DRC & Research News

This page shares the latest news in T1D research and DRC’s community.

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DRC-Funded Scientist Creates New Insulin-Producing Cells to Fight Type 1 Diabetes

Thanks in part to funding from the Diabetes Research Connection (DRC), Dr. Kristin Mussar was able to conduct an in-depth study regarding how to stimulate the body’s own cells to create new insulin-producing cells that may help treat type 1 diabetes (T1D). In individuals with T1D, the immune system attacks insulin-producing cells, destroying them and leaving the body unable to effectively regulate blood sugar.

The human body is filled with myeloid cells that all differentiate to help grow, maintain, and repair various organs. When these cells are depleted, it impacts organ health. For instance, lack of insulin-producing cells results in diabetes. However, Dr. Mussar and her team discovered that there is a population of macrophages – white blood cells that recirculate throughout the body constantly monitoring the health status of all tissues – that instruct insulin-producing cells to grow in the perinatal stage of pancreas development. During this period of prolific growth, enough insulin-producing cells are created to support glucose homeostasis throughout one’s life.

Dr. Mussar found that there is a special population of these cells that act as cargos of potent growth factors for the insulin-producing cells in the pancreas. If these cells are prevented from entering the pancreas, the growth of insulin-producing cells is arrested and diabetes ensues. This lack of cell growth, as well as cell destruction, are issues that researchers have been trying to remedy through various strategies for treating T1D.

One avenue of treatment that is being explored is finding ways to use the body’s own cells and processes to support insulin production. Current challenges in treatment include the constant monitoring and accurate dosing of insulin, as well as the use of immunosuppressants or other medications to prevent the body from destroying modified cells or specialized therapies. Using the body’s own cells can help reduce risk of immune attack or rejection.

To this effect, Dr. Mussar’s research revealed that there are precursors to these special macrophages that exist within the bone marrow of adults. When these precursors are injected into the blood stream, they are able to signal growth of insulin-producing cells. This discovery raises hopes that, by dispatching these pro-regenerative cells from the bone marrow to injured pancreatic islets, it may be possible to enhance regeneration of insulin-producing cells in individuals with type 1 diabetes. This may in turn help to stabilize blood sugar naturally using the body’s own cells.

The Diabetes Research Connection is proud to have played a role in making Dr. Mussar’s research possible by providing funding that enabled her to continue moving forward with her project and eventually get the results published in the Journal of Clinical Investigation.

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Diabetes Research Connection 2016 Year in Review

This past year has been a big one for us at Diabetes Research Connection. Our donors have stepped up to the plate and helped us fund research towards treating, curing and preventing type 1 diabetes. In fact, in 2016 we were able to raise more than $490,000 thanks to the support of our donors.

We’re committed to keeping our backers updated on all projects and DRC happenings, so we wanted to take time at the beginning of 2017 to remind ourselves and our donors of all the amazing things that happened in 2016.

In January, Sangeeta Dhawan, Ph.D. at UCLA School of Medicine started off the year with her project, Making More and Better Insulin Producing Cells with Cell Regeneration. We were able to help her raise more than $30,000.

Dr. Sangeeta Dhawan

 

In February, we launched another project, Replacement Beta-Cells From An Unexpected Source, a research study conducted by Joseph Lancman, Ph.D. — Sanford Burnham Prebys Medical Discovery Institute. We were able to raise more than $45,000 in support of this project.

Dr.Lancman in Lab

In April, we celebrated World Health Day. This year’s theme was Beat Diabetes, and we encouraged our donors and supporters to get involved in the global fight against diabetes.

In May, another project launched, and we were able to help Peter Thompson, Ph.D. at University of California San Francisco raise more than $30,000 for his project, Regrowth of Beta Cells with Small Molecule Therapy.

Peter Thompson - Regrowth of beta cells with small molecule therapy

Another new project came online in July; Agata Jurcyzk, Ph.D. of the University of Massachusetts Medical School, What is the Connection Between T1D and Depression?

