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Assessing the potential of glucokinase activators in diabetes therapy

Key Points

  • The glucose-phosphorylating enzyme glucokinase has a crucial role in glucose homeostasis as 'glucose sensor' of the insulin-producing pancreatic β-cells and as a regulatory step in the conversion of glucose to glycogen, as well as in gluconeogenesis in the liver.

  • Autosomal dominant activating or inactivating mutations of glucokinase in humans and rodents cause hyperinsulinism and diabetes, respectively.

  • The activating point mutations are clustered at a location in the enzyme structure that is distinct from the substrate binding site, which suggests that glucokinase has an allosteric activator site.

  • These and other observations highlighted glucokinase as a potential drug target.

  • Glucokinase activators (GKAs) have been discovered recently that stimulate the enzyme allosterically by lowering its glucose S0.5 (the concentration of glucose that allows half-maximal activity of the enzyme) and Hill coefficient (nH) and increasing its catalytic constant (kcat).

  • At present, approximately 100 patents on low molecular-weight compounds with GKA characteristics have been disclosed by the pharmaceutical industry.

  • GKAs lower blood glucose levels in normal laboratory animals and humans by stimulating insulin release and enhancing hepatic glucose uptake.

  • GKAs lower blood glucose in animal models of type 2 diabetes and in humans with type 2 diabetes.

  • An assessment of the current status of basic and clinical GKA-related research indicates that this new class of anti-diabetic drugs shows promise for monotherapy or combination drug therapy of type 2 diabetes.

Abstract

Glucokinase, a unique isoform of the hexokinase enzymes, which are known to phosphorylate D-glucose and other hexoses, was identified during the past three to four decades as a new, promising drug target for type 2 diabetes. Glucokinase serves as a glucose sensor of the insulin-producing pancreatic islet β-cells, controls the conversion of glucose to glycogen in the liver and regulates hepatic glucose production. Guided by this fundamental knowledge, several glucokinase activators are now being developed, and have so far been shown to lower blood glucose in several animal models of type 2 diabetes and in initial trials in humans with the disease. Here, the scientific basis and current status of this new approach to diabetes therapy are discussed.

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Figure 1: Structural topology of selected activating glucokinase mutants and their effects on tryptophan fluorescence.
Figure 2: Glucose signalling within the glucokinase (GK) system.
Figure 3: Role of glucokinase (GK), glucose, fructose and the insulin:glucagon ratio in hepatic glucose metabolism and the effect of glucokinase activators.
Figure 4: Threshold computations for glucose-stimulated insulin release in hypoglycaemia caused by activating glucokinase mutations in humans.

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Acknowledgements

Supported by grants from the National Institutes of Health. Also supported by the Benjamin Rush Endowed Professorship of Biochemistry and Biophysics of the University of Pennsylvania School of Medicine (1984–2004) and financial and material contribution from Hoffman-La Roche (1991 to date). This review benefited immensely from numerous discussion of the topic with Joe Grimsby from Hoffman-La Roche.

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DATABASES

OMIM

MODY

PHHI

PNDM

Glossary

Hill coefficient

(nH). A measure of the sigmoidal agonist concentration dependency of processes based on cooperative mechanisms.

Glucose sensing

Signalling events initiated by macromolecules that bind glucose with binding constants in the range of physiologically relevant glucose concentrations of 2–10 mM. The result is usually a positive or negative effect on blood glucose levels.

Control strength

A concept of control theory that defines the impact of regulatory steps in metabolic pathways measured in terms of a unitless numerical value ranging from 0 to 1, with unity signifying the highest possible impact. This value is the ratio of the fractional change of the rate of the pathway and the fractional change of the rate of activity of an enzyme in the pathway. In β-cell metabolism, glucokinase has a control strength approaching unity.

Glucose threshold

A well-defined glucose concentration (for example, about 5 mM) at which a cell or a complex tissue (for example, the β-cell or the liver) responds physiologically by generating an effective signal (for example, increased insulin secretion) or changing the direction of glucose flux (for example, from net glucose production to net glucose uptake).

Relative activity index (AI) of glucokinase

A numerical expression incorporating the major kinetic constants of glucokinase and its mutants relative to the wild-type enzyme constants. AI = (kcat/glucose S0.5nH)×(2.5/(2.5 + ATP Km)) extrapolating to unity for wild-type glucokinase but >1.0 for activating and <1.0 for inactivating mutant enzymes.

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Matschinsky, F. Assessing the potential of glucokinase activators in diabetes therapy. Nat Rev Drug Discov 8, 399–416 (2009). https://doi.org/10.1038/nrd2850

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