Tag: diabetes

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Delivering Cancer and Diabetes Drugs in Pills Instead of Injections

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In a new Journal of the American Chemical Society paper, researchers describe how they are developing a new way for diabetes and cancer patients to manage their conditions by enabling drugs to be delivered in pill form instead of through injections.

Some drugs for these diseases are water soluble, so transporting them through the intestines, is not feasible and makes them impossible to administer orally. However, UCR scientists have created a chemical “tag” that can be added to these drugs, allowing them to enter blood circulation via the intestines.

This tag is composed of a small peptide. “Because they are relatively small molecules, you can chemically attach them to drugs, or other molecules of interest, and use them to deliver those drugs orally,” said research leader Min Xue, UC Riverside chemistry professor.

Xue’s laboratory was testing something unrelated when the researchers observed these peptides making their way into cells.

“We did not expect to find this peptide making its way into cells. It took us by surprise,” Xue said. “We always wanted to find this kind of chemical tag, and it finally happened serendipitously.”

This observation was unexpected, Xue said, because previously, the researchers believed that this type of delivery tag needed to carry positive charges to be accepted into the negatively charged cells. Their work with this neutral peptide tag, called EPP6, shows that belief was not accurate.

Testing the peptide’s ability to move through a body, the Xue group teamed up with Kai Chen’s group in the Keck School of Medicine at the University of Southern California and fed the peptide to mice. With PET scans, the team observed the peptide accumulating in the intestines, and documented its ultimate transfer into the animals’ organs via the blood.

Having proven the tag successfully navigated the circulatory systems through oral administration, the team now plans to demonstrate that the tag can do the same thing when attached to a selection of drugs. “Quite compelling preliminary results make us think we can push this further,” Xue said.

Many drugs, including insulin, must be injected. The researchers are hopeful their next set of experiments will change that, allowing them to add this tag to a wide variety of drugs and chemicals, changing the way those molecules move through the body.

“This discovery could lift a burden on people who are already burdened with illness,” Xue said.

Source: University of California – Riverside

Categories : Metabolic DisordersTags :

Strengthening the Case for the ‘Trigger Finger’ and Diabetes Link

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Diabetes - person measures blood glucose
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Locked fingers, known as ‘trigger finger’, are more common among people with diabetes than in the general population, finds a study published in Diabetes Care. A study led by Lund University in Sweden shows that the risk of being affected increases with hyperglycaemia.

Trigger finger means that one or more fingers, often the ring finger or thumb, ends up in a bent position that is difficult to straighten out. It is due to the thickening of tendons, which bend the finger, and their connective tissue sheath, which means that the finger becomes fixed in a bent position towards the palm. It is a painful condition that can often be treated with cortisone injections, but sometimes requires surgery.

“At the hand surgery clinic, we have noted for a long time that people with diabetes, both type 1 and type 2, are more often affected by trigger finger. Over 20 percent of those who require surgery for this condition are patients who have, or will develop, diabetes,” says Mattias Rydberg, doctoral student at Lund University, resident physician at Skåne University Hospital and first author of the study.

To study whether blood sugar dysregulation increases the risk of trigger finger, the researchers examined two registers. The prevalence of trigger finger in the general population 1–1.5%, but is 10-15% among those who have diabetes, particularly in type 1 diabetes.

The study added to the evidence for a link between blood sugar and trigger finger. Hyperglycaemia increased the risk of being affected by trigger finger among both men and women in the groups with type 1 diabetes and type 2 diabetes. The group of men with the worst regulated blood sugar (HbA1c > 64) had up to 5 times as high a risk of being affected than men with well-regulated (HbA1c < 48) blood sugar.

“However, we can’t know for certain if any of the groups seek healthcare more often than others which could be a factor that affects the results,” said Mattias Rydberg.

The mechanism, or mechanisms, behind the increased risk are unknown, but there are theories that high blood sugar makes both the flexor tendons and their connective tissue sheaths thicker, thus causing them to lock more easily. It was previously known that those with unregulated blood sugar are more prone to nerve entrapments in the hand.

“It is important to draw attention to the complications from diabetes and how they can arise in order to discover them early, which enables faster treatment and thus a better outcome. In addition to nerve compressions and trigger finger, there may also be a link with thickening of the connective tissue in the palm (Dupuytren’s contracture), impairment of joint movement and the risk of arthritis at the base of the thumb. The mechanisms behind these complications probably differ in the case of diabetes. The results of this study are interesting, as we can show that blood sugar dysregulation has a connection with the development of trigger finger,” said Lars B. Dahlin, professor at Lund University and consultant in hand surgery at Skåne University Hospital.

