Several studies have associated the presence of residual insulin secretion capability (also referred to as being
C-peptide positive) with lower risk of
insulin-induced
hypoglycemia in patients with
type 1 diabetes (T1D), although the reason is unclear. We tested the hypothesis that
C-peptide infusion would enhance
glucagon secretion in response to
hyperinsulinemia during euglycemic and
hypoglycemic conditions in dogs (5 male/4 female). After a 2-hour basal period, an intravenous (IV) infusion of
insulin was started, and
dextrose was infused to maintain euglycemia for 2 hours. At the same time, an IV infusion of either saline (SAL) or
C-peptide (
CPEP) was started. After this euglycemic period, the
insulin and SAL/
CPEP infusions were continued for another 2 hours, but the
glucose was allowed to fall to approximately 50 mg/dL. In response to euglycemic-
hyperinsulinemia,
glucagon secretion decreased in SAL but remained unchanged from the basal period in
CPEP condition. During
hypoglycemia,
glucagon secretion in
CPEP was 2 times higher than SAL, and this increased net hepatic
glucose output and reduced the amount of exogenous
glucose required to maintain glycemia. These data suggest that the presence of
C-peptide during IV
insulin infusion can preserve
glucagon secretion during euglycemia and enhance it during
hypoglycemia, which could explain why T1D patients with residual insulin secretion are less susceptible to
hypoglycemia.