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Lessons from glucokinase activators: the problem of declining efficacy.
1Newcastle University, Institute of Cellular Medicine, The Medical School , Newcastle upon Tyne, NE2 4HH , UK +44 1912087033 ; loranne.agius@ncl.ac.uk.
Expert Opinion on Therapeutic Patents
|October 1, 2014
Summary
Glucokinase activators show promise for type 2 diabetes by improving glucose control. However, chronic use may reduce effectiveness due to adaptive cellular changes impacting glucose metabolism.
Area of Science:
- Biochemistry
- Metabolic Diseases
- Pharmacology
Background:
- Glucokinase (Gck) activators (GKAs) were investigated for type 2 diabetes therapy.
- GKAs effectively lowered blood glucose in preclinical and short-term human studies.
- Clinical trials faced challenges due to declining efficacy and adverse effects like hypertriglyceridemia.
Purpose of the Study:
- To explore mechanisms behind declining efficacy of GKAs during chronic exposure.
- To investigate the role of intracellular phosphometabolite homeostasis in GKA tachyphylaxis.
- To identify potential strategies for improving GKA therapy and dietary interventions for type 2 diabetes.
Main Methods:
- Review of existing literature on GKA efficacy and mechanisms of tachyphylaxis.
- Analysis of adaptive cellular responses in hepatocytes to elevated glucose and GKA treatment.
- Hypothesizing the impact of phosphometabolite homeostasis on Gck and G6pc gene expression.
Main Results:
- Declining GKA efficacy during chronic exposure is a significant clinical challenge.
- Increased hepatic triglycerides and steatosis are potential, but not sole, causes for efficacy loss.
- Elevated glucose induces glucose 6-phosphatase (G6pc) and represses Gck, an adaptive metabolic response.
Conclusions:
- Perturbed phosphometabolite homeostasis by GKAs may enhance G6pc induction and Gck repression, explaining tachyphylaxis.
- Understanding intracellular phosphometabolite homeostasis is key to developing improved diabetes therapies.
- Further research is needed to optimize GKA drug therapies and dietary interventions for type 2 diabetes management.
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