Highly selective SGLT2 inhibitors suppress glucose uptake in alpha-TC1 cells, while glucagon secretion is not affected

Abstract The existence of sodium-glucose cotransporter 2 (SGLT2) in pancreatic alpha cells and its potential roles in glucagon secretion remain controversial, despite its well-established function in renal glucose reabsorption. While some studies suggest SGLT2 presence and its involvement in glucagon regulation, others deny its expression in alpha cells. To clarify this dispute, we investigated the functional effects of highly selective SGLT2 inhibitors, dapagliflozin and empagliflozin, on glucose uptake, intracellular ATP levels, and glucagon secretion in alpha-TC1 cells, a widely used model for glucagon-secreting cells in culture. The SGLT2 inhibitors significantly suppressed basal glucose uptake in alpha-TC1 cells, indicating functional SGLT2 presence. However, the inhibitors did not affect glucagon secretion. Neither the SGLT2 inhibitors nor the more potent glucose transport inhibitor, cytochalasin B, altered intracellular ATP levels or glucagon secretion. In contrast, pharmacological inhibition of K/ATP channels increased glucagon secretion without affecting glucose uptake or ATP levels. These results suggest that while SGLT2 is functionally present at low levels and mediates basal glucose uptake in alpha-TC1 cells, its inhibition has insufficient influence on intracellular ATP levels, and therefore glucagon secretion remains stable. Furthermore, our observations support predominant involvement of K/ATP channels in regulating glucagon secretion. Further studies in human purified pancreatic alpha cells in addition to islets are warranted to fully elucidate SGLT2’s role in alpha-cell physiology. Competing Interest Statement The authors have declared no competing interest. Footnotes The authors declare no conflict of interest. Full-length research articles: Declaration of generative AI and AI-assisted technologies in the writing process. Grammatical checking and rephrasing for improved readability were performed with the assistance of Perplexity.ai.