Impaired glucose tolerance arises out of impaired postprandial insulin secretion and delayed suppression of glucagon. These defects occur early and independently in the pathogenesis of prediabetes. Quantification of the contribution of α-cell dysfunction to glucose tolerance has been lacking because knowledge of glucagon kinetics in humans is limited. Therefore, in a series of experiments examining the interaction of glucagon suppression with insulin secretion we studied 51 nondiabetic subjects (age = 54 ± 13 yr, BMI = 28 ± 4 kg/m²). Glucose was infused to mimic the systemic appearance of an oral challenge. Somatostatin was used to inhibit endogenous hormone secretion. 120 min after the start of the experiment, glucagon was infused at 0.65 ng/kg/min. The rise in glucagon concentrations was used to estimate its kinetic parameters [volume of distribution (V_d), half-life (t_1/2), and clearance rate (CL)]. A single-exponential model provided the best fit for the data, and individualized kinetic parameters were estimated: V_d = 8.2 ± 2.7 L, t_1/2 = 4 ± 1.1 min, CL = 1.4 ± 0.33 L/min. Stepwise linear regression was used to correlate V_d with BMI and sex (R²_adj = 0.44), whereas CL similarly correlated with lean body mass or BSA (both R² = 0.28). This enabled the development of a population-based model using anthropometric characteristics to predict V_d and CL. These data demonstrate that it is feasible to derive glucagon kinetic parameters from anthropometric characteristics, thereby enabling quantitation of the rate of glucagon appearance in the systemic circulation in large populations.

NEW & NOTEWORTHY State-of-the-art measurement of insulin secretion in humans is accomplished by deconvolution of peripheral C-peptide concentrations using population-derived parameters of C-peptide kinetics. In contrast, knowledge of the kinetic parameters of glucagon in humans is lacking so that measurement of glucagon secretion to date is largely qualitative. This series of experiments enabled measurement of glucagon kinetics in 51 subjects, and subsequently, stepwise linear regression was used to correlate these parameters with anthropometric characteristics. This enabled the development of a population-based model using anthropometric characteristics to predict the volume of distribution and the rate of clearance. This is a necessary first step in the development of a model to quantitate of glucagon secretion and action (and its contribution to glucose tolerance) in large populations.