Abstract
Glucagon regulates its own secretion indirectly by stimulating β-cells to secrete insulin. This may serve as a compensatory mechanism to enhance β-cell function in individuals with, or predisposed to, type 2 diabetes (T2D). However, tools to quantify glucagon-induced C-peptide secretion rate (SR) are lacking. To bridge this gap, we developed a novel model-based method to provide quantitative indices of β-cell function in response to a glucagon bolus in individuals without and with type 2 diabetes. Eight individuals without diabetes [3 M, age = 55 ± 9 yr, body mass index (BMI) = 32 ± 4 kg/m(2)] and six with T2D (1 M, age = 59 ± 5 yr, BMI = 35 ± 6 kg/m(2)) underwent a 210-min hyperglycemic clamp (∼9 mmol/L). After 180 min, a 1 mg bolus of glucagon was administered over 1 min, and plasma glucagon and C-peptide concentrations were frequently measured over 30 min. We tested a battery of mathematical models and selected the best one based on standard criteria. The optimal model assumes that C-peptide SR is made up of two components, one proportional to the above basal glucagon, through parameter Γ(s) (static), and one proportional to glucagon rate of change, through parameter Γ(d) (dynamic responsivity to the hormone). An index of total β-cell responsivity to glucagon, Γ, was also derived from Γ(s) and Γ(d). The model estimated Γ(s) and Γ were significantly higher in individuals without diabetes compared with T2D (P < 0.05), whereas Γ(d) was not. Our findings reveal notable differences in both static and total insulin secretory response to glucagon in people with diabetes as compared with those without diabetes.NEW & NOTEWORTHY In this study, we propose a new mathematical model able to quantify C-peptide secretion and β-cell responsivity in response to a glucagon bolus in individuals without and with type 2 diabetes. We show that individuals with type 2 diabetes exhibit reduced β-cell responsivity to glucagon.