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. However, tools to quantify glucagon-induced C-peptide secretion (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 (T2D). Eight individuals without diabetes (3M, age=55±9 yrs, BMI=32±4 kg/m2) and 6 with T2D (1M, age=59±5 yrs, 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 Γs (static), and one proportional to glucagon rate of change, through parameter Γd (dynamic responsivity to the hormone). An index of total β-cell responsivity to glucagon, Γ, was also derived from Γs and Γd. Model estimated Γs and Γ were significantly higher in individuals without diabetes compared to T2D (p<0.05), while Γd was not. Our findings reveal notable differences in both static and total insulin secretory response to glucagon in people with diabetes as compared to those without diabetes.