Pancreatic islet α cell function and proliferation require the arginine transporter SLC7A2
10 affiliations
- 1Department of Biology, Belmont University, Nashville, Tennessee, USA
- 2Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- 3Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, Tennessee, USA
- 4Diabetes and Complications, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA
- 5Center for Mucosal Inflammation & Cancer; and
- 6Department of Pathology, Microbiology & Immunology;
- 7Division of Gastroenterology, Hepatology & Nutrition, Department of Medicine;
- 8Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- 9Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee, USA
- 10Department of Biochemistry, University of Wisconsin–Madison, Madison, Wisconsin, USA
Abstract
Interrupting glucagon signaling decreases gluconeogenesis and the fractional extraction of amino acids by liver from blood, resulting in lower glycemia. The resulting hyperaminoacidemia stimulates α cell proliferation and glucagon secretion via a liver/α cell axis. We hypothesized that α cells detect and respond to circulating amino acids' levels via a unique amino acid transporter repertoire. We found that Slc7a2/SLC7A2 is the most highly expressed cationic amino acid transporter in α cells, with its expression being 3-fold greater in α than β cells in both mouse and human. Employing cell culture, zebrafish, and knockout mouse models, we found that the cationic amino acid arginine and SLC7A2 are required for α cell proliferation in response to interrupted glucagon signaling. Ex vivo and in vivo assessment of islet function in Slc7a2-/- mice showed decreased arginine-stimulated glucagon and insulin secretion. We found that arginine activation of mTOR signaling and induction of the glutamine transporter SLC38A5 was dependent on SLC7A2, showing that the role of both in α cell proliferation is dependent on arginine transport and SLC7A2. Finally, we identified single nucleotide polymorphisms in SLC7A2 associated with HbA1c. Together, these data indicate a central role for SLC7A2 in amino acid-stimulated α cell proliferation and islet hormone secretion.
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BibTeX
@article{spears2026pancreatic,
title = {{Pancreatic islet α cell function and proliferation require the arginine transporter SLC7A2}},
author = {Erick Spears and Jade E. Stanley and Matthew Shou and Linlin Yin and Xuan Li and Chunhua Dai and AMBER BRADLEY and Katelyn Sellick and Greg Poffenberger and Katie Colbert Coate and Shristi Shrestha and Anna Marie R Schornack and Taverlyn Shepard and Madushika M. Wimalarathne and Regina Jenkins and Kyle W. Sloop and Keith T. Wilson and Alan Attie and Mark P. Keller and Wenbiao Chen and Alvin C. Powers and E. Danielle Dean},
journal = {Journal of Clinical Investigation},
year = {2026},
month = jun,
doi = {10.1172/jci173913},
url = {https://doi.org/10.1172/jci173913},
note = {CC BY},
}
RIS
TY - JOUR
TI - Pancreatic islet α cell function and proliferation require the arginine transporter SLC7A2
AU - Erick Spears
AU - Jade E. Stanley
AU - Matthew Shou
AU - Linlin Yin
AU - Xuan Li
AU - Chunhua Dai
AU - AMBER BRADLEY
AU - Katelyn Sellick
AU - Greg Poffenberger
AU - Katie Colbert Coate
AU - Shristi Shrestha
AU - Anna Marie R Schornack
AU - Taverlyn Shepard
AU - Madushika M. Wimalarathne
AU - Regina Jenkins
AU - Kyle W. Sloop
AU - Keith T. Wilson
AU - Alan Attie
AU - Mark P. Keller
AU - Wenbiao Chen
AU - Alvin C. Powers
AU - E. Danielle Dean
PY - 2026
DA - 2026/06/14
JO - Journal of Clinical Investigation
DO - 10.1172/jci173913
UR - https://doi.org/10.1172/jci173913
AB - Interrupting glucagon signaling decreases gluconeogenesis and the fractional extraction of amino acids by liver from blood, resulting in lower glycemia. The resulting hyperaminoacidemia stimulates α cell proliferation and glucagon secretion via a liver/α cell axis. We hypothesized that α cells detect and respond to circulating amino acids' levels via a unique amino acid transporter repertoire. We found that Slc7a2/SLC7A2 is the most highly expressed cationic amino acid transporter in α cells, with its expression being 3-fold greater in α than β cells in both mouse and human. Employing cell culture, zebrafish, and knockout mouse models, we found that the cationic amino acid arginine and SLC7A2 are required for α cell proliferation in response to interrupted glucagon signaling. Ex vivo and in vivo assessment of islet function in Slc7a2-/- mice showed decreased arginine-stimulated glucagon and insulin secretion. We found that arginine activation of mTOR signaling and induction of the glutamine transporter SLC38A5 was dependent on SLC7A2, showing that the role of both in α cell proliferation is dependent on arginine transport and SLC7A2. Finally, we identified single nucleotide polymorphisms in SLC7A2 associated with HbA1c. Together, these data indicate a central role for SLC7A2 in amino acid-stimulated α cell proliferation and islet hormone secretion.
SN - 0021-9738
SN - 1558-8238
ER -