Agata-Headshot

August was a busy month for us at DRC. In mid-August, we partnered with the diaTribe Foundation for Brews & Blood Sugar. More than 100 people joined us to samples beer from one of San Diego’s premier breweries, to learn how different varieties of beer affect blood sugar and support efforts to find solutions for those with diabetes. We also launched our T1D resource center in August, where we’ve curated the best information out there pertaining to T1D. Lastly, we launched a project to raise funds for Gene-Specific Models and Therapies for Type 1 Diabetes, research being conducted by Jeremy Racine, Ph.D. of The Jackson Laboratory.

jeremy_racine_lab

In September, we were honored to be featured by The Huffington Post. We also launched our campaign on Gladitood, which helped us raise money and support for our General Fund as we began to close out the year.

In November, we celebrated National Diabetes Month. As a part of these celebrations, we launched our Double Your Dollars campaign, where every dollar donated to the General Fund was matched 100%. We upped the ante on Cyber Monday, doubling each match, making donations go even further. All told, we raised more than $80,000 in November. Additionally, we hosted a Crowdfunding Science event on Cyber Monday, where attendees joined three Rancho Santa Fe Foundation Donor Advised Fund families to learn about an exciting, successful and innovative crowdfunding platform for scientific research.

doubledollarsplaceholder

In December, we started a new blog series to help our donors meet the board, and we began by introducing you to Alberto Hayek, M.D., President of DRC.

This past year was monumental for DRC, and 2017 is already off to a great start with the launch of a new research project, Determining How Other Cells (Non-Beta) In The Pancreas Affect Diabetes by Jeffrey D. Serrill, Ph.D. of City of Hope, Los Angeles, California. We’re looking forward to seeing what the year holds as we fund research projects that will bring us closer to preventing, treating and curing T1D.

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ETH Researchers T1D

New Weapon Against Diabetes

Original article published by ETH Zurich on December 1, 2016. Click here to read the original article.

Researchers have used the simplest approach yet to produce artificial beta cells from human kidney cells. Like their natural model, the artificial cells act as both sugar sensors and insulin producers.

Researchers led by ETH Professor Martin Fussenegger at the Department of Biosystems Science and Engineering (D-BSSE) in Basel have produced artificial beta cells using a straightforward engineering approach. These pancreatic cells can do everything that natural ones do: they measure the glucose concentration in the blood and produce enough insulin to effectively lower the blood sugar level. The ETH researchers presented their development in the latest edition of the journal Science.

Previous approaches were based on stem cells, which the scientists allowed to mature into beta cells either by adding growth factors or by incorporating complex genetic networks.

For their new approach, the ETH researchers used a cell line based on human kidney cells, HEK cells. The researchers used the natural glucose transport proteins and potassium channels in the membrane of the HEK cells. They enhanced these with a voltage-dependent calcium channel and a gene for the production of insulin and GLP-1, a hormone involved in the regulation of the blood sugar level.

Voltage switch causes insulin production

In the artificial beta cells, the HEK cells’ natural glucose transport protein carries glucose from the bloodstream into the cell’s interior. When the blood sugar level exceeds a certain threshold, the potassium channels close. This flips the voltage distribution at the membrane, causing the calcium channels to open. As calcium flows in, it triggers the HEK cells’ built-in signalling cascade, leading to the production and secretion of insulin or GLP-1.

The initial tests of the artificial beta cells in diabetic mice revealed the cells to be extremely effective: “They worked better and for longer than any solution achieved anywhere in the world so far,” says Fussenegger. When implanted into diabetic mice, the modified HEK cells worked reliably for three weeks, producing sufficient quantities of the messengers that regulate blood sugar level.

Helpful modelling

In developing the artificial cells, the researchers had the help of a computer model created by researchers working under Jörg Stelling, another professor in ETH Zurich’s Department of Biosystems Science and Engineering (D-BSSE). The model allows predictions to be made of cell behaviour, which can be verified experimentally. “The data from the experiments and the values calculated using the models were almost identical,” says Fussenegger.

He and his group have been working on biotechnology-based solutions for diabetes therapy for a long time. Several months ago, they unveiled beta cells that had been grown from stem cells from a person’s fatty tissue. This technique is expensive, however, since the beta cells have to be produced individually for each patient. The new solution would be cheaper, as the system is suitable for all diabetics.

