Treatment target for diabetes, Wolfram syndrome
The bright green spots are TXNIP molecules, potential treatment targets for diabetes and Wolfram syndrome. Credit: Urano lab
Inflammation and cell stress play important roles in the death of insulin-secreting cells and are major factors in diabetes. Cell stress also plays a role in Wolfram syndrome, a rare, genetic disorder that afflicts children with many symptoms, including juvenile-onset diabetes.
Now a molecule has been identified that's key to the cell stress-modulated inflammation that causes insulin cells to die, report scientists at Washington University School of Medicine in St. Louis, the University of Massachusetts Medical School in Worcester and elsewhere.
"There are two types of inflammation," says senior investigator Fumihiko Urano, MD, PhD. "There is local inflammation within cells that can be caused by a specific type of cell stress named ER stress. There's also systemic inflammation that involves the activation of immune system cells. The molecule we've identified is involved in the initiation of local inflammation that can lead to systemic inflammation."
That molecule, called thioredoxin-interacting protein (TXNIP), provides scientists with a target to direct therapies for diabetes and Wolfram syndrome. The latter disorder causes kidney problems as well as hearing and vision loss. As patients get older, they develop ataxia, a brain dysfunction that causes a loss of muscle control and coordination, and many patients die before their 40th birthday.
The new study is published Aug. 8 in the journal Cell Metabolism.
This video is not supported by your browser at this time.
Wolfram syndrome is a rare disorder that causes insulin-dependent diabetes, kidney problems and vision and hearing loss, among other things. Now researchers at Washington University School of Medicine in St. Louis are reporting that they’ve identified a potential treatment target for Wolfram syndrome that also might help with diabetes. Jim Dryden reports… Credit: Washington University BioMed RadioUrano, an associate professor of medicine in Washington University's Division of Endocrinology, Metabolism and Lipid Research, studies a type of cell stress known as endoplasmic reticulum (ER) stress. The endoplasmic reticulum is part of a cell that's responsible for producing proteins and synthesizing cholesterol. Every cell in the body has an endoplasmic reticulum, which also is involved in transporting proteins to the parts of the cell where they are needed.
In ER stress, misfolded proteins accumulate, activating a response in the cell designed to correct the problem by making fewer proteins and eliminating the misfolded ones. But if the stress cannot be resolved, the cells self destruct.
"The endoplasmic reticulum does many important things," Urano says. "When it doesn't function properly, it can contribute to several different diseases. In the case of Wolfram syndrome and diabetes, we believe that dysfunction within insulin-secreting cells causes ER stress, which, in turn, contributes to local inflammation and cell death."
Urano's team analyzed genes that were activated in insulin-producing cells under ER stress and found that TXNIP was manufactured in large amounts in the stressed cells. Past research demonstrated that the protein was involved in inflammation, and as experiments progressed, the researchers were able to link TXNIP both to ER stress within the cell and to inflammation outside of specific populations of cells that can have an effect throughout the body.
"We found that ER stress can lead to inflammation activation through the TXNIP protein," he says. "So if we could somehow block TXNIP, we may be able to mitigate the inflammation and block the progression of diabetes and Wolfram syndrome."
Urano has found that in animal models of Wolfram syndrome, TXNIP levels are significantly increased in insulin-secreting cells. Meanwhile, other recent research has discovered that a common blood pressure medication called verapamil can interfere with TXNIP production, so Urano's team plans to test that drug in animals with Wolfram syndrome to learn whether it might delay the progression of the disease. Those experiments, Urano says, are under way.
The TXNIP protein provides the best available target for therapies because the only other known molecule involved in cell death under ER stress conditions is housed in the cell nucleus, he says. TXNIP, on the other hand, exists outside the nucleus and therefore may more easily interact with potential therapeutic agents.
Although this study involves the extremely rare disorder Wolfram syndrome, which affects about one in 500,000 people, Urano says the findings may be important to many other diseases because inflammation contributes to so many disorders, from heart disease to cancer.
"Local inflammation such as ER stress can't be detected by looking for inflammatory molecules in blood plasma, but it is very important in the pathogenesis of many chronic human diseases," he says. "By studying TXNIP in Wolfram syndrome, we may be able to uncover clues for treating other chronic diseases, including neurodegenerative diseases, such as Alzheimer's disease and similar illnesses that cause cognitive problems."
