Lycium barbarum polysaccharides ameliorate diabetes-associated cognitive impairment through modulation of peripheral glycemic homeostasis and inflammation in mice.

BACKGROUND AND PURPOSE: Diabetes-associated cognitive impairment (DCI) is a devastating complication of type 2 diabetes mellitus (T2DM), driven by abnormal glucose metabolism and chronic systemic inflammation. Lycium barbarum polysaccharide (LBP), a macromolecular bioactive component, has shown neuroprotective potential despite limited blood-brain barrier (BBB) permeability. We hypothesized that LBP ameliorates DCI through peripheral glycemic regulatory and anti-inflammatory mechanisms.

METHODS

KKAy mice (a spontaneous polygenic T2DM model) were used. Cognitive function was assessed by the Morris water maze (MWM). Fasting blood glucose was monitored throughout the study. Serum cytokines (TNF-α, IL-1β, IL-6, IL-10) were measured by ELISA. Hippocampal ultrastructure was examined by transmission electron microscopy (TEM). The TLR4/MyD88/NF-κB pathway was evaluated in peritoneal macrophages and RAW264.7 cells by Western blot and immunofluorescence.

RESULTS

LBP (20-80 mg/kg, 3 months) improved spatial learning efficiency (P < 0.05) without fully normalizing memory retention, and attenuated hippocampal neuronal damage in KKAy mice. LBP reduced fasting blood glucose and improved systemic glycemic control, with the low dose (20 mg/kg) showing pronounced efficacy in glycemic control. LBP upregulated insulin signaling proteins (IRS, PDX1, ISLET1) and protected β-cell function. Systemically, LBP suppressed pro-inflammatory cytokines (TNF-α, IL-1β) partially and elevated IL-10 by inhibiting the TLR4/MyD88/NF-κB pathway.

CONCLUSION

LBP ameliorates DCI primarily through dual peripheral actions, suggesting a peripheral-central axis mechanism: (1) stabilizing glycemic homeostasis via enhanced insulin/β-cell signaling; (2) suppressing systemic inflammation via inhibition of the TLR4/MyD88/NF-κB pathway. These findings provide a novel mechanistic framework for the clinical translation of LBP in managing DCI.