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An experimental compound reduced the complications of type 1 and type 2 diabetes in mice—not by lowering blood sugar—but by fighting the consequences of cell death, inflammation, and organ damage.
The study, published online on November 24 in the journal Science Translational Medicine, reports that a new class of compounds blocks the ability of a protein called RAGE to transmit inflammatory signals that can harm the heart and kidneys of diabetic patients. , And slow down the healing of diabetic wounds.
The result revolves around the body's immune system, which recognizes and destroys invading bacteria and viruses. The activation of this system can cause inflammation, swelling, and pain. These reactions are caused by immune cells entering the site of infection or injury. Many diseases, including diabetes, involve dislocation inflammation of damaged tissue.
Experiments conducted in human cells and mouse models found that the main research compound RAGE229 significantly reduced the short-term and long-term complications of diabetes.
"Our research results establish the molecular framework of RAGE229 as the basis for a new method targeting the effects of intracellular RAGE to combat diabetic tissue damage," said lead research author Ann Marie Schmidt, Ph.D., Iven Young, Professor of Endocrinology at New York University's Grossman College medicine. "Through further improvements, RAGE229 and its descendants have great potential to fill the gap in treatment, including most drugs currently only effective for type 2 diabetes."
The larger, central structure is the glomerulus in the mouse kidney, which is known to be damaged by diabetes, as can be seen from the scar tissue stained purple. The authors of the study showed that a compound RAGE229 can reduce the damage to the glomerulus and surrounding structures in diabetic mice.
Image: Reprinted with permission from Manigrasso et al., Science Translational Medicine, November 24, 2021.
Most narratives about diabetes say that type 2 diabetes’s diet and age or genetic differences in type 1 diabetes reduce the action or production of the insulin hormone, which controls blood sugar levels after meals and provides energy for the body. Although high blood sugar can cause inflammatory damage, past work has also shown that new drug candidates can target the mechanisms by which two types of diabetes occur later.
In particular, high blood sugar will produce more charged particles, which can tear cellular components such as DNA. This kills the cells, which fall apart and spill their contents, including molecular patterns or DAMPS associated with damage. According to the authors, this "dangerous molecule" informs the body that tissues are under stress, in some cases by activating RAGE. When DAMP is docked with RAGE on the outer surface of the cell, it changes the shape of the receptor and transmits information to the inner compartment of the cell, the cytoplasm. Dr. Schmidt and his colleagues have previously shown that the RAGE cytoplasmic "tail" (ctRAGE) interacts with a protein called DIAPH1 to transmit such messages and ultimately activate inflammation genes.
The current research team screened through a library of 59,000 compounds and finally developed RAGE229, which is the best drug candidate that interferes with the interaction of DIAPH1:ctRAGE. Using a test that measures inflammation in mice through paw swelling on a scale of 1 to 5, the team showed that mice treated with RAGE229 had a significantly lower inflammation score of 2.5, while in mice given inert solvent, the inflammation score was 3.3, also called a vehicle, used for comparison.
Other experiments reflect an increased risk of heart attacks in diabetic patients, partly due to higher levels of inflammation. In male mice with type 1 diabetes and a temporary blockage of coronary arteries that simulate a heart attack, the researchers found that in mice treated with RAGE229, the number of myocardium (infarct volume) downstream of the blockage was 28%, compared with 28% Bottom, 38% of mice treated with vehicle.
The team next incorporated the RAGE229 molecule into mouse food because dietary intake can better measure its ability to reverse long-term complications such as diabetic wounds. Hyperglycemia and related inflammation have been shown to interfere with the cells that produce scar tissue to close the wound. The researchers found that in male type 2 diabetic mice treated with RAGE229, the percentage of wound closure after 21 days was 90%, while that of mice treated with vehicle was 65%. As shown when comparing their tissues under a microscope, the healing of male and female mice treated with RAGE229 was also significantly better than that of vehicle-treated mice.
The research team also found that through a variety of measures, male and female type 1 or type 2 diabetic mice fed RAGE229 diet had significantly lower kidney damage than mice fed the control diet, including reducing inflammation-driven mesangial sclerosis-protein accumulation The ability of the organ to properly filter waste from the blood is reduced.
"If RAGE229 enters human clinical trials, the RAGE229 used in our research will not be the recommended version," said Dr. Schmidt. "We continue to actively synthesize and test new compounds and chemical modifications of RAGE229. These new molecules are expected to produce final drug candidates with the best potency in the foreseeable future."
Together with Dr. Schmidt and the first study author Michaele Manigrasso, the authors from the Diabetes Research Project and the Department of Endocrinology, Diabetes and Metabolism are Nosirudeen Quadri, Lander Egaña-Gorroño, Laura Frye and Ravichandran Ramasamy; together with Piul Rabbani of Hansjörg Wyss Plastic Surgery; And Boyan Zhou and Huilin Li of the Department of Population Health and Environmental Medicine; all at the Lange Health Center of New York University. Other authors include Lisa Ramirez, Sergey Reverdatto, Stephen Dansereau, Jinhong Pan, and co-senior author Alexander Shekhtman of the Department of Chemistry, State University of New York Albany; Vivette D'Agati of the Department of Pathology, Columbia University Irvine Medical Center; and West, New Jersey Robert DeVita of Field RJD Medicinal Chemistry and Drug Discovery Consulting LLC.
The research was funded by U.S. Public Health Service grants 1R24DK103032, 1R01DK122456-01A1, P01HL146367, and 1P01HL131481; U.S. Department of Defense awarded W81XWH-17-1-0201 and W81XWH-17-1-0202; and New York University Cancer Institute Cancer Center Support Grant 5P30CA016087-31.
Greg Williams Tel: 212-404-3500 gregory.williams@nyulangone.org
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