Future research will measure the effectiveness of operating on patients with diabetes who are affected by trigger finger.

“From our experience at the clinic, surgery goes well and there are few complications, but it takes a little longer for patients with type 1 and type 2 diabetes to regain full movement and function. We want to investigate this hypothesis further. Another interesting idea is to see if trigger finger could be a warning signal for type 2 diabetes. It is far from all who are affected by trigger finger that have diabetes, but it would be interesting to see if by using modern registers we can discover those who are in the risk zone for developing diabetes,” concluded Mattias Rydberg.

Source: Lund University

Categories : Metabolic DisordersTags : 1 Comment

Arthritis Drug Auranofin may Improve Diabetes Symptoms

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Researchers have found that rheumatoid arthritis drug auranofin can potentially be repurposed to improve diabetes-associated symptoms. The study, which used a mouse model, appeared in the journal Cell Metabolism.

Although clear links have been identified between inflammation in white adipose tissue and insulin resistance in humans and rodents, broad anti-inflammatory treatments lack durable clinical efficacy on diabetes. In the current study, the researchers delved deeper into this association between inflammation and diabetes by looking for existing drugs that might affect both conditions.

“We computationally screened a small-molecule dataset and identified auranofin, an FDA-approved drug that has been used to treat rheumatoid arthritis, a condition involving inflammation,” said first and co-corresponding author Dr Aaron R. Cox, instructor of medicine-endocrinology, diabetes and metabolism at Baylor. “Auranofin exerts anti-inflammatory properties, which many people suspected would be beneficial in obesity and diabetes; however, nothing was really known about how it might affect metabolism.”

The team evaluated the metabolic effects of auranofin in a mouse model of diabetes in which the animals consume a high-fat diet.

“We discovered that auranofin has anti-inflammatory and anti-diabetic effects that are independent from each other,” said co-corresponding author Dr Sean Hartig, associate professor at Baylor. “Auranofin improved insulin sensitivity, or the body’s ability to respond to insulin to keep blood sugar at healthy levels. The drug also normalised obesity-associated changes such as hyperinsulinaemia in the mouse model. In addition, we found that auranofin accumulation in white adipose tissue reduced inflammatory responses without altering body composition in obese mice.”

Looking into the mechanism of these metabolic changes, the team discovered that auranofin’s anti-diabetic effects involved reduction of leptin levels. Leptin is a hormone whose levels markedly increase in obesity, contributing to insulin resistance and diabetes. In addition, auranofin restored white adipose tissue’s ability to respond to catecholamines, which are signals that increase metabolic activities in adipose tissue, triggering the burning of lipids at a higher rate.

“These changes coupled together contribute to the overall improvement in insulin sensitivity of the mice, leading to blood glucose control, which is the ultimate goal of diabetes treatments,” Dr Cox said. “High levels of glucose in the blood are detrimental to many tissues in the body. Uncontrolled, diabetes can lead to organ failure.”

Source: Baylor College of Medicine

Categories : Metabolic Disorders Obstetrics & GynaecologyTags :

Obesity and Diabetes in Pregnancy may Raise Child’s ADHD Risk

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A recent study has found that children born to women with gestational diabetes and obesity may have twice the risk of developing attention-deficit/hyperactivity disorder (ADHD) compared to those born to mothers without obesity. The findings, published in the Journal of Clinical Endocrinology & Metabolism, also found found that in women with a healthy weight gain during pregnancy, this risk increase was not seen.

ADHD is a growing problem. According to data from 2016-2019, 6 million children aged 3–17 years have received an ADHD. Maternal obesity is a major risk factor for ADHD in children, and roughly 30% of women have obesity at their first doctor’s visit during pregnancy, rising to 47% in women with gestational diabetes. Excessive weight gain during pregnancy in this population is a risk factor for children developing ADHD.

“Our study found pregnant women with obesity and gestational diabetes had children with long-term mental health disorders such as ADHD,” said Verónica Perea, MD, PhD, of the Hospital Universitari Mutua Terrassa in Barcelona. “We did not find this association when these women gained a healthy amount of weight during pregnancy.”

