# Arginine regulation of alpha cell proliferation and function

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $447,894

## Abstract

PROJECT SUMMARY
Traditionally, diabetes is defined as decreased insulin action resulting in impaired glucose homeostasis.
However, inappropriate secretion of glucagon also contributes to the hyperglycemia in diabetes. Blocking
glucagon action lowers blood glucose, but also leads to hyperglucagonemia with α cell proliferation and
hyperplasia. We demonstrated that this is due to high blood levels of amino acids resulting from impaired
amino acid catabolism in liver (gluconeogenesis). These studies demonstrated a classical endocrine feedback
loop, the liver-islet α cell axis. As part of our K01 funded investigations, we discovered that high levels of
arginine are required for the effects of high amino acid levels on α cell proliferation and function. We identified
SLC7A2 (CAT2) is the major arginine transporter in pancreatic islet α cells. Using global CAT2 knockout mice,
we found that loss of CAT2 results in protection from α cell hyperplasia and a complete loss of glucagon
secretion even in response to strong depolarizing agents. This suggests that CAT2 is playing an important role
in α cells beyond affecting membrane polarization as had been previously proposed as a mechanism for
arginine-stimulated secretion. Our current objective is to define the mechanisms of arginine-stimulated α cell
proliferation and secretion. Under the support of this R01 in Aim 1, we will characterize changes in the α cell
when CAT2 expression is lost using α cell specific targeted deletion, including α cell proliferation and mass,
glucagon secretion, Ca2+ dynamics, and gene and protein expression. We will also test if the heterodimeric
amino acid exchanger LAT2 (SLC7A8/SLC3A2) is required for α cell proliferation and function. In Aim 2, we
will examine a novel putative arginine cell surface binding protein called TM4SF4 that is selectively and
robustly expressed on pancreatic α cells. We will fully characterize TM4SF4 arginine binding kinetics, protein
binding partners in α cells, effects on arginine transport, and regulation of α cell proliferation and function. An
important feature of our work is that we will translate our discoveries made in mouse islets using human islets.
These studies will provide new insights into normal α cell function and how α cells could be targeted to repair
dysregulated glucagon secretion in diabetes.

## Key facts

- **NIH application ID:** 10772080
- **Project number:** 5R01DK132669-03
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Erika Danielle Dean
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $447,894
- **Award type:** 5
- **Project period:** 2022-04-15 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10772080

## Citation

> US National Institutes of Health, RePORTER application 10772080, Arginine regulation of alpha cell proliferation and function (5R01DK132669-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10772080. Licensed CC0.

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