Market-readiness is a long way off

It remains uncertain, though, when these artificial beta cells will reach the market. They first have to undergo various clinical trials before they can be used in humans. Trials of this kind are expensive and often last several years. “If our cells clear all the hurdles, they could reach the market in 10 years,” the ETH professor estimates.

Diabetes is becoming the modern-day scourge of humanity. The International Diabetes Federation estimates that more than 640 million people worldwide will suffer from diabetes by 2040. Half a million people are affected in Switzerland today, with 40,000 of them suffering from type 1 diabetes, the form in which the body’s immune system completely destroys the insulin-producing beta cells.
[su_button url=”https://www.ethz.ch/en/news-and-events/eth-news/news/2016/12/artificial-beta-cells.html?elqTrackId=3118751de0d340b8bf7c42cba3a3a7d2&elq=3ba510d3772545b28e0cfdf8c559795e&elqaid=17762&elqat=1&elqCampaignId=10602″ target=”blank” style=”flat” background=”#64b243″ size=”6″ center=”yes” radius=”5″ icon=”icon: angle-right”]Continue Reading[/su_button]

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diabetes research

Economic 3D-Printing Approach for Transplantation of Human Stem Cell-Derived β-Like Cells

Original article published by IOP Science on December 1, 2016. Click here to read the original article.

Abstract

Transplantation of human pluripotent stem cells (hPSC) differentiated into insulin-producing βcells is a regenerative medicine approach being investigated for diabetes cell replacement therapy. This report presents a multifaceted transplantation strategy that combines differentiation into stem cell-derived β (SC-β) cells with 3D printing. By modulating the parameters of a low-cost 3D printer, we created a macroporous device composed of polylactic acid (PLA) that houses SC-β cell clusters within a degradable fibrin gel. Using finite element modeling of cellular oxygen diffusion-consumption and an in vitro culture system that allows for culture of devices at physiological oxygen levels, we identified cluster sizes that avoid severe hypoxia within 3D-printed devices and developed a microwell-based technique for resizing clusters within this range. Upon transplantation into mice, SC-β cell-embedded 3D-printed devices function for 12 weeks, are retrievable, and maintain structural integrity. Here, we demonstrate a novel 3D-printing approach that advances the use of differentiated hPSC for regenerative medicine applications and serves as a platform for future transplantation strategies.

[su_button url=”http://iopscience.iop.org/article/10.1088/1758-5090/9/1/015002/meta?elqTrackId=96062d779f46499eb7cc18d9ab30d665&elq=3d599e01edda49df92afa531a8a717ae&elqaid=17717&elqat=1&elqCampaignId=10609″ target=”blank” style=”flat” background=”#64b243″ size=”6″ center=”yes” radius=”5″ icon=”icon: angle-right”]Continue Reading[/su_button]

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DRC

An Important Talk About The Importance Of Diabetes Awareness

Original article published by The Huffington Post. Click here to read the original article.

National Diabetes Awareness Month is right around the corner, and it brings up the concern regarding how huge of an issue diabetes really is. A spokesperson from Diabetes Research Connection has agreed to answer some questions regarding Type 1 diabetes and the research that is being conducted to understand this autoimmune disease more.

1. Can you tell us a little more about type 1 diabetes; how is it different from type 2?

Type 1 diabetes (T1D) is a chronic autoimmune disease, like multiple sclerosis and muscular dystrophy. T1D is the result of the human immune system mistaking the body’s beta cells, which produce insulin, for foreign cells and destroys them. These beta cells produce insulin in response to elevated blood sugar levels. A person with T1D must constantly test his or her blood sugar and inject insulin or use an insulin pump to normalize blood glucose levels. Currently, there is no known cure for T1D.

Type 2 diabetes (T2D) is much more common than T1D. While the causes for T2D aren’t fully understood, excess weight, inactivity, age and genetics contribute to the development of this disease. Patients with T2D make insulin, but their cells can’t respond to it adequately. In some cases, T2D can be controlled by exercise, diet and weight loss.

