Publication: www.ncbi.nlm.nih.gov | Publication Date: February 13, 2014
Authors: Linshan Shang, Haiqing Hua, Kylie Foo, Hector Martinez, Kazuhisa Watanabe, Matthew Zimmer, David J. Kahler, Matthew Freeby, Wendy Chung, Charles LeDuc, Robin Goland, Rudolph L. Leibel, and Dieter Egli
Abstract
Wolfram syndrome is an autosomal recessive disorder caused by mutations in WFS1 and is characterized by insulin-dependent diabetes mellitus, optic atrophy, and deafness. To investigate the cause of β-cell failure, we used induced pluripotent stem cells to create insulin-producing cells from individuals with Wolfram syndrome. WFS1-deficient β-cells showed increased levels of endoplasmic reticulum (ER) stress molecules and decreased insulin content. Upon exposure to experimental ER stress, Wolfram β-cells showed impaired insulin processing and failed to increase insulin secretion in response to glucose and other secretagogues. Importantly, 4-phenyl butyric acid, a chemical protein folding and trafficking chaperone, restored normal insulin synthesis and the ability to upregulate insulin secretion. These studies show that ER stress plays a central role in β-cell failure in Wolfram syndrome and indicate that chemical chaperones might have therapeutic relevance under conditions of ER stress in Wolfram syndrome and other forms of diabetes.
http://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svg00The Snow Foundationhttp://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svgThe Snow Foundation2014-02-13 07:15:322020-09-07 13:08:16β-Cell Dysfunction Due to Increased ER Stress in a Stem Cell Model of Wolfram Syndrome
Hello everyone. My Botox surgery was a success. I am happy to report that I am getting up only two or three times a night instead of every hour. I don’t feel as tired anymore through out the day. This has made me feel so much better. I am able to drink a lot more and hold a lot more than every before. This gives me a lot more energy so I can talk a lot more which is just what my mom needs. LOL.
I was also able to go back to my volunteer job this week where I shred paper. Who better to shred confidential papers than someone who can’t see anything on them. ha-ha. I’ve had this job since high school which I really enjoy. The people there treat me like anyone else. They don’t pity me. In fact quite the opposite. They love to give me a hard time and tease me. It’s hard to know who is getting more harassed, them or me. My mouth is the only part of me that is not affected by WS.
I should back up and tell you a little about me. I am affected by all aspects of DIDMOAD. DI (DIABETES INSIPIDUS), DM (DIABETES MELLITUS), OA (OPTIC ATROPHY, D (DEAFNESS). I am legally blind and use a cane to get around. I wear hearing aids for high frequency hearing loss. I was diagnosed with Diabetes Mellitus when I was two years old and take insulin shots. The Diabetes Insipidus is controlled by medication. I take 20 prescription pills every day to control my WS. I was diagnosed with WS when I was 12. I have other symptoms but I will talk about them another day.
Steps toward a cure for diabetes and Wolfram Syndrome are being made and successful results are occurring in scientific research. The treatments are not yet available for Wolfram patients so it’s wise to attempt slowing Wolfram progression until treatments are available. In addition to being a Wolfram patient I am also a huge advocate for correcting one’s health on one’s own without the use of prescriptions.
From the age of 7-years old to 16-years old I was placed on nine different prescription drugs to treat my various ailments, ranging from diabetes to kidney failure to elevated cholesterol. Upon my own research, I discovered that each prescription drug will eventually require an additional prescription for resulting side effects. I took it to heart and disciplined myself to edit lifestyle and correct health issues without the use of medications; today I am down to three prescriptions and doing very well.
Diabetics without Wolfram can experience nerve damage simply due to uncontrolled glucose levels. Thus, a Wolfram patient, whose central nervous system is genetically experiencing nerve damage, along with uncontrolled diabetes will be faced with hurried progression of kidney failure, vision loss, and hearing damage. Therefore, I have spent a great deal of my life in becoming physically active and nutritionally sound so that I may more closely take control of my diabetes, my health, and my life. Through a daily exercise routine and a low sugar/carbohydrate diet I have successfully kept my blood glucose levels, cholesterol, blood pressure, kidney function, vision, and hearing at a stable and satisfactory quality.
