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Correction of diabetic alterations by glucokinase
1Department of Biochemistry and Molecular Biology, School of Veterinary Medicine, Autonomous University of Barcelona, Spain.
Summary
Restoring liver glucokinase expression in diabetic mice normalized blood glucose and ketone bodies. This suggests glucokinase expression may be a novel strategy for managing hyperglycemia in diabetes.
Area of Science:
- Biochemistry
- Metabolic Diseases
- Molecular Endocrinology
Background:
- Hyperglycemia is a hallmark of diabetes mellitus, driven by reduced glucose uptake and increased hepatic glucose production.
- Glucokinase (GCK) plays a crucial role in liver glucose metabolism, but its gene expression is diminished in diabetic conditions.
- Low GCK expression impairs glucose utilization and contributes to the metabolic dysregulation seen in diabetes.
Purpose of the Study:
- To investigate whether restoring hepatic glucokinase expression in diabetic mice can ameliorate metabolic alterations.
- To assess the impact of P-enolpyruvate carboxykinase/glucokinase chimeric gene expression on glucose metabolism in a diabetic model.
Main Methods:
- Generation of transgenic mice expressing a chimeric gene encoding P-enolpyruvate carboxykinase and glucokinase.
- Induction of diabetes using streptozotocin in both transgenic and non-transgenic mice.
- Analysis of glucokinase mRNA and enzyme activity, glucose metabolites, gene expression related to gluconeogenesis and ketogenesis, and metabolite levels in liver and hepatocytes.
Main Results:
- Streptozotocin-treated transgenic mice exhibited significantly elevated hepatic glucokinase mRNA and activity compared to non-transgenic controls.
- Restored GCK expression led to increased glucose 6-phosphate and glycogen levels, enhanced pyruvate kinase activity, and increased lactate production in the liver.
- Normalization of gluconeogenic and ketogenic gene expression, glucose and ketone body production by hepatocytes, blood glucose, ketone bodies, triglycerides, and free fatty acids was observed.
Conclusions:
- Expression of glucokinase in the liver of diabetic mice effectively induces glycolysis while suppressing gluconeogenesis and ketogenesis.
- This metabolic reprogramming normalized hyperglycemia and associated metabolic disturbances, even in the absence of insulin.
- Restoring hepatic glucokinase expression represents a promising therapeutic avenue for managing hyperglycemia in diabetes mellitus.