99-OR: SLC7A2-Dependent Arginine Transport in α-Cells Signals Arginine tone to Regulate Insulin Secretion

Diabetes results from a decline in pancreatic β-cell function with simultaneous hyperglucagonemia, resulting in hyperglycemia. Over 60 years ago, arginine was identified as a potent secretagogue of glucagon secretion, yet the mechanisms behind this are not thoroughly elucidated. Recently, we found that the cationic amino acid transporter, SLC7A2/CAT2 is the most highly expressed amino acid transporter in human pancreatic α-cells and three-fold higher in α-cells than it is in β-cells and other islet cell types in both mouse and human islets. We showed that global loss of SLC7A2 in mice resulted in impaired arginine stimulated glucagon and insulin secretion. However, based on the expression pattern of SLC7A2, we predicted β-cells might be poor arginine sensors. To assess the role of α-cell expression of SLC7A2 arginine-stimulated hormone secretion, we made either α-cell or β-cell specific Slc7a2^-/- (α7A2^KO;β7a2^KO) mice. Hormone levels were measured in 6-hour fasted and arginine challenged mice (2g/kg via intraperitoneal injection). Blood glucose, glucagon, and insulin levels were not significantly different after fasting in α7A2^KO, β7a2^KO, and Slc7a2^f/f cre- (7a2^f/f) control mice. As expected, 15 minutes after arginine bolus, α7A2^KO mice had significantly lower arginine stimulated glucagon levels compared to β7a2^KO and 7a2^f/f mice (arginine-stimulated glucagon - β7a2^KO 102.4 ± 36.8 pM vs. α7A2^KO 14.1 ± 18.7 pM vs. 7a2^f/f 103.8 ± 76.5; n=6-11 p<0.001). However surprisingly, β7a2^KO mice had similar insulin levels to control mice, while α-cell specific α7A2^KO mice had a two fold reduction in arginine stimulated insulin secretion (arginine-stimulated insulin - β7a2^KO 424.1 ± 172.3 pM vs. α7A2^KO 158.1 ± 57.5 pM vs. 7a2^f/f 368.2 ± 212.4; n=6-11 p<0.001). In summary, we found that α-cells act as the predominant arginine sensor in islets communicating arginine tone to neighboring β-cells perhaps through proglucagon-derived peptides or other α-cell products.