GSK-3 Inhibitors: Anti-Diabetic Treatment Associated with Cardiac Risk?

Excerpt

The therapeutic potential of glycogen synthase kinase-3 (GSK-3) inhibitors for treatment in diabetes was first recognized in the late 1990s. GSK-3 is a serine/threonine kinase that phosphorylates, and thereby, regulates the function of many metabolic, signaling and structural proteins. GSK-3 is constitutively active in the basal state of cells and is inhibited in response to a variety of hormones, growth factors and other mediators as a result of phosphorylation (Ser21 in the α-isoform and Ser9 in the β-isoform). Particularly, the functional role of GSK-3 in insulin signaling and glucose metabolism makes it a particularly intriguing candidate target for treatment of type 2 diabetes. Activated GSK-3 phosphorylates and thereby inactivates glycogen synthase, an enzyme involved in converting glucose to glycogen for storage. Insulin can relieve GSK-3-mediated inhibition on glycogen synthase by binding to its receptor and activating the PI3K / Akt signaling pathway. In adipose tissue of insulin-resistant obese rodent models [1] and skeletal muscle of obese type 2 diabetic patients [2] the activity and expression of GSK-3 have been reported to be elevated. Overexpression of human GSK-3 in skeletal muscle of mice results in impaired glucose tolerance and suppressed glycogen synthase activity and glycogen synthesis, further supporting a role for GSK-3 in type 2 diabetes [3]. Furthermore, overexpression of GSK-3 has been shown to attenuate insulin signaling due to phosphorylation and downregulation of insulin receptor substrate-1 [reviewed in [4]]. Therefore, it has been suggested that drugs inhibiting GSK-3 could mimic the ability of insulin to promote the conversion of glucose to glycogen, overcoming the resistance to insulin. Indeed, several studies with pre-diabetic and diabetic rodent models have shown that administration of GSK-3 inhibitors improved glucose tolerance and insulin sensitivity [reviewed in [5]]. These improvements were accompanied with elevated glycogen synthase activity in muscle and liver and increased liver glycogen accumulation. …