A new C-peptide minimal model to assess β-cell responsiveness to glucagon in individuals with and without type 2 diabetes

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/m²] and six with T2D (1 M, age = 59 ± 5 yr, BMI = 35 ± 6 kg/m²) 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 (<i>P</i> < 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.<b>NEW & NOTEWORTHY</b> 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.