ArticleBritish journal of pharmacology2013
Small molecule glucokinase activators disturb lipid homeostasis and induce fatty liver in rodents: a warning for therapeutic applications in humans.
Article in British journal of pharmacology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 73 citations in OpenAlex.
- Lifestyle Intervention for Weight Loss and Cardiometabolic Changes in the Setting of Glucokinase Regulatory Protein Inhibition: Glucokinase Regulatory Protein-Leu446Pro Variant in Look AHEAD.Circulation. Cardiovascular genetics · 2016Trial
- Resetting the glucose sensor: dorzagliatin and the evolution of glucokinase activation in diabetes therapy.BMJ open diabetes research & care · 2026Review
- Glucokinase activity suppresses hepatic cholesterol synthesis and triglyceride accumulation: A new model for the effects of the GKRP P466L common human variant.Molecular metabolism · 2026Article
- Glucokinase activity suppresses hepatic cholesterol synthesis and triglyceride accumulation: A new model for the effects of the GKRP P466L common human variant.bioRxiv : the preprint server for biology · 2026Article
- Significant Association Between Glucokinase Regulatory Protein Variants and Genetic and Metabolic Diseases.Current issues in molecular biology · 2025Review
- Current Insight on the Role of Glucokinase and Glucokinase Regulatory Protein in Diabetes.Mini reviews in medicinal chemistry · 2024Review
- Review
- Insulin Regulation of Hepatic Lipid Homeostasis.Comprehensive Physiology · 2023Review
- A comprehensive map of human glucokinase variant activity.Genome biology · 2023Article
- Glucokinase Inactivation Ameliorates Lipid Accumulation and Exerts Favorable Effects on Lipid Metabolism in Hepatocytes.International journal of molecular sciences · 2023Article
- Glucokinase regulatory protein: a balancing act between glucose and lipid metabolism in NAFLD.Frontiers in endocrinology · 2023Review
- A new class of drug in the diabetes toolbox.Nature medicine · 2022Article
- Article
- Multi-Tissue Acceleration of the Mitochondrial Phosphoenolpyruvate Cycle Improves Whole-Body Metabolic Health.Cell metabolism · 2020Article
- Human genetics as a model for target validation: finding new therapies for diabetes.Diabetologia · 2017Review
- Effects of a Novel Glucokinase Activator, HMS5552, on Glucose Metabolism in a Rat Model of Type 2 Diabetes Mellitus.Journal of diabetes research · 2017Article
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- Article
- Phosphorus ingestion improves oral glucose tolerance of healthy male subjects: a crossover experiment.Nutrition journal · 2015Article
- Article
Corrections and comments
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Authors and funding
18 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
background and purposeSmall-molecule glucokinase activators (GKAs) are currently being investigated as therapeutic options for the treatment of type 2 diabetes (T2D). Because liver overexpression of glucokinase is thought to be associated with altered lipid profiles, this study aimed at assessing the potential lipogenic risks linked to oral GKA administration. EXPERIMENTAL APPROACH: Nine GKA candidates were qualified for their ability to activate recombinant glucokinase and to stimulate glycogen synthesis in rat hepatocytes and insulin secretion in rat INS-1E cells. In vivo activity was monitored by plasma glucose and HbA1c measurements after oral administration in rodents. Risk-associated effects were assessed by measuring hepatic and plasma triglycerides and free fatty acids, as well as plasma aminotransferases, and alkaline phosphatase. KEY
resultsGKAs, while efficiently decreasing glycaemia in acute conditions and HbA1c levels after chronic administration in hyperglycemic db/db mice, were potent inducers of hepatic steatosis. This adverse outcome appeared as soon as 4 days after daily oral administration at pharmacological doses and was not transient. GKA treatment similarly increased hepatic triglycerides in diabetic and normoglycaemic rats, together with a pattern of metabolic phenotypes including different combinations of increased plasma triglycerides, free fatty acids, alanine and aspartyl aminotransferases, and alkaline phosphatase. GKAs belonging to three distinct structural families induced hepatic steatosis in db/db mice, arguing in favour of a target-mediated, rather than a chemical class-mediated, effect. CONCLUSION AND IMPLICATIONS: Given the risks associated with fatty liver disease in the general population and furthermore in patients with T2D, these findings represent a serious warning for the use of GKAs in humans. LINKED ARTICLE: This article is commented on by Rees and Gloyn, pp. 335-338 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2012.02201.x.
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