More information: Oslowski CM, Hara T, O'Sullivan-Murphy B, Kanekura K, Lu S, Hara M, Ishigaki S, Zhu LJ, Hayashi E, Hui ST, Greiner DL, Kaufman RJ, Bortell R, Urano F. Thioredoxin-interacting protein mediates ER stress-induced beta cell death through the initiation of the inflammasome. Cell Metabolism, vol. 16 (2), Aug. 8, 2012.
Journal reference: Cell Metabolism
Provided by Washington University School of Medicine
- Researchers find beta cell stress could trigger the development of type 1 diabetes Mar 22, 2012 | not rated yet | 0
- New tactic for controlling blood sugar in diabetes contradicts current view of the disease Sep 04, 2011 | not rated yet | 0
- Call of the riled: Stress signal in cancer cells triggers similar response in other cells, aiding tumor growth Apr 04, 2011 | not rated yet | 0
- Not all fat is created equal Aug 27, 2008 | not rated yet | 0
- A new strategy normalizes blood sugars in diabetes Mar 28, 2010 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
Question about perception of colors around light sources
2 hours ago When I look at a distant light source (like car headlights, or street lamp lights) I notice colors of the visible spectrum (as separated (as in after...
Does a charged particle rotate when traveling through a static Bf?
4 hours ago I have been looking at mass spectrometers, in particular the interactions between the Bf ind of a charged particle in motion in a static Bf of the...
Find a link between physics and assignment problems
5 hours ago Hi ! I've been working about assignments problems and how to solve them. I will have to do a presentation about it in few weeks. However, I'll...
Light as a source of electricity
5 hours ago Hello Dear Fellows! We all know that light is an electromagnetic wave and also we know that an antenna receives EM waves and...
A question about the energy stored in a capacitor.
5 hours ago If we imagine a simple circuit with a battery and a capacitor with negligible internal resistance, the capacitor is charged up to a point where the...
Electric field-Charge inside a metallic shell
8 hours ago I am having few doubts while studying electric field which i am putting here Suppose there is a spherical metallic shell with point charge q1 at...
- More from Physics Forums - Classical Physics
More news stories
(Medical Xpress)—Inflammation is an important response in the body - it helps you to kill off invaders such bacteria that could cause a harmful infection. But if it's chronic or uncontrolled, inflammation can also cause ...
Inflammatory disorders May 14, 2013 | not rated yet | 0 |
New research by medical students working in the Breathe Well Centre of Research Excellence at the UTAS School of Medicine has revealed swimming has health benefits for young people with asthma, with no adverse effects on ...
Inflammatory disorders May 10, 2013 | not rated yet | 0
An estimated 4,837,000 asthmatics with allergic bronchopulmonary aspergillosis (ABPA) could benefit substantially from antifungal treatment, say researchers from The University of Manchester and the University of Toronto.
Inflammatory disorders May 08, 2013 | not rated yet | 0
Type 1 (insulin-dependent) diabetes appears to increase the risk of heart disease, the leading cause of death among people with high blood sugar, partly by stimulating the production of calprotectin, a protein that sparks ...
Inflammatory disorders May 07, 2013 | 4.5 / 5 (2) | 0 |
Researchers at the University of Wisconsin have identified a potential new risk factor for obstructive sleep apnea: asthma. Using data from the National Institutes of Health (Heart, Lung, and Blood Institute)-funded Wisconsin ...
5 hours ago | not rated yet | 0 |
A new study looking at sleep-disordered breathing (SDB) and markers for Alzheimer's disease (AD) risk in cerebrospinal fluid (CSF) and neuroimaging adds to the growing body of research linking the two.
5 hours ago | 5 / 5 (1) | 0 |
In their quest to learn more about the variability of cells between and within tissues, biomedical scientists have devised tools capable of simultaneously measuring dozens of characteristics of individual ...
6 hours ago | 5 / 5 (1) | 0 |
Scientists at Johns Hopkins have turned their view of osteoarthritis (OA) inside out. Literally. Instead of seeing the painful degenerative disease as a problem primarily of the cartilage that cushions joints, ...
6 hours ago | 5 / 5 (2) | 0 |
Gourmands and foodies everywhere have long recognized ginger as a great way to add a little peppery zing to both sweet and savory dishes; now, a study from researchers at Columbia University shows purified components of the ...
5 hours ago | not rated yet | 0
The hunt for an HIV vaccine has gobbled up $8 billion in the past decade, and the failure of the most recent efficacy trial has delivered yet another setback to 26 years of efforts.
9 hours ago | not rated yet | 0