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Published on: November 16, 2011
Characterization of a novel glucokinase activator in rat and mouse models
Min Lu1, Pingping Li1, Gautam Bandyopadhyay1
1Department of Medicine, University of California San Diego, La Jolla, California, United States of America.
Abstract:
Glucokinase (GK) is a hexokinase isozyme that catalyzes the phosphorylation of glucose to glucose-6-phosphate. Glucokinase activators are being investigated as potential diabetes therapies because of their effects on hepatic glucose output and/or insulin secretion. Here, we have examined the efficacy and mechanisms of action of a novel glucokinase activator, GKA23. In vitro, GKA23 increased the affinity of rat and mouse glucokinase for glucose, and increased glucose uptake in primary rat hepatocytes. In vivo, GKA23 treatment improved glucose homeostasis in rats by enhancing beta cell insulin secretion and suppressing hepatic glucose production. Sub-chronic GKA23 treatment of mice fed a high-fat diet resulted in improved glucose homeostasis and lipid profile.
Insights
A novel glucokinase activator, GKA23, effectively improved glucose homeostasis. This diabetes therapy candidate enhanced insulin secretion and reduced glucose production in preclinical models.
Area of Science:
- Biochemistry
- Endocrinology
- Pharmacology
Background:
- Glucokinase (GK) is crucial for glucose metabolism.
- GK activators are explored for diabetes treatment.
- Understanding GK activator mechanisms is vital.
Purpose of the Study:
- To evaluate the efficacy and mechanism of a novel GK activator, GKA23.
- To assess GKA23's impact on glucose homeostasis and related pathways.
- To investigate GKA23's effects in preclinical models of metabolic dysfunction.
Main Methods:
- In vitro assays using purified rat and mouse glucokinase.
- Primary rat hepatocyte glucose uptake studies.
- In vivo studies in rats and mice, including high-fat diet models.
Main Results:
- GKA23 enhanced glucokinase's glucose affinity and hepatocyte glucose uptake.
- In vivo, GKA23 improved glucose homeostasis by boosting insulin secretion and reducing hepatic glucose production.
- Chronic GKA23 treatment in mice on a high-fat diet improved glucose and lipid profiles.
Conclusions:
- GKA23 demonstrates significant potential as a therapeutic agent for diabetes.
- The compound acts by modulating glucokinase activity to improve glucose control.
- GKA23 shows promise for managing metabolic disorders, including those associated with obesity.