Diabetes is the leading cause of adult blindness, kidney failure, cardiovascular disease, amputations, nerve damage and other complications. This is why the Diabetes Research Connection (DRC) supports research designed to prevent, cure and better the disease.

2. Explain to us what you do to research Type 1 Diabetes.

DRC is a nonprofit organization headquartered in San Diego, California. Established in 2012, DRC’s mission is to connect donors with early-career scientists enabling them to perform peer-reviewed, novel research designed to prevent and cure T1D, minimize its complications and improve the quality of life for those with the disease.

Researchers from across the country submit a grant application to members of DRC’s Scientific Review Committee, which is comprised of over 80 of the leading U.S. diabetes experts. Each research proposal is carefully scrutinized for innovation, value and feasibility.

Approved projects receive up to $50,000 in as few as 12 weeks. 100% of funds go directly to each scientist’s lab. To ensure transparency, each investigator provides updates to donors on their project. Final outcomes are posted on DRC’s website. This openness informs the research community of credible, new science. Research redundancy is less likely to occur, resulting in donated and government funds being used more efficiently.

3. There is no cure for Type 1 Diabetes, but do you think that could change anytime soon?

The discovery that insulin injections could treat T1D almost 100 years ago is the seminal finding and access to insulin is a daily necessity for people with this disease. There are a number of current research efforts to improve how external insulin is given in order to most closely control blood glucose levels, andthat is perhaps the most exciting area of medical research in our future. There are also many scientists working on preventing the onset of T1D or curing it after is has developed. Cells that can replace those lost in T1D and T2D are now a reality in several laboratories worldwide. It may be possible to create a new type of beta cell supply derived from stem cells. By using gene splicing, engineered beta cells may avoid rejection by the immune system. This futuristic approach has tremendous potential providing that the protein responsible for the immune attack to beta cells is identified, successfully targeted and silenced. Lastly, these designer cells should perform as intended without adverse side effects. A clinical trial has begun using human beta cells derived from embryonic stem cells and implanted under the skin in protective capsules to avoid their immune rejection.”

4. What are some of the greatest breakthroughs your scientists have had on a project?

Todd Brusko, Ph.D., from the University of Florida, completed his project, “Engineering Immune Cells To Stop Autoimmune Attacks” in December of 2015. The goal of his DRC supported project was to create a technology platform that would enable an optimized Treg cell (a specialized set of white cells that appear to interfere with the immune damage to beta cells) therapy for the treatment of type 1 diabetes. Therefore, Dr. Brusko set out to manufacture biodegradable nanoparticles that would release a Treg growth and survival factor binding to Treg cell surfaces. In animal experiments, his initial data supports the notion of improved engraftment and function. These findings offer critical proof-of-principle data that is closely watched by those with T1D because it addresses an important hurdle that must be overcome for a cure. If successful, this method will increase the number of protective cells which can help prevent further destruction of remaining beta cells.

Kristin Mussar, Ph.D. Candidate, from the University of Washington, completed her project, “Creating New Insulin-Producing Cells To Repair Damaged Pancreas” in August of 2016. In her project, Mussar identified a population of white cells called macrophages residing in the pancreas of newborns that is necessary for islet cells to expand in number as well as to mature into functional insulin-producing cells. Mussar found that a functionally similar population capable of boosting islet proliferation exists in the bone marrow of adult individuals, which suggests that there might be potential for islet repair in adults. The lab Mussar conducts her research in is currently investigating whether this bone marrow population can be used as a cell therapy to enhance the repair process of islet cells in adult mouse models of injury. This project is important because it has identified a different set of white blood cells that may allow the proliferation of insulin producing cells in the pancreas of diabetic patients, offering hope for a cure.

5. November is National Diabetes Awareness Month, how will your organization be promoting the Cause?

We’re launching a 30-day matching gift campaign to promote our General Fund. The fund covers program costs that support our research projects, as well as operating expenses. During the Double Your Dollars for Diabetes campaign, DRC will match donations made to the fund (up to $25,000 in matching), and on Giving Tuesday, DRC will quadruple its matching contribution. In addition, we are encourage holiday shoppers to purchase gifts through the AmazonSmile Program and select DRC as their nonprofit of choice to receive a small donation from the online retailer. More information will be available on our website prior to our November 1st launch.

