Objectives Metabolic disorders are commonly linked to the process of aging and menopause. It is assumed that exercise and vitamin D (VitD) can have positive effects on the body, specifically via changes in irisin and brain-derived neurotrophic factors (BDNF) levels. This study aimed to investigate the concurrent effect of VitD 3 and exercise training on insulin resist- ance, memory performance, irisin, and serum BDNF in postmenopausal women with diabetes. Methods In this current study, a total of 40 participants were randomly divided into four groups: placebo, VitD 3 , placebo with combined exercise, and VitD 3 with combined exercise (with each group consisting of n = 10). The exercise group underwent the respective treatments for a duration of 8 weeks. Before the implementation of interventions and 24 h after the last session, short-term/working memory performance, insulin, homeostatic model assessment–insulin resistance (HOMA), fasting blood glucose (FBG), cholesterol, low/high-density lipoprotein-cholesterol (LDL-C/HDL-C), triglyceride (TG), VitD3 levels, fasting serum BDNF and irisin were measured. Results Our data indicated the highest reduction in HOMA, insulin, cholesterol, TG, LDL-C (P < 0.001), FBG (P < 0.01), but the highest amount of increase in irisin and BDNF (P = 0.007; P = 0.004, respectively) and Digit Span Forwards and Backwards tests (P = 0.002 and P = 0.006, respectively) in VitD 3 + combined exercise compared with the placebo group. Conclusions Our findings showed that the combination of VitD 3 supplementation with combined exercise, compared with mono-therapy can effectively attenuate insulin resistance, cardiovascular risk factors, and improve memory performance in postmenopausal women diagnosed with type 2 diabetes, in part due to the signaling of BDNF and irisin.

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