Estimating hepatic glucokinase activity using a simple model of lactate kinetics

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.

RESEARCH DESIGN AND 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 (K₁₂), and whole body fractional lactate clearance (K₀₁).

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, K₁₂, and K₀₁ 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.Liver glucokinase (GCK) is rate limiting for the phosphorylation rate of glucose and is an important determinant of glucose tolerance in vivo. It has become increasingly clear that it is important to assess the activity of hepatic GCK in vivo in humans as a key to observing changes in liver glucose phosphorylation. A novel group of GCK activators has been introduced and has been shown to reduce the blood glucose level after chronic administration, thus positioning them as possible candidates for treatment of diabetes (1). Additionally, a common variant in GCK regulatory protein (GKRP) (P446 L) has been shown to be associated with reduced fasting and 2-h glucose, elevation of triglycerides, and reduced risk of type 2 diabetes (T2D), presumably by altering the ability of the liver to adapt to hyperglycemia (2). Rare mutations in GCKR have also been identified in individuals with very high triglyceride levels (3). Furthermore, we have shown that the incretin analog exenatide acts to enhance liver glucose uptake, and this may reflect altered GKRP and/or GCK activity (4).It is impractical to estimate hepatic GCK activity directly in large populations of subjects because that would require liver biopsy. Thus, for genetic studies, there is a need to complement genotype information with simpler phenotyping to evaluate the importance of specific mutations for function. Here we introduce a novel approach for estimating GCK activity in vivo. The advantage of the approach is that it exploits clinical tests to extract information regarding glucose phosphorylation in the liver. Our approach uses blood samples taken during the frequently sampled intravenous glucose tolerance test (FSIGT), which previously has been widely performed to estimate insulin sensitivity, insulin response, β-cell function (disposition index [DI]), insulin clearance rate, and glucose effectiveness (5). FSIGTs were previously applied to a subset of the participants of the Finland–United States Investigation of NIDDM Genetics (FUSION) study of T2D genetics (6), but estimates of glucose phosphorylation have not been previously attempted.The idea behind our method to estimate liver glucose phosphorylation is as follows. During acute hyperglycemia, after intravenous glucose injection, much of the acute glucose disposal is due to liver glucose uptake, which is primarily glucose dependent (7). Although the fate of the glucose could well include hepatic glycogen synthesis by the “direct pathway”, most of the glucose taken up by the liver likely traverses the glycolytic pathway. Because there is little acute energy need for increased oxidation of the resulting three-carbon moieties, much of the resultant pyruvate is converted, via lactate dehydrogenase (LDH), to lactate, which is then easily exported into the hepatic venous effluent or stored as glycogen via the gluconeogenic pathway. Thus, it is possible to develop a mathematical model of the liver response to glucose injection, based only on the phosphorylation of glucose in the liver, glycolysis, and the ultimate export of the three-carbon compounds to lactate followed by lactate clearance from the blood. It is the dynamic relationship between plasma glucose and lactate that we use in the model to estimate hepatic glucose phosphorylation, and therefore activity of the enzyme liver GCK.     

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