SUN-217 Tm4sf4 Promotes Glucagon Secretion And α-cell Identity

Abstract Disclosure: M. Wimalarathne: None. N. Shankar: None. S. Saraf: None. A. Schornack: None. K. Sellick: None. P. Bisignano: None. D. Claxton: None. E. Dean: None. The transmembrane 4 cell surface protein superfamily member TM4SF4 is highly expressed in pancreatic α-cells and considered an “α-cell identity gene” based on single-cell RNASeq studies. Known for its role in cancer, TM4SF4 inhibitors slow the growth of hepatocellular carcinoma. TM4SF4 gene expression is significantly decreased in α-cells from donors with type 1 diabetes with impaired glucagon secretion. This leads us to hypothesize that TM4SF4 plays a critical role in α-cell function, including proliferation, glucagon secretion, and differentiation. We find that Tm4sf4 siRNA knockdown in αTC1-6 cells reduces glucagon secretion. Live confocal imaging reveals that the TM4SF4 protein translocates from the cell membrane to lysosomes when briefly starved of arginine and glutamine and then restimulated with both, suggesting a role in amino acid sensing. To further investigate, we developed a mouse model to knockout TM4SF4 expression in pancreatic α-cells, αTm4sf4 (GcgCreERT2; Tm4sf4fl/fl) mice. We observe 85.4-95.5% reduction in TM4SF4 expression in α-cells when compared to Tm4sf4fl/fl mice from female and male mice, respectively. αTm4sf4 mice display decreased α-cell proliferation (4.24 fold) and significantly reduced glucagon levels when fasted and stimulated with an arginine bolus, indicating TM4SF4 regulates both glucagon secretion and cell growth. Moreover, our findings reveal a ten-fold increase in glucagon+ somatostatin+ bihormonal cells in αTm4sf4 mice, suggesting that TM4SF4 is partially responsible for maintaining a differentiated α-cell phenotype. In summary, these findings highlight the key role of TM4SF4 in pancreatic α-cell function and differentiation, suggesting potential applications for diabetes treatments and therapies that target TM4SF4. Presentation: Sunday, July 13, 2025