Integrated Glucagon Model for Estimation of Alpha-cell Responsivity to Glucose and Amino Acids During Graded Glucose Infusion

Pancreatic α-cells secrete glucagon. The glucagon secretion rate (GSR) increases when plasma glucose decreases; conversely, GSR decreases when glucose rises. In addition, amino acids (AA) stimulate GSR. Impaired GSR suppression by glucose contributes to postprandial hyperglycemia in individuals with impaired glucose tolerance, obesity, and type 2 diabetes (T2D). However, the current method to assess α-cell responsivity to glucose, ignores the contribution of AA and is a two-step approach with some limitations. To address this, we developed a model-based method to quantify α-cell responsivity to glucose during a Graded Glucose Infusion, in the presence and absence of AA. A total of 52 subjects were studied. Thirty-seven subjects from Study 1 (13M, age=54±10 years, BMI=30±5 kg/m²) were studied once. Fifteen subjects (4M, age=47±11 years, BMI=28±4 kg/m²) from Study 2 were studied twice: once with saline and once with an AA infusion (Clinisol 15%, 0.003 mL/kg/min). Plasma glucagon, glucose and AA concentrations were measured over 240 minutes. We tested several mathematical models of GSR, and the best one was selected using standard criteria. The optimal model describes GSR as an exponential decay driven by delayed plasma glucose concentration and modulated by AA. The model provides an index of α-cell responsivity, G50, i.e. the glucose increase required to suppress GSR by 50%. AA infusion increased G50 compared to the saline infusion. This model-based approach provides an index of α-cell responsiveness under both physiological and AA-stimulated conditions. Its use may help in the early detection of α-cell dysfunction in people at risk of developing T2D.