# Nutrient-dependent action of glucagon and GLP-1 in glucose metabolism and insulin secretion

> **NIH NIH F32** · DUKE UNIVERSITY · 2020 · $23,745

## Abstract

Project Summary/Abstract
 Glucagon and glucagon-like peptide 1 (GLP-1) are proglucagon gene products that regulate blood
glucose levels through insulin-dependent and insulin–independent mechanisms. Canonically, glucagon and
GLP-1 are believed to have opposing effects on pancreatic β-cell function, with glucagon from pancreatic α-cells
functioning as a counterregulatory hormone to increase blood glucose during fasting and GLP-1 augmenting
glucose-stimulated insulin secretion in the fed state to lower blood glucose. Glucagon receptor antagonism,
which should decrease hepatic glucose production, has been explored as a means to lower blood glucose during
diabetes. However, this has not translated to the clinic. More recently, drugs incorporating glucagon receptor
agonism actually improved glycemia—highlighting that glucagon’s physiological role in regulating glycemia is
likely more complex. Our preclinical data suggest that glucagon action depends on ambient glycemia, i.e., at
fasting glucose concentrations, glucagon acts canonically at the liver to maintain hepatic glucose output, while
at elevated (e.g., postprandial) glucose concentrations, glucagon acts in an incretin manner to directly stimulate
insulin secretion from pancreatic β-cells. We hypothesize that this is also true in humans. Moreover, there
appears to be intra-islet interplay between glucagon, GLP-1, and their respective receptors depending on nutrient
intake and metabolic stress. We further hypothesize that α-cell glucagon and GLP-1—not gut-derived GLP-1—
regulate nutrient-stimulated insulin secretion. To address these hypotheses, we will test whether glucagon’s
ability to increase insulin secretion is dependent on glycemia in humans (aim 1) and the relative contributions of
islet GLP-1 and glucagon toward facilitating insulin secretion in preclinical models of normal physiology and
metabolic stress (aim 2). This translational approach offers insight into novel paracrine relationships between α-
and β-cells, which has the potential to profoundly revolutionize our understanding of islet biology and offer new
treatment approaches for diabetes.

## Key facts

- **NIH application ID:** 10005025
- **Project number:** 5F32DK121420-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Sarah Marie Gray
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $23,745
- **Award type:** 5
- **Project period:** 2019-07-01 → 2020-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10005025

## Citation

> US National Institutes of Health, RePORTER application 10005025, Nutrient-dependent action of glucagon and GLP-1 in glucose metabolism and insulin secretion (5F32DK121420-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10005025. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*