Mechano-sensor Piezo1 inhibits glucagon production in pancreatic α-cells

Glucagon is a critical hormone regulating glucose metabolism. It stimulates the liver to release glucose under low blood sugar conditions, thereby maintaining blood glucose stability. Excessive glucagon secretion and hyperglycemia is observed in individuals with diabetes. Precise modulation of glucagon is significant to maintain glucose homeostasis. Piezo1 is a mechanosensitive ion channel capable of converting extracellular mechanical forces into intracellular signals, thus regulating hormonal synthesis and secretion. This study aims to investigate the role of Piezo1 in regulating glucagon production in α cells. The effects of Piezo1 on glucagon production were examined in normal- or high-fat diet fed α cell-specific Piezo1 knockout mice (Gcg-Piezo1−/−), and the murine pancreatic α cell line αTC1–6. Expression of Proglucagon was investigated by real-time PCR and western blotting. Plasma glucagon and insulin were detected by enzyme immunoassay. Under both normal- and high-fat diet conditions, Gcg-Piezo1−/− mice exhibited increased pancreatic α cell proportion, hyperglucagonemia, impaired glucose tolerance, and activated pancreatic mTORC1 signaling. Activation of Piezo1 by its agonist Yoda1 or overexpression of Piezo1 led to decreased glucagon synthesis and suppressed mTOR signaling pathway in αTC1–6 cells. Additionally, the levels of glucagon in the medium were also reduced. Conversely, knockdown of Piezo1 produced opposite effects. Our study uncovers the regulatory role of the Piezo1 ion channel in α cells. Piezo1 influences glucagon production by affecting mTOR signaling pathway.