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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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insulin

“Artificial Pancreas” Is Approved

Original article published by The JAMA Network on October 4, 2016. Click here to read the original article.

A new device that automatically monitors blood glucose levels and adjusts insulin levels has received FDA approval. The device, manufactured by Dublin-based Medtronic PLC, is the first such system to gain the agency’s blessing.

The new MiniMed 670G hybrid closed-loop system is intended for people aged 14 years or older who have type 1 diabetes. Because it operates with a smart algorithm that learns an individual’s insulin needs and delivers appropriate basal doses 24 hours a day, little user input is required. Patients who use the system will only have to enter their mealtime carbohydrates, accept bolus correction recommendations, and periodically calibrate the sensor.

[su_button url=”http://jamanetwork.com/journals/jama/article-abstract/2584035″ target=”blank” style=”flat” background=”#64b243″ size=”6″ center=”yes” radius=”5″ icon=”icon: angle-right”]Continue Reading[/su_button]

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t1d research

Antibiotic-Mediated Gut Microbiome Perturbation Accelerates Development of Type 1 Diabetes in Mice

Original article published by PubMed on August 22, 2016. Click here to read the original article.

The early life microbiome plays important roles in host immunological and metabolic development. Because the incidence of type 1 diabetes (T1D) has been increasing substantially in recent decades, we hypothesized that early-life antibiotic use alters gut microbiota, which predisposes to disease. Using non-obese diabetic mice that are genetically susceptible to T1D, we examined the effects of exposure to either continuous low-dose antibiotics or pulsed therapeutic antibiotics (PAT) early in life, mimicking childhood exposures. We found that in mice receiving PAT, T1D incidence was significantly higher, and microbial community composition and structure differed compared with controls. In pre-diabetic male PAT mice, the intestinal lamina propria had lower Th17 and Treg proportions and intestinal SAA expression than in controls, suggesting key roles in transducing the altered microbiota signals. PAT affected microbial lipid metabolism and host cholesterol biosynthetic gene expression. These findings show that early-life antibiotic treatments alter the gut microbiota and its metabolic capacities, intestinal gene expression and T-cell populations, accelerating T1D onset in non-obese diabetic mice.

[su_button url=”https://www.ncbi.nlm.nih.gov/pubmed/27782139?dopt=Abstract&utm_source=twitterfeed&utm_medium=twitter#” target=”blank” style=”flat” background=”#64b243″ size=”6″ center=”yes” radius=”5″ icon=”icon: angle-right”]Continue Reading[/su_button]

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Single-Cell Mass Cytometry Analysis of the Human Endocrine Pancreas

Single-Cell Mass Cytometry Analysis of the Human Endocrine Pancreas

Original article published by Cell Press on October 11, 2016. Click here to read the original article.

Highlights

  • Mass cytometry promotes high-throughput phenotyping of islets at a single-cell level
  • Alpha cells maintain higher basal proliferation and are more responsive to mitogens
  • Beta cells exist in distinct states

Summary

The human endocrine pancreas consists of multiple cell types and plays a critical role in glucose homeostasis. Here, we apply mass cytometry technology to measure all major islet hormones, proliferative markers, and readouts of signaling pathways involved in proliferation at single-cell resolution. Using this innovative technology, we simultaneously examined baseline proliferation levels of all endocrine cell types from birth through adulthood, as well as in response to the mitogen harmine. High-dimensional analysis of our marker protein expression revealed three major clusters of beta cells within individuals. Proliferating beta cells are confined to two of the clusters.

[su_button url=”http://www.cell.com/cell-metabolism/abstract/S1550-4131(16)30486-7?elqTrackId=6789327ac64b42228e73a1532b63e754&elq=d19a63a48c4c401c9e53b0028684553c&elqaid=16965&elqat=1&elqCampaignId=9″ 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

U.S. FDA approves Medtronic’s ‘artificial pancreas’ for diabetes

Original article published by Yahoo! Finance. Click here to read the original article.

Medtronic Plc won U.S. approval on Wednesday for an “artificial pancreas” that is the first device to automatically deliver the right dose of insulin to patients with type 1 diabetes, freeing them from continually monitoring insulin levels throughout each day.

The U.S. Food and Drug Administration, in its approval of the device, the MiniMed 670G, hailed it as a breakthrough.

The device offers type 1 diabetics “greater freedom to live their lives without having to consistently and manually monitor baseline glucose levels and administer insulin,” Dr. Jeffrey Shuren, director of the FDA’s medical device division, said in a statement.

Analysts said the FDA approved the device six months sooner than expected. However, it will not be available until the spring of 2017.

The MiniMed 670G is the first device that allows a glucose sensor to communicate with an insulin pump and automatically regulate the insulin flow. The device is approved for those aged 14 and older.

The device measures glucose levels every five minutes and automatically administers insulin as needed. Patients will still need to instruct the device to deliver extra insulin for meals and notify the device when they exercise – which lowers glucose levels.

About 1.25 million American children and adults have type 1 diabetes, a condition in which the pancreas produces little or no insulin – a hormone needed to obtain energy from food.

