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In a conceivable groundbreaking development for individuals with type 2 diabetes, a group of experimenters at the Diabetes, Obesity, and Metabolism Institute (DOMI) at the Icahn School of Medicine has pinpointed a encouraging target for safeguarding and regenerating beta cells (β cells) in the pancreas, which are responsible for producing and releasing insulin. This invention holds the potential to combat insulin resistance, offering substantial benefits to trillions of people worldwide. This study published in the journal Nature Communications in July.
All major forms of diabetes stem from a deficiency in β-cell mass. Cells produce and release more insulin to control blood glucose levels in response to factors like a high-fat diet that cause blood glucose levels in response to factors like a high-fat diet that cause blood glucose levels to rise. However, prolonged high blood glucose levels, referred to as hyperglycemia, can impair β cells’ capacity to produce and release insulin. This sets off a damaging cycle characterized by escalating glucose levels and diminishing β-cell functionality, ultimately leading to β-cell demise, a phenomenon known as glucose toxicity. Consequently, preserving and rejuvenating β cells represents a crucial therapeutic objective in managing diabetes.
Our researchers identified a molecular mechanism that occurs to play a role in conserving and rejuvenating β cells, involving a protein called carbohydrate response-element binding protein (ChREBP). Their research theory revealed that the production of an overactive variant of this protein, ChREBPβ, is essential for generating more β cells in response to heightened insulin demand resulting from a high-fat diet or substantial glucose exposure. However, prolonged elevated glucose metabolism can trigger a detrimental cycle in which ChREBPβ is overproduced, leading to glucose toxicity in β cells and their eventual demise.
The researchers discovered that it is possible to counteract the adverse effects of ChREBPβ and the observed β-cell death by increasing the expression of an alternative form of the protein, ChREBP⍺, or by activating a protein called nuclear factor-erythroid factor 2 (Nrf2), which shields cells from oxidative harm, both in mice and human β cells. This approach helps to preserve β-cell mass.
“Traditionally, ChREBP contributed in glucose toxicity, but we noticed that one form, ChREBPa, seemed to protect beta cells,” explained Donald Scott, PhD, a Professor of Medicine (Endocrinology, Diabetes, and Bone Disease) and a member of DOMI and The Mindich Child Health and Development Institute. “By using specialized tools we developed to study these protein variants independently, we found that ChREBPβ plays a pivotal role in the gradual deterioration of β cells. Consequently, we consider it a marker of hyperglycemia and glucose toxicity.”
He added, “Furthermore, we found that if you remove ChREBPβ or counteract it with drugs, you can alleviate the effects of glucose toxicity and safeguard those cells. This exciting discovery offers an opportunity to develop therapeutic agents targeting this molecular mechanism, effectively suppressing ChREBPβ production, and thereby preserving β-cell mass. This not only addresses a long-standing challenge in diabetes research but also has the potential to prevent individuals with type 2 diabetes from becoming dependent on insulin due to β-cell mass loss, significantly improving their outcomes and quality of life.”
Given these findings, the research team is keen on investigating the implications of ChREBPβ overproduction in individuals with type 1 diabetes, which differs from type 2 diabetes as the pancreas does not produce insulin. The team also plans to explore other molecular mechanisms that could potentially inhibit ChREBPβ production, thereby preventing glucose toxicity and subsequent β-cell death. Additionally, they aim to examine whether the observed detrimental cycle in this study occurs in other tissues expressing ChREBPβ, such as the kidney, liver, and adipose tissues, potentially contributing to diabetic complications.
In conclusion, the research offers a potential breakthrough in the treatment of type 2 diabetes by targeting the preservation and regeneration of vital beta cells in the pancreas. Identifying the role of ChREBPβ and its counteraction through ChREBP⍺ and Nrf2 activation provides a promising avenue for future therapeutic interventions.
This discovery holds the promise of preventing insulin resistance and improving the quality of life for millions of individuals worldwide living with diabetes. Furthermore, the study’s interdisciplinary approach highlights the importance of collaborative efforts in unravelling complex medical challenges, offering hope for more effective treatments and outcomes in diabetes management. Overall, these findings mark a significant step toward transforming the landscape of diabetes care and treatment.
