A New C-Peptide Minimal Model to Assess β-Cell Responsiveness to Glucagon in Individuals With and Without Type 2 Diabetes.

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. 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 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. Model estimated Γ_s and Γ were significantly higher in individuals without diabetes compared to T2D (p<0.05), while 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 to those without diabetes.