6. Where can people learn more about your research projects?

People can learn more about DRC and our projects by visiting our website at drcsite.wpengine.com. We encourage visitors to join the DRC family by signing up for our monthly newsletter or becoming a donor.

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t1d research

Safety of a Hybrid Closed-Loop Insulin Delivery System in Patients With Type 1 Diabetes

Original article published by The Journal of the American Medical Association. Click here to read the original article.

Closed-loop artificial pancreas technology uses a control algorithm to automatically adjust insulin delivery based on subcutaneous sensor data to improve diabetes management. Currently available systems stop insulin in response to existing or predicted low sensor glucose values, whereas hybrid closed-loop systems combine user-delivered premeal boluses with automatic interprandial insulin delivery. This study investigated the safety of a hybrid closed-loop system in patients with type 1 diabetes.

Methods

Patients aged 14 to 75 years with type 1 diabetes for at least 2 years, glycated hemoglobin (HbA1c) less than 10%, and more than 6 months of insulin pump use were recruited from 10 centers (9 in the United States, 1 in Israel) between June 2, 2015, and November 11, 2015. This before and after study had a 2-week run-in period (baseline) for patients to learn the devices without the automated features followed by a 3-month study period with the initial 6 days used to collect insulin and sensor glucose data for the hybrid closed-loop algorithm. In the study period, there was a 6-day hotel stay during which 1 day was used for frequent sampling of venous blood glucose to verify the accuracy of the system. The last patient visit was March 7, 2016. Two central and 4 local institutional review boards approved the study. Written informed consent was obtained from adults and parents, and written assent from minors.

The system included investigational continuous glucose monitoring sensors with transmitters, insulin pumps displaying real-time glucose data, a proprietary algorithm, and blood glucose meters. Patients were required to periodically calibrate sensors and enter carbohydrate estimates for meal boluses. Every midnight, multiple parameters were automatically adjusted by the algorithm.

Safety end points obtained during the run-in and study periods (including the hotel stay) were the incidence of severe hypoglycemia and diabetic ketoacidosis, serious adverse events, and device-related serious and unanticipated adverse events. Prespecified descriptive end points included time in open vs closed-loop systems; the percentage of sensor glucose values below, within, and above target range (71-180 mg/dL), including at night time; changes in HbA1c, insulin requirements and body weight; and measures of glycemic variability. End points were collected during both periods and analyzed with SAS(SAS Institute), version 9.4.

Results

Of the 124 participants (mean age, 37.8 years [SD, 16.5]; men, 44.4%), mean diabetes duration was 21.7 years, mean total daily insulin dose was 47.5 U/d (SD, 22.7), and mean HbA1c was 7.4% (SD, 0.9). Over 12 389 patient-days, no episodes of severe hypoglycemia or ketoacidosis were observed. There were 28 device-related adverse events that were resolved at home. There were 4 serious adverse events (appendicitis, bacterial arthritis, worsening rheumatoid arthritis, Clostridium difficile diarrhea) and 117 adverse events not related to the system, including 7 episodes of severe hyperglycemia due to intercurrent illness or other nonsystem causes.

The system was in closed-loop mode for a median of 87.2% of the study period (interquartile range, 75.0%-91.7%). Glycated hemoglobin levels changed from 7.4% (SD, 0.9) at baseline to 6.9% (SD, 0.6) at study end . From baseline to the end of the study, daily dose of insulin changed from 47.5 U/d to 50.9 U/d, and weight changed from 76.9 kg to 77.6 kg. The percentage of sensor glucose values within the target range changed from 66.7% at baseline to 72.2% at study end. Sensor and reference glucose values collected during the hotel stays were in good agreement, with an overall mean absolute relative difference of 10.3% (SD, 9.0).

