Estimating hepatic glucokinase activity using a simple model of lactate kinetics

Area of Science:

• Biomedical Engineering
• Metabolic Research
• Endocrinology

Background:

• Glucokinase (GCK) is crucial for glucose sensing in pancreatic beta-cells and acts as a hepatic gatekeeper for glucose phosphorylation.
• GCK mutations are linked to maturity-onset diabetes of the young (MODY), and GCKR is a diabetes susceptibility locus.
• Understanding liver GCK activity in vivo is vital for studying hepatic glucose metabolism regulation and developing diabetes treatments.

Purpose of the Study:

• To introduce a novel kinetic model for estimating liver GCK activity and glycolysis rates in vivo.
• To extend the application of the frequently sampled intravenous glucose tolerance test (FSIGT) for assessing hepatic glucose metabolism.
• To provide insights into the physiological regulation of hepatic glucose metabolism through genetic and pharmacologic studies.

Main Methods:

• Developed a simple, linear, two-compartment kinetic model.
• Utilized lactate and glucose kinetics from the frequently sampled intravenous glucose tolerance test (FSIGT).
• Estimated liver GCK activity (K(GK)), glycolysis (K(12)), and whole-body fractional lactate clearance (K(01)) in 142 non-diabetic individuals.

Main Results:

• The kinetic model precisely estimated parameters K(GK), K(12), and K(01).
• Median estimates for model parameters were consistent with previously published values.
• The model demonstrated feasibility in a cohort from the Finland-United States Investigation of NIDDM Genetics study.

Conclusions:

• The novel lactate kinetics model successfully estimates key indices of hepatic glucose metabolism, including GCK activity and glycolysis rate.
• This approach expands the utility of the FSIGT protocol beyond whole-body glucose homeostasis.
• The model offers a valuable tool for in vivo assessment of hepatic glucose metabolism, relevant for diabetes research.