Glucagon resistance and decreased susceptibility to diabetes in a model of chronic hyperglucagonemia

Elevation of glucagon levels and increase in a-cell mass are associated with states of hyperglycemia in diabetes. Our previous studies have highlighted the role of nutrient signaling via mTOR Complex 1 (mTORC1) regulation that controls glucagon secretion and a-cell mass. The current studies investigated the effects of activation of nutrient signaling by conditional deletion of the mTORC1 inhibitor, TSC2, in a-cells (aTSC2^KO). We showed that activation of mTORC1 signaling is sufficient to induce chronic hyperglucagonemia as a result of a-cell proliferation, cell size and mass expansion. Hyperglucagonemia in aTSC2^KO was associated with an increase in glucagon content and enhanced glucagon secretion. This model allowed us to identify the effects of chronic hyperglucagonemia on glucose homeostasis by inducing insulin secretion and resistance to glucagon in the liver. Liver glucagon resistance in aTSC2^KO mice were characterized by reduced expression of the glucagon receptor (GCGR), phosphoenolpyruvate carboxykinase (PEPCK) and genes involved in amino acid metabolism and urea production. Glucagon resistance in aTSC2^KO mice was associated with improved glucose levels in Streptozotocin (STZ)-induced β-cell destruction and HFD-induced glucose intolerance. These studies demonstrate that chronic hyperglucagonemia can improve glucose homeostasis by inducing glucagon resistance in the liver.