This research analyzes a new way of protecting insulin-secreting beta cells against the pathogenic action of glucolipotoxicity caused by excessive blood glucose and lipids. Glucolipotoxicity is one of the chief causative mechanisms of Type 2 Diabetes (T2D), a global disease that targets millions of individuals.
The study is centered on a protein, ChREBP, that controls beta cell glucose sensitivity. Prolonged high blood glucose activates ChREBP to induce the expression of another protein, ChREBPβ, causing beta cell stress, dysfunction, and death. To halt the harmful process is critical to maintain beta cells and slow the development of T2D.
The research presents a new class of small molecules, referred to as “molecular glues,” that promote augmented interaction of ChREBP with the 14-3-3 protein. In normal circumstances, 14-3-3 keeps ChREBP in the cytoplasm and, consequently, inhibits its capacity to trigger the activation of ChREBPβ production. In a heightened state of glucose, ChREBP moves to the nucleus, where it activates ChREBPβ, resulting in beta cell destruction. The molecular glues produced in the research enhance the interaction between ChREBP and 14-3-3, essentially keeping ChREBP confined in the cytoplasm and inhibiting the destructive chain of processes.
These compounds were tested in rat and human beta cells. The most effective ones were capable of inhibiting beta cell death, maintaining insulin production, and even improving the response of beta cells to glucose. This suggests that stabilizing ChREBP/14-3-3 interaction could be a new new treatment for T2D, aiming to maintain beta cells rather than just regulating blood sugar. Aside from diabetes, this molecular adhesion method may be applied to other diseases where regulation of protein interactions is hard to achieve. Through stabilizing essential protein complexes, this method provides a new method of controlling biological processes that were otherwise hard to treat with drugs. This finding opens up the possibility for the creation of new therapies for T2D and, potentially, other metabolic diseases.
