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Title: Blueberries and insulin protect microglial cells against high glucose-induced inflammation and restore GLUT-1

Author
item HININGER-FAVIER, ISABELLE - Universite Grenoble Alpes
item Thangthaeng, Nopporn
item BIELINSKI, DONNA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item Fisher, Derek
item Shukitt-Hale, Barbara
item POULOSE, SHIBU - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Journal of Berry Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/26/2021
Publication Date: 6/14/2021
Citation: Hininger-Favier, I., Thangthaeng, N., Bielinski, D.F., Fisher, D.R., Shukitt Hale, B., Poulose, S.M. 2021. Blueberries and insulin protect microglial cells against high glucose-induced inflammation and restore GLUT-1. Journal of Berry Research. 11(2):201-216. https://doi.org/10.3233/JBR-200628.
DOI: https://doi.org/10.3233/JBR-200628

Interpretive Summary: Inflammation is a factor leading to many diseases of the brain. This inflammation may be caused by a high level of glucose (the sugar that is the brain’s energy source). High levels of glucose occur in individuals with metabolic syndrome, in which cells become resistant to the action of insulin, a hormone known to regulate glucose levels. The high glucose condition may then cause an inflammatory response in brain cells called microglia which are part of the brain’s immune system. Blueberries have been shown to reduce inflammation in the brain by decreasing the activation of microglia. The current study examined the effects of glucose concentration, insulin, and blueberry on microglial inflammatory responses. Rat microglial cells were grown in culture with different levels of glucose, then exposed to blueberry extract (BB) and/or insulin (INS). Some of the cells were then stimulated with a well-known inflammatory agent. Results showed that high glucose induces inflammation, and this inflammation was reduced by treatment with either BB or INS. Moreover, treatment with the combination of BB and INS reduced inflammation, even under high glucose conditions. These findings suggest that BB may enhance the glucose-lowering action of INS and help to protect the brain from inflammation in individuals with metabolic syndrome.

Technical Abstract: Dysfunctional glucose metabolism has been known to cause neuroinflammation (INF) and neuronal cell death leading to the pathogenesis of neurodegenerative diseases. One possible mediator of glucose-induced neuronal death could be neurochemical alterations in microglia, the innate immune cells in the brain. Insulin is a known homeostatic agent for glucose metabolism, yet its role on microglia is largely unknown. Blueberries have been shown to reduce oxidative stress (OS) and INF, and to attenuate microglial activation, in animal and cell models. The current study examined the effects of glucose concentration, insulin (INS), and blueberry extract (BB) on microglial inflammatory responses. Highly Aggressively Proliferating Immortalized (HAPI) cells, a rat microglia cell line, were grown and maintained under either low (5mM), medium (25mM) or high (50mM) glucose in Dulbecco’s modified Eagle’s medium, and treated with either BB (2%), INS (50mM), or in combination. After 24 hours, cells were then stimulated with lipopolysaccharide (LPS; 100nM) and expression of extracellular nitric oxide (NO) production, as well the expression levels of inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF-alpha), NADPH-oxidoreductase-4 (NOX4) and glucose transporter protein-1 (GLUT1) were assessed. High glucose concentration was able to induce OS and INF, and this glucose-induced response was reduced by treatment with BB or INS. Moreover, BB and INS pre-treatment attenuated the LPS-induced inflammatory response, even under high glucose conditions, by altering the expression of signaling molecules related to OS and INF. These findings suggest that BB may enhance the neuroprotective action of INS in individuals with metabolic syndrome, where high blood glucose is commonly observed, by altering insulin sensitivity and reducing OS and INF.