In my visits to Washington University School of Medicine in St. Louis during the annual Wolfram research event, doctors have told me that my lifestyle choices have proven to slow the progression of nerve damage caused by diabetes and Wolfram Syndrome. In short, I was told to keep doing what I have been doing.
In January 2013, Adam Zwan was featured by the NBC affiliate in his hometown of Wilmington, North Carolina, WCET News. The story was to show what it is like for Adam to live with Wolfram syndrome. That night, Adam began to experience severe abdominal pain and was rushed to the hospital where he remained for a week. Despite the delay from Adam’s hospital stay, the news team came back to finish their story. Here is the five minute video on our good friend, Adam Zwan, where you can see for yourself the courage and spirit Adam exudes every day.
Being Sick and Having Surgery, NOT A Good Combination
Hello everyone! As you know I was going to have my surgery on Wednesday, but unfortunately on Monday night I was up every hour throwing up. I luckily didn’t feel sick but couldn’t keep anything down. My blood sugar started to drop a little so I drank some juice but threw it up right away. Luckily this happened later in the night so my blood sugar started to go back up again because I needed to give my insulin shot. Fortunately I stopped throwing up around 8:00 am. This was good so I could probably have the surgery if I didn’t get sick again, but bad because I was tired and weak.
I was able to sleep most of the day, but my mom who stayed up all night with me, had to stay awake during the day so when I needed up she could help me because I was so weak. She was very exhausted and still had to drive me two hours in the next morning for my surgery. She had to wait for me during the surgery and then drive 2 hours home that night.
I feel bad that my disease has to affect others in my family. My surgery went well. I got to go home that day so that was good. The surgery did not paralyze my bladder so this made me very happy. It’s still too early to tell but everything seems to be working well and better than before. I didn’t feel good for the next two days after the surgery but I am feeling good now. Hopefully next week I can tell you that the botox is working very well.
Early in life I began having to face several limitations and make many sacrifices due to Wolfram Syndrome. With the diagnosis of Type I diabetes at 7 years old I was asked to limit and sacrifice enriched white flour and sugars in order to manage glucose levels. Staying away from sugary and or starchy foods, like pasta, candy, cookies, and rice, I gained a passion for high fibrous fruits and vegetables along with drinking over a gallon of water each day. As time went on I allowed initiating a network of friends and getting involved in intimate relationships to be placed on the back burner so I could manage my health through nutrition and physical activity.
Around age 16 I was faced with the diagnosis of kidney disease (Diabetes Insipitus of the Kidneys) and was asked to limit water intake to drinking only when thirsty. Now, I cannot drink a lot of water during the day to decrease hunger, which was not to difficult to deal with but another limitation none the less.
Following the diagnosis of kidney disease and Wolfram Syndrome I began having issues with my digestive system (Autonomic Nerve Dysfunction and Gastro Paresis). My high fibrous diet and Wolfram were causing my digestive system to shutdown sporadically. After three different occurrences of sitting in the hospital for several days hunched over in pain with nothing to eat or drink, I was placed on a low residue diet (high protein – low fiber). Nutritionist and other experts advised me to increase the amount of fat in my diet to make up for caloric deficits. However, having Gastro Paresis knocked a high fat diet out of left field because fat slows down the digestive system causing glucose levels to fluctuate. At this point in time 85% of my current diet has to be sacrificed in order to keep my digestive system in working condition. It is tough getting filled up every day on eggs, yogurt, meat, and seafood, but telling myself that “It could be better but it could always be worst!” makes things easier to deal with.
The next big stepping stone was having my driver’s license taken away due to visual difficulties at 25 years old. Independent transportation taken away is yet to be the most difficult thing to get used to. Depending on family and neighbors to transport me to and from work, the pharmacy, bank, gym, and the grocery store creates a conflict when trying to make my own schedule, develop a social life, and maintain a career.
All in all, I would have to say that I would rather never experience something than to have it taken away later down the road. It is easy to get by without a girlfriend because I have never had one and so I do not really know what I am missing. On the other hand, having things, like food groups and a driver’s license, taken away makes me wish with all my heart that I could continue or have them back.
