- New York, NY
- (August 4, 2022)
In a potential game changer for patients with type 2 diabetes, a team of researchers at the Diabetes, Obesity and Metabolism Institute (DOMI) at the Icahn School of Medicine at Mount Sinai has identified a therapeutic target for preserving and beta cell regeneration. (β 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 worldwide. The results of the study were published in Nature Communications in July.
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 control blood glucose levels. But prolonged high blood glucose, known as hyperglycemia, can affect the ability of β cells to produce and secrete insulin. This results in a vicious cycle of ever-increasing glucose levels and ever-increasing β-cell function, leading to β-cell death, a phenomenon known as glucose toxicity . Thus, β-cell preservation and regeneration is a therapeutic target for diabetes.
The Mount Sinai research team found a molecular mechanism that appears to be involved in β-cell preservation and regeneration involving the 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 β cells in response to an increased demand for insulin in the body due to a high-fat diet or a significant exposure to glucose. However, the prolonged increase in glucose metabolism can result in a vicious cycle in which ChREBPβ is overproduced, leading to glucose toxicity in 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 the nuclear factor- erythroid factor 2 (Nrf2). protein that protects cells from oxidative damage, in mice and human β-cells, thereby preserving β-cell mass.
“ChREBP was traditionally thought to be a mediator of 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 interrogate these isoforms independently, we found that ChREBPβ plays a key role in the gradual destruction of β-cells. We therefore believe that it is a marker of hyperglycemia and toxicity for glucose”.
“Furthermore, we discovered that if you knock out ChREBPβ or counteract it pharmacologically, you can mitigate 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 thus preserve β-cell mass.This would not only address the challenge that has driven diabetes research for years, but also prevent type 2 diabetes patients from becoming insulin-dependent patients 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 insulin. The team is also interested in searching for more molecular mechanisms that have the potential to block ChREBPβ production and thereby prevent glucose toxicity and subsequent β-cell death. In addition, there are plans to investigate whether the vicious cycle observed in this study occurs in other tissues in which ChREBPβ is expressed, such as kidney, liver, and adipose, or in the body, fat and therefore could contribute to diabetic complications.
“This study was made possible by bringing together all of DOMI’s expertise in areas such as RNA sequencing, three-dimensional imaging and bioinformatics. Our findings provide a basis for preserving existing β-cell mass and for developing new approaches therapeutics that have the potential to successfully prevent thousands of patients with type 2 diabetes from progressing to insulin dependence,” said lead study author Liora S. Katz, PhD. Adjunct Professor of Medicine at Icahn Mount Sinai.
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Mount Sinai Health System is one of the largest academic medical systems in the New York metropolitan area, with more than 43,000 employees working in eight hospitals, more than 400 outpatient offices, nearly 300 laboratories, a school of nursing and a leading school of medicine and postgraduate education. Mount Sinai advances health for all people, everywhere, by taking on the most complex health challenges of our time: discovering and applying new scientific knowledge and insights; develop safer and more effective treatments; educate the next generation of medical leaders and innovators; and support local communities by providing high quality care to all who need it.
Through the integration of its hospitals, laboratories and schools, Mount Sinai offers comprehensive health care solutions from birth to geriatrics, leveraging innovative approaches such as artificial intelligence and informatics while maintaining the medical and emotional needs of patients at the center of all treatment. The Health System includes approximately 7,300 primary care and specialty doctors; 13 joint venture ambulatory surgery centers in the five boroughs of New York City, Westchester, Long Island and Florida; and more than 30 affiliated community health centers. We are consistently ranked by US News & World Report’s Best Hospitals, receiving high “Letter of Honor” status, and are highly ranked: #1 in Geriatrics and Top 20 in Cardiology/Cardiac Surgery, Diabetes/Endocrinology, Gastroenterology /gastrointestinal surgery, neurology. /Neurosurgery, Orthopedics, Pneumology/Pulmonary surgery, Rehabilitation and Urology. The New York Eye and Ear Infirmary of Mount Sinai ranks #12 in ophthalmology. US News & World Report’s “Best Children’s Hospitals” ranks Mount Sinai Kravis Children’s Hospital among the nation’s best in 4 out of 10 pediatric specialties. The Icahn School of Medicine at Mount Sinai is one of only three medical schools to be distinguished by multiple metrics: it is consistently ranked in the top 20 by US News & World Report’s “Best Medical Schools,” aligned with a US News & World Report. “Honor Roll” hospital and top 20 in the nation for National Institutes of Health funding and top 5 in the nation for numerous areas of basic and clinical research. Newsweek’s “World’s Best Smart Hospitals” ranks Mount Sinai Hospital as #1 in New York and in the top five in the world, and Mount Sinai Morningside in the top 20 in the world.
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