Discussion

To our knowledge, this is the largest outpatient study to date and it demonstrated that hybrid closed-loop automated insulin delivery was associated with few serious or device-related adverse events in patients with type 1 diabetes. Limitations include lack of a control group, restriction to relatively healthy and well-controlled patients, the relatively short duration, and an imbalance between the length of the study periods. Differences in HbA1c levels may be attributable to participation in the study. A similar study in children is under way. Longer-term registry data and randomized studies are needed to further characterize the safety and efficacy of the hybrid closed-loop system.

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diabetes research

Get Involved in Innovative Type 1 Diabetes Research

We were established in 2012 by five proponents of diabetes research, and our visionis to support innovative scientific inquiry until type 1 diabetes is eliminated. However, we can’t do it without the valuable contributions from our donors and supporters.

Want to get involved in type 1 diabetes research? Read below to find out how you can make a difference.

Help Fund Type 1 Diabetes Research

Many scientific breakthroughs come from the inventiveness of early-career scientists. Unfortunately, mainstream funding rarely goes to support these innovative researchers, with 97% of funding for type 1 diabetes research going to established scientists. This means that it’s often hard for new diabetes research ideas to get off the ground.

That’s where the Diabetes Research Connection comes in; we grant up to $50,000 to support type 1 diabetes research from early-career scientists.

Consider financially supporting one of the following type 1 diabetes research projects.

Gene-Specific Models and Therapies for Type 1 Diabetes

Multiple genetic factors contribute to type 1 diabetes, but researchers are limited to using mice models with one genetic profile. Jeremy Racine, Ph.D. of The Jackson Laboratory in Bar Harbor, Maine is working to create a new mouse model with a genetic blank slate for insertion of relevant HLA gene variants that are related to the development of diabetes. Additionally, he plans to test a therapy that has been specifically designed for a diabetes susceptible gene variation known as HLA-A*0201 (A2.1). Click here to support this project. 

Identify Biomarkers for Susceptibility to Both Type 1 Diabetes and Mental Disorders

Recent studies have found that those with diabetes have a much higher rate of depression, and young people with type 1 diabetes have a much higher rate of suicide than their peers. Agata Jurcyzk, Ph.D., a research instructor at the University of Massachusetts Medical School, is working to identify genetic signatures in white blood cells that distinguish non-progressor T1D patients and T1D patients that progress to psychiatric illness. Click here to support this project.

Regrowth of Beta Cells with Small Molecule Therapy

Type 1 diabetes develops when beta cells are destroyed and the body can no longer produce enough insulin to convert the sugar we eat into energy. Peter Thompson, Ph.D., a researcher at the University of California San Francisco Diabetes Center, is working to identify new events during the progression to T1D in order to design new interventions that could prevent or reverse the progression to T1D. Click here to support this project. 

Replacement Beta-Cells From An Unexpected Source

A cure for diabetes will involve replacing the insulin-producing beta cells that have been lost due to the disease. Joseph Lancman, Ph.D. of Sanford Burnham Prebys Medical Discovery Institute is researching to find a way to make in vivo cell lineage reprogramming safe and practical. This will make it possible to convert nearly any cell type into replacement beta cells, without removing them from the body. Click here to support this project.

Participate in Diabetes Research Studies

Diabetes Research Connection is currently partnering with four great research studies, but there are many more type 1 diabetes studies currently taking place. If you would like to get involved in these, consider participating in a type 1 diabetes clinical research study. We suggest checking out Type 1 Diabetes TrialNet.

TrialNet is a network of researchers seeking to prevent, delay or reverse the progression of type 1 diabetes. The organization works with 18 Clinical Centers in the U.S. and across the globe, and also partners with more than 150 medical centers and doctors’ offices.

Studies are available for those recently diagnosed with Type 1 diabetes, as well as those who have relatives with type 1 diabetes who are at a greater risk of developing the disease. You’ll need to participate in a screening to find out if you are eligible to join a TrialNet study.

For more information about type 1 diabetes research, sign up for our monthly newsletter!

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Kristin-Mussar in a labcoat

Type 1 Diabetes Research Updates

We’re so grateful for everyone who donates to individual projects and our General Fund – it allows us to accomplish our vision of supporting innovative scientific inquiry until type 1 diabetes is eliminated.

