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Inhibition of Foxo1 function is associated with improved fasting glycemia in diabetic mice
Jennifer Altomonte1, Anja Richter, Sonal Harbaran
1Carl C. Icahn Institute for Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.
Abstract:
Excessive hepatic glucose production is a contributing factor to fasting hyperglycemia in diabetes. Insulin suppresses hepatic glucose production by inhibiting the expression of two gluconeogenic enzymes, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G-6-Pase). The forkhead transcription factor Foxo1 has been implicated as a mediator of insulin action in regulating hepatic gluconeogenesis, and a Foxo1 mutant (Foxo1-Delta256), devoid of its carboxyl domain, has been shown to interfere with Foxo1 function and inhibit gluconeogenic gene expression in cultured cells. To study the effect of Foxo1-Delta256 on glucose metabolism in animals, the Foxo1-Delta256 cDNA was delivered to the livers of mice by adenovirus-mediated gene transfer. Hepatic Foxo1-Delta256 production resulted in inhibition of gluconeogenic activity, as evidenced by reduced PEPCK and G-6-Pase expression in the liver. Mice treated with the Foxo1-Delta256 vector exhibited significantly reduced blood glucose levels. In contrast, blood glucose levels in control vector-treated animals remained unchanged, which coincided with the lack of alterations in the expression levels of PEPCK and G-6-Pase. When tested in diabetic db/db mice, hepatic production of Foxo1-Delta256 was shown to reduce fasting hyperglycemia. Furthermore, we showed that hepatic Foxo1 expression was deregulated as a result of insulin resistance in diabetic mice and that Foxo1-Delta256 interfered with Foxo1 function via competitive binding to target promoters. These results demonstrated that functional inhibition of Foxo1, caused by hepatic expression of its mutant, is associated with reduced hepatic gluconeogenic activity and improved fasting glycemia in diabetic mice.
Insights
A novel mutant form of the forkhead transcription factor Foxo1 (Foxo1-Delta256), when delivered to mouse livers, reduced glucose production and fasting hyperglycemia in diabetic mice. This suggests a potential therapeutic strategy for managing diabetes by inhibiting gluconeogenic gene expression.
Area of Science:
- Metabolic regulation
- Molecular endocrinology
- Gene expression control
Background:
- Excessive hepatic glucose production contributes to hyperglycemia in diabetes.
- Insulin normally suppresses gluconeogenic enzymes PEPCK and G-6-Pase.
- The transcription factor Foxo1 mediates insulin's regulation of hepatic gluconeogenesis.
Purpose of the Study:
- To investigate the in vivo effects of a dominant-negative Foxo1 mutant (Foxo1-Delta256) on glucose metabolism.
- To determine if inhibiting Foxo1 function can reduce hepatic glucose production and improve hyperglycemia in diabetic models.
Main Methods:
- Adenovirus-mediated gene transfer of Foxo1-Delta256 cDNA into mouse livers.
- Measurement of gluconeogenic enzyme expression (PEPCK, G-6-Pase) and blood glucose levels.
- Testing in both non-diabetic and diabetic (db/db) mouse models.
Main Results:
- Hepatic expression of Foxo1-Delta256 inhibited PEPCK and G-6-Pase expression.
- Mice treated with Foxo1-Delta256 showed significantly reduced blood glucose levels.
- Foxo1-Delta256 reduced fasting hyperglycemia in diabetic db/db mice by interfering with Foxo1 function.
Conclusions:
- Functional inhibition of Foxo1 in the liver reduces gluconeogenic activity.
- Hepatic expression of Foxo1-Delta256 improves fasting glycemia in diabetic mice.
- This approach offers a potential strategy for treating hyperglycemia associated with diabetes.