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

A research team from the Diabetes, Obesity, and Metabolism Institute (DOMI) at the Icahn School of Medicine at Mount Sinai has identified a potential game changer for patients with type 2 diabetes and a therapeutic target for the maintenance and regeneration of beta cells (β- Cells) Cells in the pancreas that produce and distribute insulin. The discovery could prevent insulin resistance, bringing significant benefits to millions of people worldwide. The results of the study were published in nature communication in July.

All major forms of diabetes are caused by insufficient β-cell mass. When blood sugar levels in the body rise, for example in response to a high-fat diet, β-cells respond by producing and releasing more insulin to bring blood sugar levels under control. But persistently high blood sugar, known as hyperglycemia, can impair the ability of β-cells to produce and secrete insulin. This leads to a vicious cycle of ever-increasing glucose levels and ever-decreasing β-cell function, resulting in β-cell death -; a phenomenon known as glucose toxicity. Thus, maintenance and regeneration of β-cells is a therapeutic target for diabetes.

The Mount Sinai research team found a molecular mechanism that appears to be involved in β-cell maintenance and regeneration, involving the carbohydrate response element binding protein (ChREBP). The researchers showed that production of a hyperactive isoform of this protein, ChREBPβ, is necessary to produce more β-cells in response to an increased need for insulin in the body due to a high-fat diet or significant glucose exposure. However, prolonged, increased glucose metabolism can lead to a vicious cycle in which ChREBPβ is overproduced, leading to glucose toxicity in the β-cells and their subsequent death.

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

Traditionally, ChREBP was thought to be a mediator of glucose toxicity, but we found that one form, ChREBPa, appeared to protect beta cells. By using tools we developed that allowed us to interrogate these isoforms independently, we found that ChREBPβ plays a key role in the gradual destruction of β-cells. Therefore, we believe it is a marker for hyperglycemia and glucose toxicity.”

Donald Scott, PhD, Professor of Medicine (Endocrinology, Diabetes and Bone Diseases) at Icahn Mount Sinai and a member of DOMI and the Mindich Child Health and Development Institute

“Furthermore, we found that if you remove or pharmacologically counteract ChREBPβ, you can mitigate the effects of glucose toxicity and protect these cells. This would not only address the challenge that has driven diabetes research for years, but also prevent patients with Type 2 diabetes becomes insulin dependent due to the loss of β-cell mass, which would have a significant impact on outcomes and quality of life.”

Based on these findings, the research team is interested in investigating the effects 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 keen to look for additional molecular mechanisms that have the potential to block ChREBPβ production and thus prevent glucose toxicity and subsequent β-cell death. In addition, to investigate whether the vicious circle observed in this study occurs in other tissues where ChREBPβ is expressed, such as kidney, liver and fat or body, fat, and thus could contribute to diabetic complications.

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