# Orexin glucose-inhibited neurons and hypoglycemia unawareness

> **NIH NIH R01** · RUTGERS BIOMEDICAL AND HEALTH SCIENCES · 2024 · $586,531

## Abstract

Abstract:
All individuals with type 1 and >30% of those with type 2 diabetes mellitus (T1/2DM) require intensive insulin
therapy to manage their blood glucose levels. This therapy comes at a great price: increased incidence of
iatrogenic insulin-induced hypoglycemia. Insulin-induced hypoglycemia is not only acutely life-threatening,
repeated hypoglycemia (RH) impairs the ability of the brain to detect and correct subsequent hypoglycemia
allowing glucose levels to fall to dangerous, even lethal, levels. Declining glucose first triggers the hormonal
(e.g., glucagon, epinephrine) counterregulatory response (CRR) to stimulate gluconeogenesis. Further glucose
decline leads to the behavioral response known as hypoglycemia awareness which includes neurogenic (e.g.,
palpitations, anxiety) and neuroglycopenic (e.g., tiredness, confusion) symptoms that alert the individual of
hypoglycemia. RH impairs these hormonal and behavioral responses leading to hypoglycemia associated
autonomic failure (HAAF) and hypoglycemia unawareness, respectively. While the CRR and HAAF have been
studied extensively, little is known about the mechanisms underlying hypoglycemia awareness/unawareness.
This oversight was due to lack of an animal model. However, the Levin lab recently developed a rat model for
hypoglycemia awareness which we have translated into the mouse. This model enables us for the first time to
investigate how RH causes hypoglycemia unawareness. Our data suggest that orexin expressing neurons in the
perifornical hypothalamus (PFH) which are inhibited by glucose (glucose inhibited or GI) play a role in
hypoglycemia awareness. We find that RH blunts activation of PFH orexin-GI neuron in low glucose. Using our
mouse model of hypoglycemia awareness/unawareness we have shown that the dopamine reuptake inhibitor
modafinil restores hypoglycemia awareness after RH. Modafinil also restores glucose sensing by PFH orexin-GI
neurons. In this proposal we will test the hypothesis that RH increases the inhibitory effect of glucose on
PFH orexin-GI neurons leading to hypoglycemia unawareness. Modafinil, via the dopamine 1 receptor,
restores both glucose sensitivity of PFH orexin-GI neurons and hypoglycemia awareness. We will
determine how RH alters the glucose sensitivity of PFH orexin-GI neurons and how this is corrected by modafinil.
We will also determine the role of dopamine receptors in modafinil’s effect. Finally, we will determine the role of
diabetic hyperglycemia per se in hypoglycemia awareness/unawareness. These studies are the first to shed light
on the mechanisms of hypoglycemia awareness/unawareness and as such are of critical importance for patients
with T1/2DM.

## Key facts

- **NIH application ID:** 10807260
- **Project number:** 1R01DK135857-01A1
- **Recipient organization:** RUTGERS BIOMEDICAL AND HEALTH SCIENCES
- **Principal Investigator:** MITCHELL F ROITMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $586,531
- **Award type:** 1
- **Project period:** 2024-03-01 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10807260

## Citation

> US National Institutes of Health, RePORTER application 10807260, Orexin glucose-inhibited neurons and hypoglycemia unawareness (1R01DK135857-01A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10807260. Licensed CC0.

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