Effect of Liver Glycogen Content on Hypoglycemic Counterregulation

There is universal agreement that iatrogenic hypoglycemia is the single most prominent barrier to the safe, effective management of blood sugar in people with type 1 diabetes (T1D). The typical patient with T1D is required to "count" the number of carbohydrates they consume, estimate their own insulin doses and deliver this insulin subcutaneously to manage their own glycemic level. With these multiple degrees of freedom, it is not surprising that people with T1D frequently over-insulinize, thereby putting themselves at increased risk of developing hypoglycemia and its associated comorbidities.

As the glycemic level falls in people who are generally healthy (i.e., non-T1D), the first response is an abatement of insulin secretion. This reduction is then followed by an increase in the release of the counterregulatory hormones glucagon and epinephrine as glycemia continues to fall. Collectively, this hormonal milieu causes an increase in liver glycogen mobilization and gluconeogenesis such that hepatic glucose production (HGP) increases, thereby preventing serious hypoglycemia from occurring. However, people with T1D are unable to reduce their own insulin levels (due to subcutaneous insulin delivery) and often have a diminished capacity to secrete both glucagon and epinephrine during insulin-induced hypoglycemia. Predictably, the HGP response to hypoglycemia in people with T1D is a fraction of that seen in non-T1D controls, thereby increasing the depth and duration of the hypoglycemic episode.

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.

The finding that an acute increase in hepatic glycogen can augment hypoglycemic counterregulation has important clinical implications. However, despite the potential of this therapeutic avenue to reduce the risk of iatrogenic hypoglycemia, it remains unclear at this point if such a strategy translates to humans with T1D. Therefore, the overarching theme of this proposal is to determine whether an acute increase in liver glycogen content can augment the hepatic and hormonal responses to insulin-induced hypoglycemia in humans with and without T1D. Herein we are proposing studies that will advance the field, with the specific aims being as follows:

Specific Aim #1: To determine the effect of increasing liver glycogen deposition on insulin-induced hypoglycemic counterregulation in humans with and without T1D.