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 4

SLC7A2 is required for α cell proliferation in response to interrupted glucagon signaling.

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SLC7A2 is required for α cell proliferation in response to interrupted g...
(A and B) Representative immunostaining for C-peptide, glucagon, and somatostatin from Slc7a2+/+ and Slc7a2–/– mouse pancreas (scale bar = 50 mm). (C–E) Mass analysis for α (C), β (D), and δ (E) cells and total islet mass (F) from Slc7a2+/+ (n = 7) and Slc7a2–/– (n = 9) mice. (G–J) Representative images of islets from Slc7a2+/+ and Slc7a2–/– mouse pancreas after 2 weeks of treatment with GCGR mAb or control IgG (scale bar = 50 μm; inset K–N scale bar = 10 μm). (O) Quantification of α cell proliferation as determined by percent Ki67+/Gcg+ cells per total Gcg+ cells in Slc7a2+/+ and Slc7a2–/– mouse islets after 2 weeks of treatment with GCGR mAb or control IgG (n = 5 each). (P–R) Representative images of 5 dpf islets from Tg(gcga:EGFP) zebrafish, α cell–specific EGFP, with CRISPR/Cas9-induced loss of glucagon receptors (gcgra/b) and/or slc7a2 stained for EdU to assess proliferation (scale bar = 20 μm). (S) Quantification of total α cell numbers (n = 14, 18, 29, 46, and 20, respectively, for each genotype) and (T) quantification of EdU-positive α cells from zebrafish islets (n = 12, 18, and 9, respectively, for each genotype). **P < 0.005, ***P < 0.0005, and ****P < 0.0001.