Resumen de Estimating Hepatic Glucokinase Activity Using a Simple Model of Lactate Kinetics
Darko Stefanovski, Jang Youn, Matthew Rees, Richard Watanabe, Marilyn Ader, Viorica Ionut, Anne Jackson, Michael Boehnke, Francis S. Collins, Richard N. Bergman
Glucokinase (GCK) acts as a component of the "glucose sensor" in pancreatic ß-cells and possibly in other tissues, including the brain. However, >99% of GCK in the body is located in the liver, where it serves as a "gatekeeper", determining the rate of hepatic glucose phosphorylation. Mutations in GCK are a cause of maturity-onset diabetes of the young (MODY), and GCKR, the regulator of GCK in the liver, is a diabetes susceptibility locus. In addition, several GCK activators are being studied as potential regulators of blood glucose. The ability to estimate liver GCK activity in vivo for genetic and pharmacologic studies may provide important physiologic insights into the regulation of hepatic glucose metabolism. Here we introduce a simple, linear, two-compartment kinetic model that exploits lactate and glucose kinetics observed during the frequently sampled intravenous glucose tolerance test (FSIGT) to estimate liver GCK activity (K^sub GK^), glycolysis (K^sub 12^), and whole body fractional lactate clearance (K^sub 01^). To test our working model of lactate, we used cross-sectional FSIGT data on 142 nondiabetic individuals chosen at random from the Finland-United States Investigation of NIDDM Genetics study cohort. Parameters K^sub GK^, K^sub 12^, and K^sub 01^ were precisely estimated. Median model parameter estimates were consistent with previously published values. This novel model of lactate kinetics extends the utility of the FSIGT protocol beyond whole-body glucose homeostasis by providing estimates for indices pertaining to hepatic glucose metabolism, including hepatic GCK activity and glycolysis rate.
