Elevation of glucagon levels and increase in α-cell mass are associated to states of hyperglycemia in diabetes. However, little is known about the mechanisms that control glucagon secretion and α-cell mass expansion in normal or diabetogenic conditions. The current studies investigated the effects of activation of nutrient signaling by conditional deletion of the mTORC1 inhibitor, TSC2, in α-cells (αTSC2KO), we showed that activation of mTORC1 signaling is sufficient to induce chronic hyperglucagonemia as a result of α-cell proliferation, cell size and mass expansion. Hyperglucagonemia in αTSC2KO was associated to increase in glucagon content, enhanced glucagon secretion and defective adaptation to fasting. This model allowed us to identify the beneficial effects of chronic hyperglucagonemia in glucose homeostasis by inducing insulin secretion and resistance to glucagon in the liver. Liver glucagon resistance in αTSC2KO mice was characterized by reduced expression of the glucagon receptor (GCGR), phosphoenolpyruvate carboxykinase (PEPCK) and genes involved in amino acid metabolism and urea production. Surprisingly, hyperglucagonemia in αTSC2KO mice was associated to improved glucose levels in models of Streptozotocin (STZ)-induced β-cell destruction and high fat diet-induced glucose intolerance. Contrary to our current understanding of glucagon action, these studies demonstrate that endogenous chronic hyperglucagonemia improve glucose homeostasis by augmenting insulin secretion and by inducing glucagon resistance in the liver. These novel in vivo findings support the concept that enhancing glucagon action could be used as an alternative strategy to treat hyperglycemia in diabetes.
C. Lubaczeuski: None. N. Bozadjieva: None. M. Blandino-Rosano: None. E. Bernal-Mizrachi: None.
U.S. Department of Veterans Affairs (IBX002728A); Diabetes Research Connection