Type 2 diabetes remains a major public health problem: in the U.S. alone about 30 million people are estimated to have it. Driven largely by overweight and obesity, it features the loss of normal blood sugar regulation, and brings a multitude of complications including coronary disease, stroke, retinal degeneration, progressive kidney failure, nerve damage, and some cancers. There are many drugs for treating type 2 diabetes, but none that works well for every patient. They aim for the correction of blood glucose fluctuations, woth the principle that this would avoid the onset of tissue damage and complications themselves. Now a team of scientists from Scripps Research has conducted promising early tests of a new strategy that might one day prevent or treat this condition. The scientists tested an experimental compound called IXA4 in obese mice, and activates a natural signaling pathway that protects the animals from harmful, obesity-driven metabolic changes that would normally lead to diabetes.
This is called the endoplasmic reticulum stress response (ERSR) that in turn lead to the Unfolding Protein Response (UPR). The endoplasmic reticulum provides a conserved protein quality control system and plays a fundamental role in cell growth and homeostasis. Disturbances in the ER homeostasis may originate especially from hypoxia, glucose deficiency, presence of mutant proteins, that directly impair protein folding capacity and after deposition of unfolded and misfolded proteins within ER lumen trigger ER stress conditions. This subsequently activates the UPR branches, which have a dual pro-adaptive or cell killing role depending on the severity and time of duration of ER stress conditions. For several years, scientists has been studying a ER signaling involving two proteins called IRE1 and XBP1s. When activated by a certain type of cellular stress, IRE1 activates XBP1s, which in turn alters the activity of a host of genes, including many metabolic genes, in an effort to reduce the cellular stress.
Prior studies suggest that the activity of this pathway, at least in the short-term, can protect liver and fat cells from stresses caused by obesity (stresses that can harm these cells in ways that promote diabetes). The IRE1/XBP1s pathway is not a straightforward diabetes drug target, however. Past research has shown that keeping IRE1/XBP1 switched on chronically ends up harming cells, triggering inflammation and worsening overall metabolic dysfunction. In the new study, the researchers showed that a compound they identified a few years ago, IXA4, activates IRE1/XBP1s for just a few hours at a time. Because it otherwise allows IRE1 to turn off, it can in principle be given daily without triggering the deleterious signaling seen with constant IRE1 activation, making it a promising candidate to explore for human treatments. The team treated mice that were obese from a high-fat, high-calorie diet. After just 8 weeks, the treated mice had improved glucose metabolism and insulin activity, less fat buildup and inflammation in the liver.
Interestingly, this compound does not stimulate further stressful cellular pathways, like TRAF2-JNK or NF-κB signaling, likely reflecting its ability to induce only a transient, modest activation of IRE1. If this would not be so, the drug may directly kill target cells or trigger a secondary inflammatory response that could do the same with a “bystander” effect. IXA4 can reach only a limited set of tissues including the liver and pancreas, it does not produce a loss in pancreatic cells and so the team is now developing other compounds that can get into a broader set of cells including fat cells.
- Edited by Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Madhavan A et al. Nat Commun. 2022 Feb 1; 13(1):608.
Grandjean JDM et al. J Biol Chem 2020; 295(46):15692.
Rozpedek W et al. Curr Mol Med 2017; 17(2):118-132.
Liu ZW et al. Cardiovasc Diabetol. 2013 Nov 2; 12:158.
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