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.
The discovery of ways by which the risk of iatrogenic hypoglycemia can be reduced in
people with T1D is a priority. The proposed experiments will improve our understanding of
the mechanisms by which increased glycogen improves hypoglycemic counterregulation. If
hypoglycemia is reduced by increased glycogen, it will focus attention on the ways in
which liver glycogen levels can be normalized in people with T1D. This would be a
significant step forward in the ongoing effort to reduce the risk of iatrogenic
hypoglycemia in people with T1D.