabolic dysfunctions and reduced insulin sensitivity in the insulin tolerance test as well as HOMA-IR. PALI produced insignificant effects on vascular and metabolic aberrations. Our results suggest that RISP, but not PALI, aggravates the metabolic abnormalities and vascular dysfunction associated with diabetes, which may be mediated by upregulation of VCAM-1, ICAM-1, and E-selectin. Nevertheless, future investigation for the possible mechanisms underlying the difference noticed between the 2 AAPs is warranted.