Studying 1036 children born to women with gestational diabetes, the researchers found that 13% of these children were diagnosed with ADHD. When compared to mothers without obesity, the researchers found children of women with gestational diabetes and obesity were twice as likely to have ADHD compared to those born to mothers without obesity.

Notably, this association was only seen in women with gestational diabetes, obesity and excessive weight gain during pregnancy. There was no increased risk of ADHD in children of women with gestational diabetes and obesity if the amount of weight these women gained during pregnancy was within the normal range.

“It’s important for clinicians to counsel their patients on the importance of healthy weight gain during pregnancy,” Perea said.

Source: The Endocrine Society

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Overweight Can be The Result of Insufficient Insulin Processing

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Obesity
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Lifestyle leading to overweight increases the risk of metabolic diseases such as diabetes – but the relationship also works in reverse, according to a new study. If insulin production is compromised, as is the case in the early stages of type 2 diabetes, this can contribute to overweight. The researchers report their findings in the journal Nature Communications.

When hormone activation goes awry

The research group, led by Dr Daniel Zeman-Meier of the University Hospital of Basel, focused on protease PC1/3 – a key enzyme in the body that transforms various inactive hormone precursors into the final, active forms. Sever endocrine disorders can result if PC1/3 does not function properly. The consequences include a feeling of uncontrollable hunger and severe overweight.

“Until now, it was assumed that this dysregulation is caused by a lack of activation of satiety hormones,” explained Dr Zeman-Meier. “But when we turned off PC1/3 in the brains of mice, the animals’ body weight did not change significantly.” The researchers concluded from this that something other than a brain malfunction must be responsible.

Incorrect activation of insulin leads to hunger and overweight

In their next step, they tested whether overweight could be caused by incorrect activation of other hormones. Among other things, PC1/3 activates insulin. “Investigating the role of insulin production as a cause of overweight was obvious,” said Dr Zeman-Meier. The researchers shut off PC1/3 specifically in the insulin-producing beta cells of the pancreas in mice. The animals consumed significantly more calories and soon became overweight and diabetic.

An important mechanism in humans

“These results are also interesting because PC1/3 is reduced in the pancreas of patients with prediabetes,” says Professor Marc Donath, research leader and final author of the study. This indicates that incorrect insulin activation could cause overweight as well as result from it.

But PC1/3 is also important in the weight regulation of healthy individuals, Prof Donath stressed. The researchers were able to show that the gene expression of PC1/3 in the pancreas is negatively correlated with body weight in the general population — meaning that sufficient PC1/3 promotes a healthy body weight.

The finding that a defect in the beta cells is a trigger of overweight promises new therapeutic possibilities. For example, it is conceivable that medications could be used to reduce the production of immature insulin precursors, creating a new tool in the fight against overweight and diabetes.

Source: University of Basel

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Breakthrough in Development of an Oral Insulin Tablet

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A team of researchers working on developing oral insulin tablets as a replacement for daily insulin injections have made a game-changing discovery, which they published in Scientific Reports. The University of British Columbia team found that it’s not so much the composition of the pill so much as where it’s absorbed.

Researchers have discovered that insulin from the latest version of their oral tablets is absorbed by rats in the same way that injected insulin is.

“These exciting results show that we are on the right track in developing an insulin formulation that will no longer need to be injected before every meal, improving the quality of life, as well as mental health, of more than nine million Type 1 diabetics around the world.” said Professor Anubhav Pratap-Singh, the principal investigator.

He said the inspiration behind the search for a non-injectable insulin comes from his diabetic father, who has had to inject insulin for the past 15 years.

According to Dr Alberto Baldelli, they are now seeing nearly 100% of the insulin from their tablets go straight into the liver. In previous attempts to develop a drinkable insulin, most of the insulin would accumulate in the stomach.

“Even after two hours of delivery, we did not find any insulin in the stomachs of the rats we tested. It was all in the liver and this is the ideal target for insulin – it’s really what we wanted to see,” said PhD candidate Yigong Guo, first author of the study.

Changing the mode of delivery

When it comes to insulin delivery, injections are not the most comfortable or convenient for diabetes patients. But with several other oral insulin alternatives also being tested and developed, the UBC team worked to solve where and how to facilitate a higher absorption rate.

The team instead developed a different kind of tablet that isn’t made for swallowing, but instead dissolves when placed between the gum and cheek.

