# Role of Ghrelin in the Counter-Regulatory Response to Insulin-Induced Hypoglycemia

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $539,502

## Abstract

PROJECT SUMMARY/ABSTRACT
Defense against hypoglycemia is critical for survival, and is of particular importance in the clinically-significant
setting of insulin-induced hypoglycemia. Insulin-induced hypoglycemia is prevalent in Type 1 and advanced
Type 2 diabetes mellitus, and is associated with a far-ranging negative impact, including reduced work
productivity and quality of life, decreased adherence to or recommendations for intensive insulin regimens,
increased incidence of accidents and other morbidities, and occasionally death. While the body has developed
a highly integrated defense system with which to prevent or correct hypoglycemia, in diabetes patients
experiencing recurrent hypoglycemia due to over-insulinization, these counter-regulatory defenses are
compromised, contributing to what can become a vicious cycle of hypoglycemia and often hypoglycemia
unawareness (hypoglycemia-associated autonomic failure; HAAF) stemming from an abrogated
sympathoadrenal arm of the counter-regulatory response. Several facets of ghrelin biology suggest that ghrelin
may participate in the counter-regulatory response to insulin-induced hypoglycemia: 1) ghrelin secretion is
directly stimulated by low glucose and sympathoadrenal activation; 2) the ensuing raised ghrelin has at its
disposal many potential downstream targets with which to influence glucose handling, including interactions
with several traditional counter-regulatory response hormones. However, while ghrelin regulation of blood
glucose and by blood glucose have been evaluated in contexts such as caloric restriction, the overall role of
the ghrelin system in the counter-regulatory response to insulin-induced hypoglycemia has not been fully
assessed experimentally, for instance by re-creating insulin-induced hypoglycemia or HAAF in mice without an
intact ghrelin system. Here, we will test the concept that ghrelin plays a key, protective, counter-regulatory role
in the body’s response to insulin-induced hypoglycemia. In particular, we will dissociate the direct effects of
insulin versus hypoglycemia on ghrelin secretion by performing insulin bolus-induced hypoglycemia tests,
hyperinsulinemic-hypoglycemic clamps, and ex vivo ghrelin secretion studies in mice lacking insulin receptors
selectively in ghrelin cells and phloridzin-hypoglycemic clamps in ghrelin-KO mice. We will determine
requirement and sufficiency for GHSRs in AgRP neurons or SF1 neurons on the counter-regulatory response
using Cre-lox transgenic mice and chemogenetic technology. Also, we will determine if ghrelin deletion
increases susceptibility to HAAF by assessing the ghrelin response to hypoglycemia in wild-type mice with
HAAF and the overall counter-regulatory response following recurrent hypoglycemia in mice lacking ghrelin.
Our one-of-a-kind toolbox of recombinant mouse models targeting the ghrelin system, our team’s expertise in
studying both ghrelin action and secretion, and our expertise in glucose metabolism including perfor...

## Key facts

- **NIH application ID:** 10394285
- **Project number:** 5R01DK119341-04
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Eric Berglund
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $539,502
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10394285

## Citation

> US National Institutes of Health, RePORTER application 10394285, Role of Ghrelin in the Counter-Regulatory Response to Insulin-Induced Hypoglycemia (5R01DK119341-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10394285. Licensed CC0.

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