OR12-03 The Pancreatic Islet Alpha Cell Arginine Transporter SLC7A2 Regulates Arginine-induced Glucagon Secretion and Glycemia

Disclosure: J.E. Stanley: None. A. Reuter: None. K. Sellick: None. A.D. Attie: None. M.P. Keller: None. E. Dean: None. Glucagon secreted from pancreatic islet α cells stimulates both hepatic glycogenolysis and gluconeogenesis resulting in the fractional extraction of amino acids from the blood. Thus, glucagon stimulates hepatic glucose output and raises blood glucose. When liver glucagon signaling is impaired, amino acid accumulation (hyperaminoacidemia) promotes subsequent α cell hyperplasia and hyperglucagonemia via this liver-α-cell axis, an endocrine feedback loop. We show that high levels of both glutamine and recently arginine are required to stimulate α cells to proliferate. Arginine also potently stimulates glucagon secretion, but the mechanisms behind this are not well defined. We find 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 in both mouse and human islets. We also find two SNPs in the human SLC7A2 locus are strongly associated with HbA1c (rs142010226 (A/G) - chr8: 17,367,112; p=9.11e(-18); β=0.0113 and rs2517232 - chr8: 17,367,421; p=2.553e(-14); β=-0.0283). Both SNPs are in the first intron of SLC7A2 but appear to exert opposite effect on HbA1c and associated with distinct haplotype blocks. ATAC-Seq analyses of human islets show that these SNPs are within 1 kb of binding sites for MAFB and FOXA2 transcription factors, both critical for α cell gene expression. To test if α cell expression of SLC7A2 plays a role in both glycemia and arginine-stimulated glucagon secretion, we generated α cell-specific Slc7a2(-/-) (α7A2(KO)) mice. Blood glucose and glucagon levels were not significantly different after a 6-hour fast in α7A2(KO) and 7A2(WT)(Cre+) mice. After a 6-hour fast, mice were administered an arginine bolus (2g/kg) via intraperitoneal injections and their blood glucose and glucagon levels were measured 15 minutes post-injection. α7A2(KO) mice had a significantly higher blood glucose level than 7A2(WT)(cre+) mice after stimulation with arginine (arginine-stimulated blood glucose - 7A2(WT)(Cre+) 124.3 ± 26.7 mg/dl vs. α7A2(KO) 159.6 ± 32.1 mg/dl n=23-25 p=0.0019). However, glucagon secretion was significantly lower after stimulation with arginine in the α7A2(KO) mice compared to the 7A2(WT)(Cre+) mice (arginine-stimulated glucagon - 7A2(WT)(Cre+) 321.8 ± 171.9 pM vs. α7A2(KO) 74.6 ± 22.8 pM n=4-6; p<0.0001). Together, these data indicate that SLC7A2 mediates arginine’s effects in α cells and plays an important role in regulating glycemia. Presentation: Friday, June 16, 2023