Acute glucose fluctuation impacts microglial activity, leading to inflammatory activation or self-degradation

Abstract

Diabetes mellitus is associated with an increased risk of Alzheimer’s dementia and cognitive decline. The cause of neurodegeneration in chronic diabetic patients remains unclear. Changes in brain microglial activity due to glycemic fluctuations may be an etiological factor. Here, we examined the impact of acute ambient glucose fluctuations on BV-2 microglial activity. Biochemical parameters were assayed and showed that the shift from normal glucose (NG; 5.5 mM) to high glucose (HG; 25 mM) promoted cell growth and induced oxidative/inflammatory stress and microglial activation, as evidenced by increased MTT reduction, elevated pro-inflammatory factor secretion (i.e., TNF-α and oxygen free radicals), and upregulated expression of stress/inflammatory proteins (i.e., HSP70, HO-1, iNOS, and COX-2). Also, LPS-induced inflammation was enlarged by an NG-to-HG shift. In contrast, the HG-to-NG shift trapped microglia in a state of metabolic stress, which led to apoptosis and autophagy, as evidenced by decreased Bcl-2 and increased cleaved caspase-3, TUNEL staining, and LC3B-II expression. These stress episodes were primarily mediated through MAPKs, PI3K/Akt, and NF-κB cascades. Our study demonstrates that acute glucose fluctuation forms the stress that alters microglial activity (e.g., inflammatory activation or self-degradation), representing a novel pathogenic mechanism for the continued deterioration of neurological function in diabetic patients.

New Insights for nicotinamide Metabolic disease autophagy and mTOR

“…These neural aggregates lead to behavior impairments that can be resolved with the maintenance of autophagy pathways in neurons (191). Autophagy also is involved in a number of other disorders that may be tied to aging such as dementia (40,(192)(193)(194)(195)(196), AD (7,12,39,40,193,[197][198][199][200][201], Huntington's disease (HD) (172,(202)(203)(204), and DM (21,27,39,40,62,193,205).…”

“…Exercise in mice has been shown to promote the induction of autophagy and regulate glucose homeostasis (325). Autophagy also can improve insulin sensitivity during high fat diets in mice (297) and may be protective to microglia during acute glucose fluctuations (193).…”

“…Nicotinamide can protect against palmitate-induced hepatotoxicity via SIRT1-dependnet induction of autophagy. In addition, autophagy can improve insulin sensitivity during high fat diets and may protect microglia during acute glucose fluctuations (193). Yet, autophagy activation also can injure endothelial progenitor cells, lead to mitochondrial oxidative stress, and block angiogenesis during periods of elevated glucose levels.…”

Immunometabolic Changes in Glia – A Potential Role in the Pathophysiology of Obesity and Diabetes

“…Like in astrocytes, emerging evidence supports an intimate relationship between metabolism and inflammatory responses in microglia ( Churchward et al, 2018 , Nair et al, 2019 ). Microglia are sensitive to in vitro changes in ambient glucose levels which impact their function ( Hsieh et al, 2019 ) and express the glucose transporters GLUT1, GLUT2 and GLUT5 ( Payne et al, 1997 ). Microglia also express ATP-sensitive K + (K ATP ) channels ( Ramonet et al, 2004 ).…”

An association between mitochondria and microglia effector function: what do we think we know?

“…Acute fluctuation of available glucose impacts microglia activity with an elevated response to LPS upon shifting from a normal to high glucose level. Shifting from a high to normal glucose level can also induce metabolic stress [153] . Glucose levels can influence pro-inflammatory gene transcription by several mechanisms.…”