Liver glycogen is the first substrate used to defend against hypoglycemia. Interestingly, hepatic glycogen levels in people with T1D are lower than those of non-T1D controls and their ability to mobilize liver glycogen to combat insulin-induced hypoglycemia is also diminished. Because of this, we carried out experiments in dogs to determine whether hepatic glycogen content is a determinant of the HGP response to insulin-induced hypoglycemia. Results of those studies showed that a 75% increase in liver glycogen (such as occurs in a non-T1D individual over the course of a day) generated a signal in the liver that was transmitted to the brain via afferent nerves which, in turn, led to an increase in the secretion of both epinephrine and glucagon. As expected, this increase in counterregulatory hormone secretion caused a 2.4-fold rise in HGP, despite insulin levels that were ~ 400 µU/mL at the liver.