To show our gratitude, it’s important to us that we keep our donors updated on the research they’ve helped fund. Scientific research can at times be an arduous process, which is why we sometimes go months without any updates. However, our researchers are constantly working to complete their research projects and are dedicated to spending every day finding innovative new ways to treat and cure diabetes.

Update: Creating New Insulin-Producing Cells To Repair Damaged Pancreas

Kristin Mussar provided the following update to her research at the end of April:

In our last update we identified a population of macrophages residing in the pancreas of newborns that was necessary for islet cells to expand in number as well as to mature into functional insulin-producing cells. Recently, we found that a functionally similar population capable of boosting islet proliferation exists in the bone marrow of adult individuals, which suggests that there might be potential for islet repair in adults. We are currently investigating whether this bone marrow population can be used as a cell therapy to enhance the repair process of islet cells in adult mouse models of injury. Additionally, we are still working to characterize the molecular signals underlying the effects that this cell population has on islet cell expansion and maturation. Thank you again for donating and making this research possible!

Visit her project page to learn more about this study.

Once again, thanks for your support in helping our mission to prevent, treat and cure type 1 diabetes. It may sound cliché, but we truly couldn’t do it without you. Stay tuned for more updates later this summer. We’re expecting to hear from Dr. Subhadra Gunawardana and Wendy Yang, in particular!

To support more innovative research project like this, click here.

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Salk researchers Michael Downes, Ron Evans and Eiji Yoshihara. — Salk Institute

Salk Makes Step Toward Cellular Diabetes Treatment

Original article written by Bradley J. Fikes and published by The San Diego Union-Tribune on April 15, 2016. Click here to read the original article.

Salk Institute scientists say they’ve discovered a key ingredient needed to make functional insulin-producing beta cells. With that knowledge, the scientists say they can realize a dream in treating Type 1 diabetes: growing replacement beta cells from the patients themselves.

If these replacement cells can be implanted and protected, they will make insulin as the body needs, just as the original cells do. That means type 1 diabetes would, for the first time ever, be curable.

The ingredient is a protein called ERR-gamma that turns up energy production in the beta cells, said Ron Evans, a Salk researcher who co-led the study with colleague Michael Downes. These cells are made from artificial embryonic stem cells, called induced pluripotent stem cells. Typically produced from skin, these IPS cells cells are being examined for their potential to treat a variety of diseases.

The study, published Tuesday in the journal Cell Metabolism, provides more evidence that cell replacement therapy may eventually provide a cure for type 1 diabetes, caused by the destruction of beta cells through an autoimmune reaction. The study can be found atj.mp/evansbeta. The first author was Eiji Yoshihara, first author of the paper and a Salk research associate.

Type 2 diabetes is even more common than Type 1. In the United States as of 2012, about 1.25 million children and adults have type 1 diabetes, and 29.1 million had the type 2 form, according to the American Diabetes Association. In San Diego County as of 2012, about 140,600 or 6.2 percent have type 2 diabetes.

In type 2 diabetes, the body becomes resistant to insulin, and the pancreas may become disease and have trouble producing sufficient insulin. As a result, blood sugar rises beyond normal, producing all sorts of damage. This can include weight gain, heart problems, poor limb circulation leading to amputation, kidney disease and blindness. These patients may also come to require insulin.

Disease reversal

Unlike the first kind, type 2 diabetes can be reversed, at least in some cases. Dieting and exercise leading to weight loss is key, according to recent research. A 2013 study in the journal Diabetes Care found that causing patients to burn more substantially more calories than they consume, either by diet or bariatric surgery, restores insulin sensitivity over a period of 8 weeks.

Bariatric surgery, which a portion of the gut is removed to limit food absorption, appears to reverse type 2 diabetes in nearly all patients, according to other studies.

But diets are notoriously hard to adhere to, and bariatric surgery is a drastic step many people are reluctant to take. So scientists are focusing on how type 2 diabetes arises in the first place, with the hope of finding some way of preventing it from taking place at all.

A 2014 study by UCSD researchers led by Dr. Jerrold Olefsky found that a lack of oxygen in fat cells is the trigger that starts the process that ends up causing type 2 diabetes. The study, published in the journal Cell, examined the disease in mouse models, considered a good proxy for human diabetes.