This method makes use of the buccal mucosa to deliver all the insulin to the liver without wasting or decomposing any insulin along the way.

“For injected insulin we usually need 100iu per shot. Other swallowed tablets being developed that go to the stomach might need 500iu of insulin, which is mostly wasted, and that’s a major problem we have been trying to work around,” explained Yigong.

Most swallowed insulin tablets in development tend to release insulin slowly over two to four hours, while fast-release injected insulin can be fully released in 30–120 minutes.

“Similar to the rapid-acting insulin injection, our oral delivery tablet absorbs after half an hour and can last for about two to four hours long,” said Dr Baldelli.

Potential broad benefits

The study is yet to go into human trials, and for this to happen Prof Pratap-Singh says they will require more time, funding and collaborators. But beyond the clear potential benefits to diabetics, he says the tablet they are developing could also be more sustainable, cost-effective and accessible.

“More than 300 000 Canadians have to inject insulin multiple times per day,” Prof Pratap-Singh said. “That is a lot of environmental waste from the needles and plastic from the syringe that might not be recycled and go to landfill, which wouldn’t be a problem with an oral tablet.”

He explains that their hope is to reduce the cost of insulin per dose since their oral alternative could be cheaper and easier to make. Pills would be easier for diabetics as well, since currently their doses need to be kept cool.

Source: University of British Columbia

Categories : Metabolic DisordersTags :

Why Only Some Obese Patients Develop Diabetes

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A 3D map of the islets in the human pancreas. Source: Wikimedia

Oregon State University researchers have used a new analytical method to shed light on an enduring mystery in type 2 diabetes: why some obese patients develop diabetes and others don’t. The reason is down to a genetic pathway linking diet and gut microbiota to macrophages and white adipose tissue. Their findings appear in the Journal of Experimental Medicine.

Type 2 diabetes is frequently associated with obesity. Ins some patients, that means insulin resistance. Later stages of the disease sees the pancreas producing insufficient insulin to maintain normal glucose levels.

In either case, hyperglycaemia is the result, which, if left untreated, impairs many major organs, sometimes to disabling or life-threatening degrees. Overweight status is a key risk factor for type 2 diabetes, often a result of eating too much fat and sugar in combination with low physical activity.

Associate Professors Andrey Morgun and Natalia Shulzhenko of OSU and Giorgio Trinchieri of the National Cancer Institute developed a novel analytical technique, multi-organ network analysis, to explore the mechanisms behind early-stage systemic insulin resistance.

The scientists sought to learn which organs, biological pathways and genes are playing roles.

The findings showed that a particular type of gut microbe leads to white adipose tissue containing macrophage cells associated with insulin resistance.

“Our experiments and analysis predict that a high-fat/high-sugar diet primarily acts in white adipose tissue by driving microbiota-related damage to the energy synthesis process, leading to systemic insulin resistance,” said Morgun. “Treatments that modify a patient’s microbiota in ways that target insulin resistance in adipose tissue macrophage cells could be a new therapeutic strategy for type 2 diabetes.”

The human gut microbiome is incredibly complex, comprising more than 10 trillion microbial cells from about 1000 different bacterial species.

Associate Profs Morgun and Shulzhenko, in earlier research developed a computational method, transkingdom network analysis, that predicts specific types of bacteria controlling the expression of mammalian genes connected to specific medical conditions such as diabetes.

“Type 2 diabetes is a global pandemic, and the number of diagnoses is expected to keep increasing over the next 10 years,” Associate Prof Shulzhenko said. “The so-called ‘western diet’ – high in saturated fats and refined sugars – is one of the primary factors. But gut bacteria have an important role to play in mediating the effects of diet.”

In the new study, the scientists made use of transkingdom network analysis and multi-organ network analysis. Mouse experiments examined the intestine, liver, muscle and white adipose tissue, and the molecular signature (gene expression) of white adipose tissue macrophages in obese human patients.

“Diabetes induced by the western diet is characterised by microbiota-dependent mitochondrial damage,” Associate Prof Morgun said. “Adipose tissue has a predominant role in systemic insulin resistance, and we characterised the gene expression program and the key master regulator of adipose tissue macrophage that are associated with insulin resistance. We discovered that the Oscillibacter microbe, enriched by a western diet, causes an increase of the insulin-resistant adipose tissue macrophage.”

The researchers add, however, that Oscillibacter is likely not the only microbial regulator for expression for the genetic pathway they discovered, while clearly instrumental, is probably not the only important pathway, depending on which gut microbes are present.

