A proof of concept study was conducted to investigate the safety and tolerability of a novel oral
glucokinase activator, LY2599506, during multiple dose administration to healthy volunteers and subjects with
Type 2 diabetes mellitus (T2DM). To analyze the study data, a previously established semi-mechanistic integrated
glucose-
insulin model was extended to include characterization of
glucagon dynamics. The model captured endogenous
glucose and
insulin dynamics, including the amplifying effects of
glucose on
insulin production and of
insulin on
glucose elimination, as well as the inhibitory influence of
glucose and
insulin on hepatic
glucose production. The hepatic
glucose production in the model was increased by
glucagon and
glucagon production was inhibited by elevated
glucose concentrations. The contribution of exogenous factors to glycemic response, such as ingestion of
carbohydrates in meals, was also included in the model. The effect of LY2599506 on
glucose homeostasis in subjects with T2DM was investigated by linking a one-compartment, pharmacokinetic model to the semi-mechanistic, integrated
glucose-
insulin-
glucagon system.
Drug effects were included on pancreatic insulin secretion and hepatic
glucose production. The relationships between LY2599506,
glucose,
insulin, and
glucagon concentrations were described quantitatively and consequently, the improved understanding of the
drug-response system could be used to support further clinical study planning during
drug development, such as dose selection.