Why do I study such a rare disease as Wolfram Syndrome?
I am often asked, “Why do you study such a rare disease, Wolfram?” My answer is, “It is the weapon to combat common diseases.” My secret answer is, “I want to help Wolfram patients and their families.”
Why it is so important to study Wolfram syndrome, a rare condition characterized by juvenile-onset diabetes, optic atrophy, and neurodegeneration? It is a frightening condition. Wolfram syndrome is always on my mind just like pediatric cancer was always on my mind when I was a young doctor (some people still think that I am a young doctor…thank you). I just want to help them. That’s all I want. This is my last research project.From a scientific standpoint, I always believe that there is a tremendous benefit for us to study Wolfram syndrome. Increasing evidence now indicates that endoplasmic reticulum (ER) dysfunction is involved in more common diseases, especially type 1 diabetes. I propose that Wolfram syndrome is the “weapon to combat type 1 diabetes.“Despite its rarity, Wolfram syndrome probably represents the best model currently available for identifying treatments for diseases associated with ER dysfunction. Wolfram syndrome arises from mutation of a single gene (WFS1), a gene shown to be also involved in β cell dysfunction and death in other forms of diabetes mellitus. Its monogenic etiology makes Wolfram syndrome more amenable to dissecting out the mechanisms underpinning cellular responses to ER dysfunction than other diabetic conditions, such as type 1 diabetes mellitus, in which multiple factors typically interact to produce the disease manifestations.
Dr. Fumihiko Urano
Dr. Fumihiko Urano a renowned physician and scientist developing therapeutics and diagnostics for Wolfram syndrome and juvenile onset diabetes. His areas of expertise include Wolfram syndrome, type 1 diabetes, Pediatric pathology and genetics and Molecular Endocrinology. He is currently employed at the Washington University School of Medicine where he holds the Samuel E. Schechter Professor of Medicine, 2012 – present.
http://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svg00Dr. Fumihiko Uranohttp://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svgDr. Fumihiko Urano2014-02-01 21:19:332020-09-07 20:10:40The Power of Wolfram: The Weapon to Combat Type 1 Diabetes
Today I am going to visit my grandmother celebrating her 80th birthday. I love my grandma and it is always fun to get together with all my relatives. After my doctor visit on Monday, I found out that my urologist is going to try something new for my bladder issues. I have a neuro stimulator implanted for my bladder that constantly spasms. It worked really well before but lately its not working as well. I get up almost hourly every night to go to the bathroom. This really tires me out because I never get any sleep. He is going to inject botox into my bladder to keep the spasms from occurring. He said he has had a lot of luck with this. He said it was done often on patients with MS or Cerebal Palsy. So I agreed to try it. It will last for one year. The doctor also had to inform me that there was a chance that it could paralyze my bladder. This thought really scared me. I thought, I get all the weird things happening to my body, so does that mean that I will have a paralyzed bladder? It this occurs, I would have to catherize myself for a year. Even though I am reluctant to do it, I will if it means I could get some sleep. My mom wishes they would inject it into my mouth so I quit talking so much. My mom is mad because the doctor won’t take a little extra and apply it to my mom’s face. LOL.
Well I have had my presurgical checkup and will have the surgery done on Wednesday. It is a 2 hour trip both ways to get to Omaha where my doctor is. I can’t wait to see if it works or not. Today I saw my psychiatrist. It was just a quick visit. He wanted to know how my constant checking things were doing. Was the medication doing what it is supposed to do for my bipolar diagnosis? It was all fine. We have to make a 1 ½ hour trip each way to see him. We are only there for a total of ½ hour. I feel bad my mom has to drive me everywhere. This has been a busy week. I will let you know next week how the surgery went.
LEFT TO RIGHT: Dr. Bess Marshall, Dr. Fumi Urano, Dr. Tamara Hershey
Instead of introducing my research activities, I would like to introduce my colleagues today. I have a lot of colleagues who have been helping me develop diagnostics and therapeutics for Wolfram at the Washington University Medical Center. Without their help, I cannot accomplish anything. I give many lectures and talks on Wolfram syndrome, but I feel that I am just a spokesperson or a salesman of our team.
