Interrupting glucagon receptor signaling results in hyperaminoacidemia, which stimulates alpha cell hyperplasia. Arginine, a potent secretagogue for both insulin and glucagon, is required for hyperaminoacidemia-stimulated alpha cell proliferation. To investigate the role of arginine transport, we compared the expression of amino acid transporters in published datasets of sorted mouse and human islet cells and found that Slc7a2, cationic amino acid transporter, is the most highly expressed amino acid transporter in both mouse and human alpha cells and that its expression is three-fold higher in alpha cells than in beta cells. Following glucose/arginine injection, global Slc7a2 knockout mice (Slc7a2-/-) had 20% higher blood glucose (+/+ vs. -/-: 412±23 vs. 517±25mg/dL, n=11-12, p=0.004), 80% lower serum insulin (3.7±0.6 vs. 0.7±0.4nM, p=0.0008) and 59% lower serum glucagon (64.3±23.1pM vs. 26.3±11.4pM, p=0.009) than Slc7a2+/+ animals. Slc7a2+/- mice had 55% decreased insulin levels (+/+ vs. +/-: 3.7±0.6 vs. 1.7±0.3nM, n=8, p=0.012), but showed no difference in serum glucose or glucagon levels, indicating that Slc7a2 expression may be rate limiting for beta cell, but not alpha cell, function. Isolated islets from Slc7a2-/- mice had normal morphology, but reduced high amino acid-stimulated alpha cell proliferation by 90% and 58% in Slc7a2-/- and Slc7a2+/- islets, respectively (+/+ vs.-/-: 3.7±1.7 vs. 0.4±0.2%, p=0.007, n=4; +/+ vs. +/-: 3.7±1.7 vs. 1.5±0.6%, p=0.038, n=4). Knockdown with Slc7a2 shRNA in the aTC1-6 mouse alpha cell line also decreased proliferation. Taken together, these data indicate a central role for Slc7a2 in amino acid-stimulated alpha cell proliferation and glucagon and insulin secretion.
E. Spears: None. M. Shou: None. W.A. Siv: None. C. Dai: None. W. Chen: None. A.C. Powers: None. D. Dean: None.