Discovery could prevent insulin resistance and have significant benefits for people with type 2 diabetes

In a potential game changer for patients with type 2 diabetes, a team of researchers from the Diabetes, Obesity and Metabolism Institute (DOMI) of the Icahn School of Medicine at Mount Sinai has identified a therapeutic target for the preservation and regeneration of beta cells ( -cells); cells in the pancreas that produce and distribute insulin. The discovery could prevent insulin resistance and thus have significant benefits for millions of people around the world. The results of the study were published in nature communication in July.

All major forms of diabetes are caused by insufficient -cell mass. When blood glucose levels rise in the body, such as in response to a high-fat diet, cells respond by producing and releasing more insulin to control blood glucose levels. But prolonged high blood glucose, known as hyperglycemia, can decrease the ability of cells to produce and secrete insulin. This results in a vicious cycle of ever-increasing glucose levels and ever-decreasing β-cell function, leading to β-cell death -; a phenomenon known as glucose toxicity. Conservation and regeneration of cells is thus a therapeutic target for diabetes.

The Mount Sinai research team has identified a molecular mechanism that appears to be involved in the maintenance and regeneration of cells using carbohydrate response element binding protein (ChREBP). The researchers showed that the production of a hyperactive isoform of this protein, ChREBPβ, is required to produce more cells in response to an increased demand for insulin in the body as a result of a high-fat diet or significant exposure to glucose. However, prolonged, elevated glucose metabolism can result in a vicious cycle in which ChREBPβ is overproduced, resulting in glucose toxicity in the cells and their subsequent death.

The research team found that it was possible to counteract the effects of ChREBPβ and their observed β-cell death by increasing the expression of an alternative form of the protein, ChREBP⍺, or by nuclear factor erythroid factor 2 (Nrf2). – to activate; a protein that protects cells from oxidative damage – in mice and human -cells, preserving β-cell mass.

ChREBP was traditionally thought to be a mediator of glucose toxicity, but we found that one form, ChREBPa, appeared to protect beta cells. Using tools we developed to independently investigate these isoforms, we found that ChREBPβ plays a key role in the gradual destruction of β cells. So we think it’s a marker of hyperglycemia and glucose toxicity.”

Donald Scott, PhD, professor of medicine (endocrinology, diabetes, and bone disease) at Icahn Mount Sinai, and a member of DOMI and of the Mindich Child Health and Development Institute

“In addition, we found that if you remove ChREBPβ or counteract it pharmacologically, you can reduce the effects of glucose toxicity and protect those cells. This exciting discovery creates an opportunity to develop therapeutic agents that target this molecular mechanism, the production of ChREBPβ effectively blocking, thereby preserving -cell mass. 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 -cell mass, which has a significant impact would have on outcomes and quality of life.”

Based on these findings, the research team is interested in investigating the impact of ChREBPβ overproduction in patients with type 1 diabetes, which differs from type 2 diabetes in that the pancreas does not produce insulin. The team is also interested in screening for more molecular mechanisms that have the potential to block ChREBPβ production and thus prevent glucose toxicity and subsequent death of cells. Furthermore, there are plans to investigate whether the vicious circle observed in this study extends to other ChREBPβ-expressing tissues, such as kidney, liver and adipose tissue, or body fat, thus contributing to diabetic complications.

“This study was made possible by bringing together the full breadth of DOMI expertise in areas such as RNA sequencing, three-dimensional imaging and bioinformatics. Our findings provide a basis for preserving existing -cell mass and for developing new ones. therapeutic approaches that have the potential to successfully prevent thousands of type 2 diabetes patients from transitioning to insulin dependence,” said lead author Liora S. Katz, PhD, assistant professor of medicine at Icahn Mount Sinai, the study’s lead author.


Mount Sinai Health System

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