Metformin improves cognition and restores microglial autophagy in experimental models of type 2 diabetes mellitus

GONZALEZ PEREZ N; VINUESA A; BENTIVEGNA M; BELLOTTO M; GREGOSA A; PRESA J; BRITES F; BEAUQUIS J; SARAVIA F; POMILIO C

Porto

Congreso; ISN-ESN 2023 Meeting; 2023

International Society for Neurochemistry

The incidence of type 2 diabetes mellitus (T2D) is increasing worldwide, representing a major issue for global health systems. In advanced stages, T2D affects brain cellular metabolism and causes chronic neuroinflammation by activating microglial cells, promoting neurodegeneration and dementia. Neuroinflammation is linked to a progressive loss of proteostasis, autophagy impairment and altered cell metabolism in microglial cells, adopting a dystrophic phenotype.Metformin, the first-line drug used for T2D treatment, emerges as a potential therapeutic strategy with pleiotropic effects on central nervous system dysfunction. Our aim was to evaluate microglial dystrophy during T2D and their potential reversion by metformin.After high fat diet (HD) exposure from weaning until 5 months old we verified dyslipidemia, hepatic and brain insulin resistance.Interestingly, this protocol caused a deficit in spatial learning and increased anxious-like behavior evaluated by the novel object location recognition and the open field tests. The administration of metformin (4%, 3 i.p. injections/week during the last 3 weeks) was associated with a trend towards a better performance in behavioral tests. In the hippocampus of HD mice, we found reactive microglial cells observed by Iba1 immunohistochemistry that in addition showed accumulation of p62, an autophagic substrate, evidence of autophagy impairment. Metformin recovered cell morphology and microglial autophagy, showing a status like the control group. We also employed an in vitro model for metabolic insult by exposing the microglia-derived cell line BV2 to palmitate during 24 h, adding 2 mM metformin or vehicle during the last 30 min. We found that palmitate induced a blockage of autophagy (assessed by immunofluorescence against LC3 marker) and an increased expression of the proinflammatory cytokine IL-1ß, levels that were restored after metformin treatment. Remarkably, palmitate induced changes in the number and size of mitochondria and also an accumulation of mitochondria into LC3+ autophagic vesicles, suggesting mitochondrial dysfunction. Metformin reverted these parameters. Our data from in vivo and in vitro experiments point out a neuroprotective role for metformin modulating brain functions affected by T2D, with emphasis on microglia and cell energy.