C-peptide enhances glucagon secretion in response to hyperinsulinemia under euglycemic and hypoglycemic conditions

Abstract

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.

Keywords: Glucose metabolism; Metabolism.

Figure 1. Schematic representation of the metabolic studies.

Figure 2. Hormonal responses during the euglycemic (eugly) Pd1 and the hypoglycemic (hypo) Pd2.

Arterial insulin (A), hepatic sinusoidal insulin (B), C-peptide (C), epinephrine (D), norepinephrine (E), and cortisol (F). *P < 0.001 between treatments. Data were analyzed using 2-way repeated measures ANOVA. CPEP, C-peptide; Pd1, euglycemic period; Pd2, hypoglycemic period; SAL, saline.

Figure 3. Glucagon responses during the euglycemic Pd1 and the hypoglycemic Pd2.

Arterial (A), hepatic portal vein (C), and hepatic sinusoidal (E) plasma glucagon responses during the euglycemic Pd1 and the hypoglycemic Pd2. To the right of these respective graphs (B, D, and F) are the Δ AUC values during the final 90 minutes of Pd1 and Pd2. *P ≤ 0.05 between treatments. ^#P ≤ 0.10 between treatments. Time course data were analyzed using 2-way repeated measures ANOVA. Data for Δ AUC were analyzed using paired 1-way t test.

Figure 4. Glucoregulatory responses during the euglycemic Pd1 and the hypoglycemic Pd2.

Arterial plasma glucose (A), the exogenous glucose infusion rate (GIR; B), and the GIR AUC during the final 90 minutes of Pd2 (inset), net hepatic glucose balance (C), and AUC for net hepatic glucose balance during the final 90 minutes of Pd2 (D). *P ≤ 0.05 between treatments. ^#P = 0.06 between treatments. Time course data were analyzed using 2-way repeated measures ANOVA. AUC data were analyzed using paired 2-way t test.

Figure 5. Glucagon secretory responses during the euglycemic Pd1 and during the hypoglycemic Pd2.

Glucagon secretion (A) and the Δ AUC values (last 90 minutes) for glucagon secretion during Pd1 (B) and during Pd2 (C). *P ≤ 0.05 between treatments. Time course data were analyzed using 2-way repeated measures ANOVA. Data for Δ AUC were analyzed using paired 2-way t test.