1735-P: AKT Modulates Glucose Sensing and Glucagon Secretion in Alpha Cells

In both T1DM and T2DM, glucagon secretion is impaired and no longer inhibited by hyperglycemia nor insulin, suggesting a defect in the insulin signaling via IRS/PI3k/Akt on pancreatic α-cells. Using a mouse model with constitutive activation of Akt in α-cells (αpCall), we investigated the impact of insulin signaling activation on glucagon secretion at different glucose concentrations. The αpCall mice exhibited lower body weight and hypoglycemia in early life. Given the mosaic expression of the transgene in α-cells, αpCall mice displayed normal glucose homeostasis, glucagon, and insulin secretion. In isolated islets, α-cells from αpCall mice showed increased expression of glucagon and the activation of mTORC1 signaling. In addition, α-cells from αpCall mice exhibited increased exocytosis and glucagon secretion stimulated by low glucose. This result was accompanied by elevated expression levels of Na+ and Ca2+ channels, along with an increase in Na+ and Ca2+ currents. Conversely, exposure of Akt-expressing α-cells to escalating glucose concentrations demonstrated a better suppression of glucagon secretion at high glucose levels. Throughout these experiments, insulin expression and secretion remained consistent under all glucose-stimulated conditions. In summary, our findings highlight the crucial role of AKT signaling activation in α-cells: it suppresses glucagon secretion in hyperglycemic conditions while enhancing glucagon secretion in low-glucose environments. This suggests that insulin signaling through the Akt pathway regulates α-cell sensitivity and glucagon secretion in response to glucose. Disclosure A.F. Neves: None. C. Lubaczeuski: Employee; Fractyl Health, Inc. N. Bozadjieva Kramer: None. R. Andrade Louzada Neto: None. E. Bernal-Mizrachi: None. Funding National Institutes of Health (5I01BX002728-08)