Pancreatic islet α cell function and proliferation require the arginine transporter SLC7A2
Erick Spears, Jade E. Stanley, Matthew Shou, Linlin Yin, Xuan Li, Chunhua Dai, Amber Bradley, Katelyn Sellick, Greg Poffenberger, Katie C. Coate, Shristi Shrestha, Anna Marie R. Schornack, Taverlyn Shepard, Madushika Wimalarathne, Regina Jenkins, Kyle W. Sloop, Keith T. Wilson, Alan D. Attie, Mark P. Keller, Wenbiao Chen, Alvin C. Powers, E. Danielle Dean
Erick Spears, Jade E. Stanley, Matthew Shou, Linlin Yin, Xuan Li, Chunhua Dai, Amber Bradley, Katelyn Sellick, Greg Poffenberger, Katie C. Coate, Shristi Shrestha, Anna Marie R. Schornack, Taverlyn Shepard, Madushika Wimalarathne, Regina Jenkins, Kyle W. Sloop, Keith T. Wilson, Alan D. Attie, Mark P. Keller, Wenbiao Chen, Alvin C. Powers, E. Danielle Dean
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Research Article Cell biology Endocrinology Metabolism

Pancreatic islet α cell function and proliferation require the arginine transporter SLC7A2

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.

Authors

Erick Spears, Jade E. Stanley, Matthew Shou, Linlin Yin, Xuan Li, Chunhua Dai, Amber Bradley, Katelyn Sellick, Greg Poffenberger, Katie C. Coate, Shristi Shrestha, Anna Marie R. Schornack, Taverlyn Shepard, Madushika Wimalarathne, Regina Jenkins, Kyle W. Sloop, Keith T. Wilson, Alan D. Attie, Mark P. Keller, Wenbiao Chen, Alvin C. Powers, E. Danielle Dean

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Figure 7

SLC7A2 is required for upregulation of Slc38a5 expression during interrupted glucagon signaling.

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SLC7A2 is required for upregulation of Slc38a5 expression during interru...
(A–D) Representative images of islets from Slc7a2+/+ and Slc7a2–/– mouse pancreas stained for glucagon (green) and SLC38A5 (red) after 2 weeks of treatment with GCGR mAb or control IgG (scale bar = 50 μm; inset E–H scale bar = 10 μm). (I) Quantification of SLC38A5 expression in α cells by percent SLC38A5+/GCG+ cells per total Gcg+ cells (% SLC38A5+ α cells) in Slc7a2+/+ and Slc7a2–/– mouse islets after injection with GCGR mAb or control IgG (n = 4–5). (J) Quantification of Slc38a5 mRNA levels assessed by quantitative PCR in Slc7a2+/+ and Slc7a2–/– mice treated with IgG or GCGR mAb. (K–N) Representative images of Slc7a2+/+ and Slc7a2–/– islet grafts from Slc7a2+/+ kidney capsules after 2 weeks of treatment with GCGR mAb or control IgG and stained for glucagon and SLC38A5 (scale bar = 50 μm; inset O–R scale bar = 10 μm). Dashed yellow lines indicate kidney graft boundary. (S) Quantification of SLC38A5 in α cells as determined by percent SLC8A5+/Gcg+ cells per total Gcg+ cells in wild-type mouse islets after 4-day culture in high amino acid–containing medium (High AA) or in otherwise high AA medium with low arginine (Low R) or low glutamine (Low Q). *P < 0.05, **P < 0.005, ***P < 0.0005, ****P < 0.00005.