Time dependent effects of endogenous hyperglucagonemia on glucose homeostasis and hepatic glucagon action.

Elevation of glucagon levels and increase in alpha cell proliferation is associated with states of hyperglycemia in diabetes. A better understanding of the molecular mechanisms governing glucagon secretion could have major implications in understanding abnormal responses to hypoglycemia in diabetes patients and provide novel avenues for diabetes management. Our previous studies have highlighted the role of nutrient signaling via mTOR complex 1 (mTORC1) regulation that controls glucagon secretion and alpha cell mass and that hyperglucagonemia can improve glucose homeostasis by diminishing glucagon action in the liver. However, it is unclear if short-term effects of mTORC1 activation are sufficient to induce glucagon secretion without changes in alpha cell mass and whether short-term hyperglucagonemia reduces liver glucagon action in a reversible manner. Using mice with inducible induction of the regulator of the mTORC1 complex (Rheb) in alpha cells (αRhebTg), we showed that short-term activation of mTORC1 signaling is sufficient to induce hyperglucagonemia as a result of increased glucagon secretion. Hyperglucagonemia in the αRhebTg was also associated with an increase in alpha cell size and mass expansion. This model allowed us to identify the effects of chronic and short-term hyperglucagonemia on glucose homeostasis by regulating glucagon signaling in the liver. Short-term hyperglucagonemia impaired glucose tolerance, which was reversible over time. Decrease in liver glucagon effects in αRhebTg mice was associated with reduced expression of the glucagon receptor (GCGR) and genes involved in gluconeogenesis, amino acid metabolism, and urea production. However, only genes regulating gluconeogenesis returned to baseline upon improvement of glycemia. Overall, these studies demonstrate that hyperglucagonemia exerts a biphasic response on glucose metabolism: short-term hyperglucagonemia leads to glucose intolerance, whereas chronic exposure to glucagon generates decrease on hepatic glucagon action along with improved glucose tolerance.