# Pharmacological Approach to the Restoration of Hypoglycemia Awareness

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2021 · $381,250

## Abstract

Abstract:
 Hypoglycemia is the most prevalent clinical complication in the daily management of diabetes and is the
major obstacle to normalizing blood sugar. For people with Type 1 diabetes (T1DM), hypoglycemia associated
autonomic failure (HAAF) increases the risk for severe hypoglycemia by a factor of 25 or more. A major component
of HAAF is hypoglycemia unawareness, which involves in the loss/diminution of warning symptoms to
hypoglycemia that would normally prompt a corrective behavioral response (e.g., eating food). With a goal of
identifying existing biological compounds that could restore hypoglycemia awareness (ie, repurpose existing FDA-
approved drugs), our laboratory recently completed a drug screen using a novel animal model of hypoglycemia
unawareness in which preconditioned rats failed to increase food consumption in response to an episode of insulin
induced hypoglycemia. Of all drugs tested, the dopamine antagonist metoclopramide consistently restored
hypoglycemia awareness in several of our animal models tested. The goal of Aim 1 in the proposed grant is to
validate in T1DM animal models of HAAF whether leading drugs identified in our recent drug screen restore both,
1) hypoglycemia awareness, and 2) the impaired sympathoadrenal response to hypoglycemia. Utilizing the gold
standard hyperinsulinemic hypoglycemic clamp technique, drug validation studies are proposed in two
independent T1DM rodent models of HAAF (both hypoglycemia unaware rats as well rats with recurrent
hypoglycemia-induced sympathoadrenal deficiency) to determine if treatment with our leading drugs reverse these
two principal pathologic components of HAAF. In Aim 2, a clinical trial is proposed to test whether the lead
compound identified in our drug screen can restore both hypoglycemia awareness and the counterregulatory
response to hypoglycemia in subjects with T1DM and HAAF. A placebo controlled, randomized trial will test
whether four weeks of treatment with metoclopramide (our lead drug noted to particularly efficacious in several
preclinical models) will, 1) reduce the incidence of hypoglycemia, 2) improve hypoglycemia symptom recognition,
and 3) improve the sympathoadrenal response to hypoglycemia. Indices of improvement will be assessed, 1) in
the outpatient setting with hypoglycemia event diaries, hypoglycemia awareness questionnaires, and continuous
glucose monitors, and 2) in the laboratory setting with stepped hypoglycemic clamps which quantifies
measurements of symptomatic awareness and counterregulatory hormone responses. By proceeding forward with
the novel results from our recent drug screen, the proposed studies are the logical next step in seeking to
repurpose existing FDA approved drugs to treat hypoglycemia associated autonomic failure in people with Type 1
diabetes.

## Key facts

- **NIH application ID:** 10130505
- **Project number:** 5R01DK118082-03
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** SIMON J FISHER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $381,250
- **Award type:** 5
- **Project period:** 2019-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10130505

## Citation

> US National Institutes of Health, RePORTER application 10130505, Pharmacological Approach to the Restoration of Hypoglycemia Awareness (5R01DK118082-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10130505. Licensed CC0.

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