PUBLICATION
Conserved glucokinase regulation in zebrafish confirms therapeutic utility for pharmacologic modulation in diabetes
- Authors
- Schmitner, N., Thumer, S., Regele, D., Mayer, E., Bergerweiss, I., Helker, C., Stainier, D.Y.R., Meyer, D., Kimmel, R.A.
- ID
- ZDB-PUB-241124-12
- Date
- 2024
- Source
- Communications biology 7: 15571557 (Journal)
- Registered Authors
- Helker, Christian, Meyer, Dirk, Schmitner, Nicole, Stainier, Didier
- Keywords
- none
- MeSH Terms
-
- Diabetes Mellitus/drug therapy
- Diabetes Mellitus/genetics
- Diabetes Mellitus/metabolism
- Homeodomain Proteins
- Trans-Activators/genetics
- Trans-Activators/metabolism
- Disease Models, Animal
- Glucokinase*/genetics
- Glucokinase*/metabolism
- Liver/drug effects
- Liver/metabolism
- Hypoglycemic Agents/pharmacology
- Hypoglycemic Agents/therapeutic use
- Zebrafish*
- Animals
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- Animals, Genetically Modified
- PubMed
- 39580550 Full text @ Commun Biol
Citation
Schmitner, N., Thumer, S., Regele, D., Mayer, E., Bergerweiss, I., Helker, C., Stainier, D.Y.R., Meyer, D., Kimmel, R.A. (2024) Conserved glucokinase regulation in zebrafish confirms therapeutic utility for pharmacologic modulation in diabetes. Communications biology. 7:15571557.
Abstract
Glucokinase (GCK) is an essential enzyme for blood glucose homeostasis. Because of its importance in glucose metabolism, GCK is considered an attractive target for the development of antidiabetic drugs. However, a viable therapeutic agent has still to emerge, prompting efforts to improve understanding of the complex regulation and biological effects of GCK. Using the vertebrate organism zebrafish, an attractive model to study metabolic diseases and pharmacological responses, we dissected the complexities of gck regulation and unraveled effects of Gck modulation. We found that while gck expression in zebrafish islet cells is constitutive, gck expression in the liver is regulated by nutritional status, confirming similarity to the mammalian system. A combination of transgenic gck reporter lines and our diabetes model, the pdx1 mutant, allowed monitoring of gck expression under pathological conditions, revealing reduced gck expression and activity in the liver, which was unresponsive to nutrient stimulation, and decreased expression in the islet due to the reduced number of β-cells. Gck activation substantially ameliorated hyperglycemia in pdx1 mutants, without inducing oxidative stress responses in liver or islet. In-depth characterization of Gck activity and regulation at the cellular level in a whole-organism diabetes model clarifies its applicability as a drug target for therapies.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping