# Amino acid regulation of pancreatic islet alpha cell proliferation and function

> **NIH NIH K01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $145,292

## Abstract

Project Summary
Hyperglucagonemia contributes to the hyperglycemia of type 2 diabetes (T2D). As such, antagonism of
glucagon action has great promise as a therapeutic intervention for T2D. However, interrupted glucagon
signaling by multiple approaches leads to α-cell proliferation and hyperplasia. Using a multidisciplinary
approach we recently discovered when glucagon signaling is interrupted in the liver, the accumulation of blood
amino acids (hyperaminoacidemia or AAHi), particularly glutamine and arginine, drive α-cell proliferation. These
studies also revealed a previously unappreciated and conserved (fish to man) hepatic-islet α-cell axis where
hepatic glucagon signaling regulates serum amino acid levels and increased AA, especially glutamine (Q),
regulate glucagon secretion and α-cell proliferation and mass. AAHi is necessary and sufficient to cause -cell
proliferation in an mTORC1-dependent manner. We hypothesize that AAHi exerts the effect specifically in α-
cells because of the high expression of a unique set of AA transporters and catalytic enzymes, leading to
mTORC1 activation, glucagon secretion and α-cell proliferation. I will pursue an experimental strategy that
leverages the advantages of mouse models for identifying pathways and defining mechanisms while in parallel
testing the translation my findings into primary human islets. Plus, I will utilize a new in vitro assay for islet α-
cell proliferation to complement in vivo studies in mouse with transplanted human islets. These studies will
expand our understanding of the molecular mechanisms controlling α-cell biology, function, proliferation, and
mass and provide insight into pathways for controlled and safe expansion of islet cell mass. These studies
should also provide new insights into normal α-cell function and how the α-cell dysfunction in T2D could be
mitigated.

## Key facts

- **NIH application ID:** 9971529
- **Project number:** 5K01DK117969-03
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Erika Danielle Dean
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $145,292
- **Award type:** 5
- **Project period:** 2018-08-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9971529

## Citation

> US National Institutes of Health, RePORTER application 9971529, Amino acid regulation of pancreatic islet alpha cell proliferation and function (5K01DK117969-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9971529. Licensed CC0.

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