Patients take insulin injections at various times of the day. But blood sugar can drop to dangerously low levels if too much insulin circulates in the bloodstream, requiring patients to frequently or continually monitor their insulin levels throughout the entire day.

“This device will mean peace of mind, in knowing a person will be in normal blood sugar range a great majority of the time,” said Derek Rapp, chief executive officer of the Juvenile Diabetes Research Foundation, which has spent $116 million on research in the artificial pancreas field.

Rapp, who has a college-age son with type 1 diabetes, said his son as a child had to be awakened many times each evening so his finger could be pricked for a blood sample, to ensure his blood sugar level was in an acceptable range. If too low, his son would be given fruit juice or a snack. If too high, he would be given insulin.

“It is a major news event that a system of this kind has been approved – the first time a pump will administer insulin as a result of information it receives from a sensor,” Rapp said.

The Medtronic device includes a coin-size sensor with a protruding needle that is slipped under the skin and continually monitors glucose levels. It is held in place with a sticky backing. The other main component is an insulin pump, often worn on the side of the abdomen, which has tubes that lead to a catheter that delivers the insulin.

Insulin pumps are currently used by more than a third of U.S. patients with type 1 diabetes, but they require manual adjustment to administer the needed insulin dose. Many patients also wear sensors that continually monitor their glucose levels.

Several insulin pump makers, including Johnson & Johnson , Tandem Diabetes Care Inc and Insulet Corp , are teaming up with sensor maker Dexcom Inc to develop devices like Medtronic’s but are several years behind, according to Jefferies analyst Raj Denhoy.

He said the Medtronic system is a big step for patients, but the Holy Grail would be a completely automatic artificial pancreas that does not need any intervention, including for meals or exercise. Such a product is probably at least five years away from development, he said.

Although Medtronic has not announced a price for the MiniMed 670G, Denhoy estimated it may cost $5,000 to $8,000, with the annual cost of disposable sensors another few thousand dollars.

[su_button url=”http://finance.yahoo.com/news/u-fda-approves-medtronics-artificial-185726604.html” target=”blank” style=”flat” background=”#64b243″ size=”6″ center=”yes” radius=”5″ icon=”icon: angle-right”]Continue Reading[/su_button]

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Gladitood

Support a Cure for Type 1 Diabetes on Gladitood

Millions of children and adults struggle with type 1 diabetes (T1D). Throughout the month of October, we’ll be raising money to help find a cure on Gladitood, a crowdfunding platform that helps nonprofits raise funds for important causes. This is an exciting opportunity but we need your help

Consider Autumn, a woman in her mid-20s who was diagnosed at the age of nine. Every day she is carefully balancing her blood sugar through painfully pricking her fingers to manage her blood sugar. She’s been hospitalized for diabetic ketoacidosis, a condition where they body produces excess blood acid, which can quickly become fatal if not treated. Diabetes doesn’t just affect her, it affects her family, friends and co-workers too.

We need to raise $5,000 by the end of October.

How Can You Help?

Donate to Diabetes Research Connection on Gladitood. Donating to DRC through Gladitood is easy. Simply visit our campaign page, choose a donation level to the right that you’d like to contribute to, then follow the prompts to donate through Gladitood’s secure platform. In exchange for donating, you’ll be able to choose from a variety of “rewards,” ranging from a Facebook shout-out, to tickets to our Brews and Blood Sugar event, to a Q&A session with a T1D researcher. There is no minimum or maximum donation; donors can contribute as little or as much as they want, and all donations are tax-deductible as DRC is a 501(c)(3) nonprofit organization.

Spread the word about our Gladitood campaign! Whether you post about it on Facebook, email it to your contacts or share the link with your co-workers, we’re grateful for everyone who shares our project and helps us raise $5,000 through Gladitood. For those that want to be more involved, Gladitood allows volunteers to create a fundraising page, set a personal fundraising goal, and share their unique URL link with their network in order to raise money on behalf of DRC.

Why Is DRC Raising Money on Gladitood?

Gladitood offers the ability for donors to fundraise on DRC’s behalf by creating and sharing a custom fundraising page with your network of family and friends. Running a project on Gladitood helps spread the word about our mission, just by taking our organization to donors looking for a place to give. The more visibility, the more likely we are to meet our goal and continue to fund innovative, peer-reviewed T1D research.

How Will the Money Raised Through Gladitood be Used?

Donations to the General Fund collected through Gladitood will help early-career scientists get their ideas off the ground by providing funds to conduct peer-reviewed research designed to prevent, cure and treat T1D. The General Fund, after reasonable reserves, may be used to complete funding for research projects that are short of their goal. DRC’s operating costs are kept as low as possible and are targeted to be less than 10% of gross revenue.

Unfortunately, scientific research is expensive. Just consumable supplies needed for a research project can cost $20,000 or more. By raising money that goes directly to the scientists researching T1D, we’re able to ease the financial burden of research and fight for a cure for T1D.

Visit our Gladitood campaign page today to support our T1D research and help us reach our $5,000 goal by the end of October.

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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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