A study led by researchers from the Icahn School of Medicine at Mount Sinai has homed in on a newly discovered molecular mechanism that could prevent insulin resistance in type 2 diabetics. The research indicates disrupting the expression of a certain protein could protect beta cells and prevent patients from becoming insulin resistant.
Type 2 diabetes can develop when insulin-producing beta cells in the pancreas become dysfunctional, often following long-term high blood glucose levels. Eventually, those crucial beta cells begin to die, with the body unable to effectively regenerate them.
The new research focused on a particular protein called ChREBP (carbohydrate response-element binding protein). This protein can be expressed in two forms: ChREBP-alpha and ChREBP-beta.
In the presence of high blood glucose, beta cells rely on ChREBP-beta to regenerate. But, in cases of type 2 diabetes, persistent levels of high blood glucose leads to over expression of ChREBP-beta which ultimately kills more beta cells than can be produced.
ChREBP-alpha, on the other hand, has been found to be somewhat protective from the damage caused by over expressed ChREBP-beta. These two forms of ChREBP work in tandem to preserve healthy beta cell function, and this new research investigated how that balance can be restored as a hypothetical treatment for type 2 diabetes.
Two methods were found that blocked the toxic effects of excessive ChREBP-beta activity. The first, and most obvious method, was artificially over-expressing ChREBP-alpha. But more interestingly, the researchers discovered the beneficial effects from over-expressing ChREBP-alpha came from the activation of another protein called nuclear factor-erythroid factor 2 (Nrf2).
Nrf2 protects cells from oxidative damage and there are several drugs designed to activate Nrf2 currently in early stages of human clinical trials. Donald Scott, a researcher working on the new study, says it’s possible these novel drugs could serve as future type 2 diabetes treatments.
“This exciting discovery creates an opportunity to develop therapeutic agents that target this molecular mechanism, effectively block ChREBPβ production, and thus preserve β-cell mass,” Scott said. “This would not only address the challenge that has driven diabetes research for years but also prevent patients with type 2 diabetes from becoming insulin dependent due to loss of β-cell mass, which would have a significant impact on outcomes and quality of life.”
It’s early days for the research, and this preliminary discovery can only really inform more targeted future studies. For example, the researchers do note Nrf2 activator compounds will likely need to be specifically targeted at beta cell tissue to avoid broader systemic side effects from a treatment.
But it certainly is an intriguing and promising new foundational pathway allowing new kinds of therapeutic approaches to be explored in the hopes of preventing type 2 diabetes patients from progressing to more severe forms of disease.
The new study was published in the journal Nature Communications.
Source: Mount Sinai