# Prevention of hypoglycemia associated autonomic failure by enhancing melanocortin 4 receptor function

> **NIH NIH R03** · UNIVERSITY OF ROCHESTER · 2020 · $115,500

## Abstract

Risk of fatal hypoglycemia due to insulin or its secretagogues is a major limiting factor for optimal glucose
control in management of diabetes. Hypoglycemia causes about 6 to 10% of deaths in diabetes patients and
costs nearly $1.4 billion annually in the US. Moreover, repeated hypoglycemia leads to hypoglycemia
associated autonomic failure (HAAF), which is a phenomenon of progressive decline in counterregulatory
response to subsequent episodes of hypoglycemia. To effectively prevent or counteract HAAF, it is imperative
that we first understand the mechanisms underlying this potentially fatal condition. We have observed that
melanocortin 4 receptor (MC4R) deficiency in the paraventricular nucleus of the hypothalamus (PVH) impairs
the stimulation of the release of counterregulatory hormones such as glucagon and epinephrine in response to
hypoglycemia in mice (findings from my K01-funded project). Moreover, administration of MC4R agonist in the
PVH of diabetic mice restored their counterregulatory response to hypoglycemia. Collectively, these data
indicate that normal MC4R signaling is critical to counteract hypoglycemia. Therefore, weakening of the MC4R
function can lead to defective hypoglycemia counterregulation. Based on our preliminary data and the role of
MC4R in stimulating the sympathetic nervous system activity, it is likely that recurrent hypoglycemia causes
autonomic failure by diminishing the function of MC4R in the PVH. Hence, we hypothesize that HAAF is a
consequence of dysfunctional MC4R in the PVH and that enhancement of the MC4R function will prevent
HAAF in health and diabetes. To test our hypothesis, in Aim 1, we will determine if recurrent hypoglycemia
impairs the stimulation of release of counterregulatory hormones by reducing the function of MC4R, which in
turn decreases adrenal sympathetic nerve activity to mediate HAAF. Moreover, in Aim 2, we will evaluate the
efficacy of genetic and pharmacological enhancement of MC4R function in the PVH to prevent HAAF in health
and diabetes. Through my career development award - K01, I have acquired necessary skills and experience
to accomplish the goals of this project. Moreover, the University of Rochester has outstanding resources and
facilities to support the project. In summary, we will establish whether or not recurrent hypoglycemia diminishes
the function of MC4R in the PVH to mediate HAAF. Enhancing MC4R function may emerge as a strategy to
prevent HAAF in diabetes. Importantly, this R03 funding program will augment the progress of my K award and
facilitate the generation of sufficient preliminary data for my subsequent R01 grant application focusing on
further unraveling the MC4R downstream pathways that are responsible for stimulating the counterregulatory
response to hypoglycemia and mitigating HAAF.

## Key facts

- **NIH application ID:** 9997948
- **Project number:** 5R03DK122190-02
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Kavaljit H Chhabra
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $115,500
- **Award type:** 5
- **Project period:** 2019-08-16 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9997948

## Citation

> US National Institutes of Health, RePORTER application 9997948, Prevention of hypoglycemia associated autonomic failure by enhancing melanocortin 4 receptor function (5R03DK122190-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9997948. Licensed CC0.

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