Impact of serum prolactin on cognitive function, brain structure, and function in type 2 diabetes mellitus

CONTEXT: Diabetes-associated cognitive dysfunction (DACD) is characterized by crosstalk between metabolic disturbances and neural dysfunction. Prolactin (PRL), a pituitary hormone involved in glucose regulation and neuroinflammation, may contribute to DACD development. OBJECTIVE: This study aims to investigate the relationships and underlying mechanisms between serum PRL and DACD in patients with type 2 diabetes (T2DM) via neuroimaging. METHODS: Five hundred twenty-two with normal cognition and 418 with mild cognitive impairment (MCI) were included after age- and gender-matching among 1167 participants with T2DM. Two hundred forty-seven individuals underwent functional magnetic resonance imaging scans to assess brain structure and function. Structural equation modeling (SEM) was used to explore the mechanism linking serum PRL to cognition. RESULTS: Relative weight analysis indicated that PRL and luteinizing hormone (LH) accounted for 8.14% and 7.53% of MCI risk in T2DM across 1167 participants. However, multivariate logistic regression analysis showed that PRL, rather than LH, was an independent risk factor for MCI in T2DM (odds ratio [OR] = 0.907, 95% confidence intervals [95% CI]: 0.849-0.968, P = .003), with the lowest PRL tertile group showing significant cognitive deficits and reduced hippocampal-amygdaloid volumes. Moreover, SEM indicated that PRL positively influenced cognition and exerted an indirect effect via limbic structures, contributing 14.07% to the total effect. Additionally, the lowest PRL tertile group exhibited a significant decreased functional connectivity between the right amygdala and right frontal lobe, partially mediating the link between serum PRL and MoCA scores. CONCLUSION: Decreased serum PRL is associated with reduced hippocampal and amygdaloid volumes, impaired amygdala functional connectivity, and diminished cognitive performance in T2DM.