It reported that certain fatty acids, especially saturated fats, increased the need for oxygen in fat cells, causing them to fall into an oxygen-deprived state. This led to inflammation, an immune reaction and insulin resistance.

If the study results are borne out in people, it may be possible to produce a drug that would stop this process in the bud. It won’t stop obesity, but the most drastic health problems would be prevented.

For type 1 diabetes, no treatment exists to reverse the disease.

A very limited form of cell replacement therapy is already used for those with the most dangerous form of type 1 diabetes. They get transplants of islet cells or pancreases from cadavers. Those treated belong to a small subset of type 1 diabetics who get no warning signs that their blood sugar has fallen too far. They can die as a result.

Cell replacement

San Diego’s ViaCyte is already testing a replacement therapy using progenitor cells derived from human embryonic stem cells. In animal testing, these cells mature into beta and other pancreatic “islet” cells.

Another approach with induced pluripotent stem cells is being researched in the lab of Harvard University researcher Douglas Melton. He and colleagues have come up with their own formula for producing beta cells, and published studies outlining the approach.
Melton’s group reports that the cells express genetic activity very similar to adult beta cells, and regulated blood sugar when transplanted into mice whose own beta cells were destroyed.

These therapies all face difficulties, the trickiest perhaps being the patient’s own immune system, which destroyed their own islet cells in the first place.

Islet and pancreatic transplant patients are given immunosuppresive drugs. These drugs are toxic and make the patients more vulnerable to infection. Therefore, these procedures are used only on type 1 diabetics at greatest risk, said Julia L. Greenstein, vice president of discovery research at the research foundation JDRF.

ViaCyte has pioneered another approach to the problem. The islet cells are encapsulated in a semipermeable membrane that keeps out the immune system, but allows nutrients to flow in, and insulin and waste products to flow out. Moreover, the islet cells may potentially produce other blood sugar-relating hormones besides insulin.

Whether that strategy works is the point of clinical testing of ViaCyte’s product, now in a Phase 1 trial. This trial tests for safety. Participants receive easily removable implants of encapsulated cells, which are expected to mature in place and produce insulin. These implants are being removed periodically and examined to make sure the maturation process is going smoothly and that the membrane remains intact.

Presumably, other stem cell-based replacement therapies such as that the Salk scientists or Melton are developing will require an immune system-blocking barrer like ViaCyte’s, to protect the cells. Meanwhile, research continues on ways to modulate the immune system of type 1 diabetes to stop the autoimmune reaction.

Power to the cells

The Salk Institute’s Evans said applying the ERR-gamma protein promotes the growth of mitochondria, the power plants of cells. This gives the cells energy to make insulin.

“It turns on the light, it turns on the energy that flows into the cell. And that we think is the missing link,” Evans said. “It is a switch that controls mitochondrial numbers and activity. You really rev up the power of the cell. Instead of having a weak or indolent cell, you rev it up to the level that it needs to be able to release insulin in response to glucose. And that takes a lot of energy.”

In mouse models, the effect of the therapy is immediate, he said.

“The day that we implant them, the diabetes starts going away,” Evans said. “These cells, you can purify them in a dish. You can grow them exactly the way you want, to hundreds of millions of cells that all share common features. For human therapy, you need that.”

Further research may enable production of different islet cells that make other important hormones to regulate blood sugar, Evans said. And a few more years of testing and preclinical development, it should be possible to test the therapy in humans.

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Novel Diabetes Research

The Diabetes Research Connection is pleased to present THREE extraordinary research projects. Scientists from the University of Florida, University of Washington, and University of Michigan seek your support in order to pursue novel investigations into a cure for diabetes.
  • Dr. Todd Brusko at the University of Florida seeks funding to generate a vaccine to avert autoimmune T1D.
  • Dr. Kristin Mussar at the University of Washington seeks funding to uncover new cell replacement approaches for the treatment of type 1 diabetes.
  • Dr. Corentin Cras-Méneur of the University of Michigan seeks funding to explore ways to improve pancreatic function.

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