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These authors contributed equally and are listed alphabetically as co-first authors

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Current Address: Department of Neuroscience Icahn School of Medicine at Mount Sinai 19th Floor Annenberg Building Room# 291 1468 Madison Ave. NY, NY 10029. Email: vishwendra.patel@mssm.edu

Perifornical hypothalamus (PFH) orexin glucose-inhibited (GI) neurons that facilitate arousal have been implicated in hypoglycemia awareness. Mice lacking orexin exhibit narcolepsy and orexin mediates the effect of the anti-narcolepsy drug, modafinil. Thus, hypoglycemia awareness may require a certain level of arousal for awareness of the sympathetic symptoms of hypoglycemia (e.g., tremors, anxiety). Recurrent hypoglycemia (RH) causes hypoglycemia unawareness. We hypothesize that RH impairs the glucose sensitivity of PFH orexin-GI neurons and that modafinil normalizes glucose sensitivity of these neurons and restores hypoglycemia awareness after RH. Using patch clamp recording, we found that RH enhanced glucose inhibition of PFH orexin-GI neurons from male mice, thereby blunting activation of these neurons in low glucose. We then used a modified conditioned place preference (CPP) behavioral test to demonstrate that modafinil reversed hypoglycemia unawareness in male mice after RH. Similarly, modafinil restored normal glucose sensitivity to PFH orexin-GI neurons. We conclude that impaired glucose sensitivity of PFH orexin-GI neurons plays a role in hypoglycemia unawareness and that normalizing their glucose sensitivity after RH is associated with restoration of hypoglycemia awareness. This suggests that the glucose sensitivity of PFH orexin-GI neurons is a therapeutic target for preventing hypoglycemia unawareness.

This article contains supplementary material online at https://doi.org/10.2337/figshare.21714221.

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