Sorafenib decreases glycemia by impairing hepatic glucose metabolism

Area of Science:

• Biochemistry
• Pharmacology
• Endocrinology

Background:

• Sorafenib, a kinase inhibitor, has shown potential hypoglycemic effects in prior studies.
• The precise mechanism behind sorafenib's blood glucose-lowering action remains largely unexplored.
• Understanding this mechanism is crucial for optimizing its therapeutic use and managing potential side effects.

Purpose of the Study:

• To investigate the hypoglycemic effects of sorafenib in mouse models of type 2 diabetes and normal mice.
• To elucidate the molecular mechanisms underlying sorafenib's impact on blood glucose regulation.
• To explore the role of hepatic glucose metabolism and related signaling pathways.

Main Methods:

• A type 2 diabetes mouse model was established using a high-fat diet and streptozotocin (STZ).
• Glucose tolerance, insulin tolerance, and pyruvate tolerance tests were performed on mice treated with sorafenib.
• In vivo and in vitro experiments were conducted to analyze hepatic glucose metabolism signaling, focusing on the ERK/c-MYC pathway and gluconeogenic gene expression.

Main Results:

• Sorafenib significantly reduced blood glucose levels in both diabetic and normal mice, with a more pronounced effect in diabetic subjects.
• Diabetic mice treated with sorafenib demonstrated improved glucose and insulin tolerance.
• Sorafenib treatment led to a significant decrease in the expression of gluconeogenesis-related enzymes (PCK1, G6PC, PCB) by downregulating the ERK/c-MYC signaling pathway.

Conclusions:

• Sorafenib exerts hypoglycemic effects by inhibiting hepatic gluconeogenesis through the downregulation of key genes via the ERK/c-MYC pathway.
• The findings highlight the potential for sorafenib to impact glucose metabolism, particularly in type 2 diabetes.
• Close monitoring of blood glucose levels in patients with type 2 diabetes receiving sorafenib is recommended to mitigate the risk of hypoglycemia.