Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Glutamate Rescues Altered Mitochondrial Function Following Recurrent Low Glucose in Hypothalamic But not Cortical Primary Rat Astrocytes

Version 1 : Received: 12 August 2022 / Approved: 18 August 2022 / Online: 18 August 2022 (14:24:35 CEST)

How to cite: Weightman Potter, P.G.; Ellacott, K.L.J.; Randall, A.; Beall, C. Glutamate Rescues Altered Mitochondrial Function Following Recurrent Low Glucose in Hypothalamic But not Cortical Primary Rat Astrocytes. Preprints 2022, 2022080351 (doi: 10.20944/preprints202208.0351.v1). Weightman Potter, P.G.; Ellacott, K.L.J.; Randall, A.; Beall, C. Glutamate Rescues Altered Mitochondrial Function Following Recurrent Low Glucose in Hypothalamic But not Cortical Primary Rat Astrocytes. Preprints 2022, 2022080351 (doi: 10.20944/preprints202208.0351.v1).

Abstract

Recurrent hypoglycaemia, a common side-effect of insulin therapy in the treatment of type 1 diabetes, induces impaired glucose-sensing. Better understanding of how astrocytes, important non-neuronal cells in the brain, function in low glucose environments may improve our understanding of recurrent hypoglycaemia-induced defective counterregulation. Astrocytes contribute to glutamatergic signalling, which is required for hypoglycaemia counterregulation and is impaired by recurrent insulin-induced hypoglcyaemia. This study examined the glutamate response of astrocytes when challenged with acute and recurrent low glucose (RLG) exposure. The metabolic responses of cortical (CRTAS) and hypothalamic (HTAS) primary rat astrocytes were measured in acute and recurrent low glucose using extracellular flux analyses. RLG caused mitochondrial adaptations in both HTAS and CRTAS, many of which were attenuated by glutamate exposure during low glucose treatments. We observed an increase in capacity of HTAS to metabolise glutamine after RLG exposure. Demonstrating astrocytic heterogeneity in the response to LG, CRTAS increased cellular acidification, a marker of glycolysis in LG, whereas this decreased in HTAS. The directional change in intracellular Ca2+ levels of each cell type, correlated with the change in extracellular acidification rate (ECAR) during LG. Further examination of glutamate-induced Ca2+ responses in low glucose treated CRTAS and HTAS identified sub-populations of glucose-excited- and glucose-inhibited-like cells with differing responses to glutamate. Lastly, release of the gliotransmitter ATP by HTAS was elevated by RLG, both with and without concurrent glutamate exposure. Therefore, hypothalamic astrocytes adapt to RLG by increasing glutamate uptake and oxidation in a manner that attenuates RLG-induced mitochondrial adaptations.

Keywords

astrocytes; hypoglycemia; diabetes mellitus, type 1; mitochondria; glycemic control; hypothalamus; glutamic acid.

Subject

MEDICINE & PHARMACOLOGY, General Medical Research

Comments (0)

We encourage comments and feedback from a broad range of readers. See criteria for comments and our diversity statement.

Leave a public comment
Send a private comment to the author(s)
Views 0
Downloads 0
Comments 0
Metrics 0


×
Alerts
Notify me about updates to this article or when a peer-reviewed version is published.

We use cookies on our website to ensure you get the best experience.
Read more about our cookies here.