# Novel metabolic actions of GIP

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $350,843

## Abstract

Summary of Work
Incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), are
intestinally derived hormones that regulate postprandial metabolism. The incretin system accounts for up to
70% of postprandial insulin secretion in healthy individuals and diminishes to ~30% in people with type 2
diabetes (T2D). Understanding the mechanisms that regulate incretin control of insulin secretion, and how this
becomes dysfunctional with metabolic stress, is central to understanding the pathophysiology of T2D. We have
recently discovered that proglucagon products from alpha-cells are essential for normal beta-cell function – a
phenomenon termed alpha-to-beta cell communication. Specifically, we found that intra--cell tone is dictated
by the level of cAMP generated by input from proglucagon peptides. Impairing alpha-to-beta cell communication
greatly diminishes insulin secretion and results in glucose intolerance in the context of metabolic stress. The GIP
receptor (GIPR) and GLP-1 receptor (GLP-1R) are expressed on beta-cells and potentiate glucose-stimulated
insulin secretion. On the other hand, alpha cells only express the GIPR and not the GLP-1R. Indeed, GIP
stimulates glucagon secretion, while GLP-1R decreases it. The goal of this project is to understand the importance
of GIPR activity in alpha cells and the potential contribution to metabolic regulation in both healthy and diseased
states. Our recent discovery that glucagon production from alpha cells is necessary for nutrient stimulated insulin
secretion, support the hypothesis that GIPR activity in alpha cells enhances alpha-to-beta cell communication.
A corollary to this hypothesis is that GIPR activity in alpha cells contribute meaningfully to the incretin effect in
a postprandial situation by enhancing insulin secretion. Moreover, interventions that limit GIPR activity in alpha
cells would be expected to decrease insulin secretion and impair glucose tolerance. Testing this hypothesis has
the potential to extend our concept of the incretin effect beyond beta cell activity to incorporate the alpha cell as
a vital component. Furthermore, clarification of GIPR activity in alpha cells can provide insight into the new
generation of anti-diabetic medications that incorporate GIPR activity, potentially explaining the increased
efficacy achieved by these compounds above and beyond GLP-1R monoagonism.

## Key facts

- **NIH application ID:** 10851804
- **Project number:** 5R01DK125353-05
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Jonathan E Campbell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $350,843
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10851804

## Citation

> US National Institutes of Health, RePORTER application 10851804, Novel metabolic actions of GIP (5R01DK125353-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10851804. Licensed CC0.

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