Insufficient ß – cell mass is the root cause of all major types of diabetes. When blood glucose levels in the body rise, such as in response to a high-fat diet, β cells respond by creating and releasing more insulin to manage blood glucose levels. Hyperglycemia, or persistently high blood glucose, may, however, hinder the ability of β cells to produce and secrete insulin. This leads to a vicious cycle of rising glucose levels and declining β–cell activity, which eventually ends in the death of β cells, a phenomenon known as glucose toxicity. Thus, β cell preservation and regeneration are therapeutic goals for diabetes. The Mount Sinai researchers discovered a molecular mechanism involving carbohydrate response-element binding protein (ChREBP) that seems to be involved in β-cell preservation and regeneration. The researchers discovered that a hyperactive isoform of this protein, ChREBPβ, is required for the body to create more β cells in response to an elevated demand for insulin caused by a high-fat diet or significant glucose exposure. The overproduction of ChREBPβ, which leads to glucose toxicity in the β cells and eventual β cell death, might occur as a consequence of prolonged, increased glucose metabolism. The research team found that it was possible to counteract the effects of ChREBPβ and the β-cell death they observed by increasing expression of an alternate 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, thus preserving β-cell mass. “Traditionally, ChREBP was thought to be a mediator of glucose toxicity, but we noticed one form, ChREBPa, appeared to protect beta cells,” said Donald Scott, Ph.D., a 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. “By using tools we developed that enabled us to interrogate these isoforms independently, we found that ChREBPβ plays a key role in the gradual destruction of β cells. Thus, we believe it is a marker of hyperglycemia and glucose toxicity.” “Moreover, we found that if you remove ChREBPβ or counteract it pharmacologically, you can mitigate the effects of glucose toxicity and protect those cells. 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. This would not only address the challenge that has driven diabetes research for years but also prevents 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.” Based on these findings, the research team is interested in exploring the impact of ChREBPβ overproduction in patients with type 1 diabetes, which differs from type 2 diabetes in that the pancreas does not produce any 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 the subsequent death of β cells. Furthermore, there are plans to investigate whether the vicious cycle that was observed in this study occurs in other tissues in which ChREBPβ is expressed, such as kidney, liver, and adipose, or body, fat, and thus might contribute 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 foundation for preserving existing β-cell mass and for developing new therapeutic approaches that have the potential to successfully prevent thousands of type 2 diabetes patients from progressing to insulin dependence,” said the study’s lead author Liora S. Katz, Ph.D., Assistant Professor of Medicine at Icahn Mount Sinai. Reference: “Maladaptive positive feedback production of ChREBPβ underlies glucotoxic β-cell failure” by Liora S. Katz, Gabriel Brill, Pili Zhang, Anil Kumar, Sharon Baumel-Alterzon, Lee B. Honig, Nicolás Gómez-Banoy, Esra Karakose, Marius Tanase, Ludivine Doridot, Alexandra Alvarsson, Bennett Davenport, Peng Wang, Luca Lambertini, Sarah A. Stanley, Dirk Homann, Andrew F. Stewart, James C. Lo, Mark A. Herman, Adolfo Garcia-Ocaña and Donald K. Scott, 30 July 2022, Nature Communications.DOI: 10.1038/s41467-022-32162-x
