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Updated: Oct 15, 2025
Hyperinsulinemic-euglycemic Clamps in Conscious, Unrestrained Mice
Published on: November 16, 2011
Glucokinase activation leads to an unsustained hypoglycaemic effect with hepatic triglyceride accumulation in db/db
Shinichiro Kawata1, Akinobu Nakamura1, Hideaki Miyoshi2
1Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
Aim:
To investigate how subchronic administration of a glucokinase activator (GKA) results in attenuation of the hypoglycaemic effect in the diabetic condition.
Materials And Methods:
Six-week-old db/db mice were fed standard chow containing a GKA or the sodium-glucose cotransporter 2 inhibitor ipragliflozin for 1, 6, 14 or 28 days. We performed histological evaluation and gene expression analysis of the pancreatic islets and liver after each treatment and compared the results to those in untreated mice.
Results:
The unsustained hypoglycaemic effect of GKAs was reproduced in db/db mice in conjunction with significant hepatic fat accumulation. The initial reactions to treatment with the GKA in the liver were upregulation of the gene expression of carbohydrate response element-binding protein beta (Chrebp-b) and downregulation of phosphoenolpyruvate carboxykinase (Pepck) on day 1. Subsequently, the initial changes in Chrebp-b and Pepck disappeared and increases in the expression of genes involved in lipogenesis, including acetyl-CoA carboxylase and fatty acid synthase, were observed. There were no significant changes in the pancreatic β cells nor in hepatic insulin signalling.
Conclusions:
The GKA showed an unsustained hypoglycaemic effect and promoted hepatic fat accumulation in db/db mice. Dynamic changes in the expression of hepatic genes involved in lipogenesis and gluconeogenesis could affect the unsustained hypoglycaemic effect of the GKA despite no changes in pancreatic β-cell function and mass.
Insights
Glucokinase activators (GKAs) show a temporary blood sugar-lowering effect in diabetic mice, leading to liver fat buildup. Gene expression changes in the liver, not pancreas, likely cause this effect
Area of Science:
- Metabolism
- Pharmacology
- Diabetes Research
Background:
- Glucokinase activators (GKAs) are investigated for diabetes treatment.
- Understanding the long-term effects and limitations of GKAs is crucial.
Purpose of the Study:
- To investigate the attenuation of the hypoglycaemic effect of GKAs with subchronic administration.
- To explore the underlying mechanisms, including hepatic and pancreatic changes.
Main Methods:
- Subchronic administration of a GKA or ipragliflozin in db/db mice.
- Histological evaluation and gene expression analysis of pancreatic islets and liver.
- Comparison with untreated control groups.
Main Results:
- GKAs reproduced an unsustained hypoglycaemic effect and caused hepatic fat accumulation.
- Initial liver gene expression changes (Chrebp-b, Pepck) were transient.
- Upregulation of lipogenesis genes (acetyl-CoA carboxylase, fatty acid synthase) was observed.
- No significant changes in pancreatic beta cells or hepatic insulin signaling.
Conclusions:
- GKAs have an unsustained hypoglycaemic effect and promote hepatic fat accumulation.
- Dynamic hepatic gene expression changes in lipogenesis and gluconeogenesis may explain the transient effect.
- Pancreatic beta-cell function and mass remained unaffected.
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