Today I would like to introduce Dr. Bess Marshall and Dr. Tamara Hershey. Dr. Marshall is a pediatric endocrinologist and serves as a medical director of our annual Wolfram clinic. Dr. Marshall is an experienced, smart, and caring physician scientist. Dr. Hershey is a neuropsychologist and serves as a scientific director of our Wolfram clinic. Dr. Hershey is thoughtful, smart, and extremely good at getting things done. They are powerful driving force of our Wolfram project! I always appreciate their continuous support and advice. Here is their picture! (From left to right: Dr. Marshall, Fumi, and Dr. Hershey)
Dr. Fumihiko Urano a renowned physician and scientist developing therapeutics and diagnostics for Wolfram syndrome and juvenile onset diabetes. His areas of expertise include Wolfram syndrome, type 1 diabetes, Pediatric pathology and genetics and Molecular Endocrinology. He is currently employed at the Washington University School of Medicine where he holds the Samuel E. Schechter Professor of Medicine, 2012 – present.
Some people are glorified for an invention or for a remarkable breakthrough in science. However, others make their mark in history by being diagnosed with a rare illness that shortens life expectancy by half. My place in history start in 1987 on September 18, living life as a healthy young man only to find health beginning to spiral downward in 1994. The diagnosis of Type I diabetes was only the first mile marker in my marathon known as Wolfram Syndrome. As one of 18 patients with Wolfram in the United States I found myself obligated to beat the statistics and surpass the life expectancy of 31 years old by controlling my diabetes and staying as physically active as I possibly could. I took a realistic look at myself and said that Wolfram Syndrome is the hand that I was dealt in life and it is my responsibility to make the best of what I have.
[pullquote style=”right”]I took a realistic look at myself and said that Wolfram Syndrome is the hand that I was dealt in life and it is my responsibility to make the best of what I have.
[/pullquote] fitness routine has become the highlight of my every day and I use Wolfram as my driving force to continue staying physically active. My clique is “No one needs an excuse to exercise everyday but it’s nice to know that I have one.” Each day starts at Gold’s Gym from 6a.m until 8a.m. then I continue teaching fitness classes from 9a.m. until 12p.m. at a wellness and rehabilitation center and then finish each day with teaching Taekwondo classes from 3p.m.til 6p.m. Simply put, being physically active, and helping others stay active, and rising above the natural struggles of health are just a few of the things I would like to define my life.
We are taking an unconventional approach to develop therapeutics for Wolfram syndrome. I would call it “patient-based therapeutics.” This implies a few things. One of these is the “mechanism-based treatment.” How can we achieve this component of “patient-based therapeutics” for Wolfram syndrome? Here are our current efforts.
1. Looking for FDA-approved drugs that can potentially halt progression of Wolfram syndrome (drug repurposing).
We looked for drugs that can protect cell death mediated by the leakage of calcium from the endoplasmic reticulum (ER) to the cytosol. We found four FDA approved drugs and one supplement so far. We are testing these drugs in Wolfram iPSC-derived neural progenitor cells and mouse models of Wolfram syndrome.
2. Looking for a new class of drugs that can protect cell death mediated by endoplasmic reticulum dysfunction.
We have developed a drug screening method to identify drugs that can protect cell death mediated by ER dysfunction. In collaboration with a non-profit organization, we are actively looking for a new class of drugs that can potentially halt the progression of Wolfram.
3. Testing if MANF (mesencephalic astrocyte-derived neurotrophic factor) can suppress the ER calcium leakage-mediated neuronal cell dysfunction in Wolfram iPSC-derived neural progenitor cells.
I will talk about more on MANF some other time. I thought that this was a good biomarker for Wolfram syndrome because expression of this molecule is increased by ER dysfunction. However, the increase of MANF might be an adaptive mechanism of our cells to cope with abnormal ER function.
Dr. Fumihiko Urano a renowned physician and scientist developing therapeutics and diagnostics for Wolfram syndrome and juvenile onset diabetes. His areas of expertise include Wolfram syndrome, type 1 diabetes, Pediatric pathology and genetics and Molecular Endocrinology. He is currently employed at the Washington University School of Medicine where he holds the Samuel E. Schechter Professor of Medicine, 2012 – present.
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