Advances in targeting glycogen synthase kinase 3β for diabetes therapy

Abstract

Diabetes mellitus is a chronic metabolic disease characterized by hyperglycemia, which is caused by absolute or relative insulin deficiency in secretion and impaired insulin utilization. The newly added content is as follows: Diabetes mellitus is typically classified into two main types: type 1 diabetes (T1DM) and type 2 diabetes (T2DM). Type 1 diabetes primarily arises from the erroneous attack on pancreatic β-cells by the autoimmune system, resulting in β-cell damage and an absolute deficiency in insulin secretion. Genetic factors play a crucial role in its pathogenesis. In contrast, the pathogenesis of type 2 diabetes is more complex, mainly involving insulin resistance and relative insulin deficiency. Its onset is closely linked to both genetic factors and lifestyle, with high-calorie diets, insufficient physical activity, and obesity being significant risk factors.Despite the differences in their pathogenic mechanisms, insulin plays an extremely important role in both types of diabetes. Glycogen synthase kinase 3 (GSK3) is a highly conserved kinase that can activate glycogen synthase. As a key molecule in the glucose metabolic pathway, GSK3β is involved in various cellular activities and plays a crucial role in multiple diseases. Therefore, pharmacological inhibition of the activity and expression of GSK3β represents a promising approach for the treatment of diabetes. In recent years, GSK3 has been implicated in skeletal muscle insulin resistance in obese animal models and obese individuals with type 2 diabetes mellitus (T2DM). It leads to increased glucose production and decreased insulin sensitivity by inhibiting glycogen synthase. These findings indicate that studies utilizing specific and sensitive GSK3 inhibitors have provided new insights into the role of GSK3 in regulating the effect of insulin on glucose transport in muscles. However, diabetes therapeutic drugs targeting GSK3β directly have not yet been approved for marketing worldwide. Herein, we describe the role of GSK3β in diabetes, clarify the central role of GSK3β in cellular signaling pathways, and summarize GSK3β inhibitors for the treatment of diabetes. Finally, we hope that these latest research advances will facilitate the discovery of safe and effective GSK3β inhibitors for the treatment of diabetes.