The Antinarcolepsy Drug Modafinil Reverses Hypoglycemia Unawareness and Normalizes Glucose Sensing of Orexin Neurons in Male Mice

Abstract

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.

Serotonergic neurons are involved in the counter‐regulatory response to hypoglycemia

“…Another possibility would be a role played in hypoglycemia awareness, a state of conscientiousness which includes a variety of symptoms (e.g., palpitations, anxiety, confusion) alerting for hypoglycemia and initiating behavioral responses to find energy. This is the case for lateral hypothalamus GI orexin neurons as it has recently been shown 44 . Other brain functions, including memory, motivation could be controlled, in addition to the CRR, by GSNs of these different neuronal networks.…”

“…This is the case for lateral hypothalamus GI orexin neurons as it has recently been shown. 44 Other brain functions, including memory, motivation could be controlled, in addition to the CRR, by GSNs of these different neuronal networks. Significant work is still needed to fully understand the functions controlled by these specific neurons.…”

Still Excited, but Less Aroused—The Effects of Nutritional Ketosis on Epinephrine Response and Hypothalamic Orexin Neuron Activation Following Recurrent Hypoglycemia in Diabetic Rats

“…Since the activation of OX neurons is strongly associated with waking during an insulin induced hypoglycemia [ 53 ], this may have serious repercussions during nocturnal hypoglycemia, when timely arousal is necessary to rectify the falling BG levels, even when the epinephrine response is unaffected and precedes the awakening [ 54 ]. Indeed, a recent preclinical study demonstrated that OX neurons are a promising therapeutic target for restoration of hypoglycemia awareness in the recurrent hypoglycemia settings [ 55 ].…”

Experimental pharmacological approaches to reverse impaired awareness of hypoglycemia—a review

“…Mechanisms by which modafinil exerts these effects are under study, with one study suggesting recurrent hypoglycemia impairs glucose sensitivity of perifornical hypothalamus (PFH) orexin glucose inhibited (GI) neurons which may play a role in development of IAH. In this rodent model, modafinil normalized glucose sensitivity to PFH orexin GI neurons post recurrent hypoglycemia with restoration of IAH ( Patel et al, 2023 ). In 2021, Espes et al published results from their proof-of-concept trial of six patients with T1D who were given a controlled release formulation of GABA, Remygen (Diamyd Medical) ( Espes et al, 2021 ).…”