title: Estimating hepatic glucokinase activity using a simple model of lactate kinetics.
abstract: OBJECTIVE
  Glucokinase (GCK) acts as a component of the "glucose sensor" in pancreatic β-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.
  
  
  METHODS
  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(GK)), glycolysis (K(12)), and whole body fractional lactate clearance (K(01)). RESULTS 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(GK), K(12), and K(01) were precisely estimated. Median model parameter estimates were consistent with previously published values.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Darko
authors.initials: D
authors.lastname: Stefanovski
authors.forename: Jang H
authors.initials: JH
authors.lastname: Youn
authors.forename: Matthew
authors.initials: M
authors.lastname: Rees
authors.forename: Richard M
authors.initials: RM
authors.lastname: Watanabe
authors.forename: Marilyn
authors.initials: M
authors.lastname: Ader
authors.forename: Viorica
authors.initials: V
authors.lastname: Ionut
authors.forename: Anne U
authors.initials: AU
authors.lastname: Jackson
authors.forename: Michael
authors.initials: M
authors.lastname: Boehnke
authors.forename: Francis S
authors.initials: FS
authors.lastname: Collins
authors.forename: Richard N
authors.initials: RN
authors.lastname: Bergman
mesh_terms: D000818:Animals; D005941:Glucokinase / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006019:Glycolysis / Q000502:physiology; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism*; D008099:Liver / Q000201:enzymology*; D008962:Models, Theoretical
chemical_list: D019344:Lactic Acid; D005941:Glucokinase