All major forms of diabetes are caused by insufficient β-cell mass. When blood glucose levels rise in the body, such as in response to a high-fat diet, β cells respond by producing and releasing more insulin to bring blood glucose levels under control. But prolonged high blood glucose, known as hyperglycemia, can impair the ability of β 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. Thus, the maintenance and regeneration of β cells is a therapeutic goal for diabetes. The Mount Sinai research team found a molecular mechanism that appears to be involved in β-cell maintenance and regeneration involving carbohydrate response element binding protein (ChREBP). The researchers showed that the production of an overactive isoform of this protein, ChREBPβ, is necessary to produce more β cells in response to increased demand for insulin in the body due to a high-fat diet or significant exposure to glucose. However, prolonged, elevated glucose metabolism can lead to a vicious cycle in which ChREBPβ is overproduced, resulting in glucose toxicity to β-cells and their subsequent death. The research team found that it was possible to counteract the effects of ChREBPβ and the β-cell death they observed by increasing the 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 mouse and human β cells, thus preserving β-cell mass. “ChREBP has traditionally been thought to mediate glucose toxicity, but we observed that one form, ChREBPa, appeared to protect beta cells,” said Donald Scott, PhD, Professor of Medicine (Endocrinology, Diabetes and Bone Diseases) at Icahn Mount Sinai. , and member of DOMI and The Mindich Child Health and Development Institute. “Using tools we developed that allowed us to investigate these isoforms independently, we found that ChREBPβ plays a key role in the gradual destruction of β cells. So we think it’s an indicator of hyperglycemia and glucose toxicity.” “Furthermore, we found that if you remove ChREBPβ or fight it pharmacologically, you can reduce the effects of glucose toxicity and protect these cells. This exciting discovery creates an opportunity to develop therapeutic agents that target this molecular mechanism, effectively block ChREBPβ production, and thereby preserve β-cell mass. This would not only address the challenge that has driven diabetes research for years, but would 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 the 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 testing for more molecular mechanisms that have the potential to block ChREBPβ production and thus prevent glucose toxicity and subsequent β cell death. Additionally, there are plans to investigate whether the vicious cycle observed in this study occurs in other tissues where ChREBPβ is expressed, such as kidney, liver, and fat, or body fat, and thus may contribute to diabetic complications. “This study was made possible by combining the full range of DOMI’s expertise in areas such as RNA sequencing, 3D imaging and bioinformatics. Our findings provide the basis for preserving existing β-cell mass and for developing new therapeutic approaches that have the potential to successfully prevent thousands of patients with type 2 diabetes from developing insulin dependence,” said lead study author Liora S. Katz, PhD. Assistant Professor of Medicine at Icahn Mount Sinai. 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