“We previously showed that Romboutsia ilealis worsens glucose tolerance by inhibiting insulin levels, which may be relevant to more advanced stages of type 2 diabetes,” Shulzhenko said.

Source: Oregon State University

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Diabetes may Weaken Teeth, Promoting Tooth Decay

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People with both Type 1 and Type 2 diabetes are prone to tooth decay, and a new study published in Archives of Oral Biology may explain why: reduced strength and durability of enamel and dentin, the hard substance under enamel that gives structure to teeth.

Researchers induced Type 1 diabetes in 35 mice and used a Vickers microhardness tester to compare their teeth with those of 35 healthy controls over 28 weeks. Although the two groups started with comparable teeth, enamel grew significantly softer in the diabetic mice after 12 weeks, and the gap continued to widen throughout the study. Significant differences in dentin microhardness arose by week 28.

“We’ve long seen elevated rates of cavity formation and tooth loss in patients with diabetes, and we’ve long known that treatments such as fillings do not last as long in such patients, but we did not know exactly why,” said Mohammad Ali Saghiri, an assistant professor of restorative dentistry at the Rutgers School of Dental Medicine.

The study advances a multiyear effort by Assistant Prof Saghiri and other researchers to understand how diabetes affects dental health and to develop treatments that counter its negative impact. Previous studies have established that people with both types of diabetes have significantly elevated rates of most oral health issues, both in the teeth and the soft tissues that surround them. Assistant Prof Saghiri and other researchers also have demonstrated that diabetes can interfere with the ongoing process of adding minerals to teeth as they wear away from normal usage.

“This is a particular focus of mine because the population of people with diabetes continues to grow rapidly,” Assistant Prof Saghiri said. “There is a great need for treatments that will allow patients to keep their teeth healthy, but it has not been a major area for research.”

Source: EurekAlert!

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How Breast Cancer Cells Sabotage Insulin Production to Fuel Themselves

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Scanning Electron Micrograph of a breast cancer cell. Credit: NIH

Breast cancer and diabetes have long been suspected to have some kind of relationship, but now new research in Nature Cell Biology reveals how breast cancer cells sabotage insulin production to fuel their own cravings for glucose.

Diabetes risk begins to increase two years after a breast cancer diagnosis, and by 10 years post-diagnosis, the risk is 20% higher in breast cancer survivors than in age-matched women without breast cancer.

But these epidemiological linkages are not clear-cut or definitive, and some studies have found no associations at all. In the paper, a research team describe a possible biological mechanism connecting the two diseases, in which breast cancer suppresses the production of insulin, resulting in diabetes, and the impairment of blood sugar control promotes tumour growth.

“No disease is an island because no cell lives alone,” said corresponding study author Shizhen Emily Wang, PhD, professor of pathology at UC San Diego School of Medicine. “In this study, we describe how breast cancer cells impair the function of pancreatic islets to make them produce less insulin than needed, leading to higher blood glucose levels in breast cancer patients compared to females without cancer.”

The researchers name the culprit as extracellular vesicles (EV), which carry DNA, RNA, proteins, fats and other materials between cells, a sort of cargo communication system.

The cancer cells were found to be secreting microRNA-122 into the vesicles. When vesicles reach the pancreas, Prof Wang said, they can enter the islet cells, offload their miR-122 cargo and damage the islets’ critical function in maintaining a normal blood glucose level.

“Cancer cells have a sweet tooth,” Prof Wang said. “They use more glucose than healthy cells in order to fuel tumor growth, and this has been the basis for PET scans in cancer detection. By increasing blood glucose that can be easily used by cancer cells, breast tumors make their own favorite food and, meanwhile, deprive this essential nutrient from normal cells.”

Feeding mice slow-releasing insulin pellets or an SGLT2 inhibitor restored normal control of glucose in the presence of a breast tumour, in turn suppressed the tumour’s growth.

“These findings support a greater need for diabetes screening and prevention among breast cancer patients and survivors,” remarked Prof Wang, noting that a miR-122 inhibitor is currently in clinical trial as a potential treatment for chronic hepatitis C. It has been found to be effective in restoring normal insulin production and suppressing tumour growth in mouse models of breast cancer.

“These miR-122 inhibitors, which happen to be the first miRNA-based drugs to enter clinical trials, might have a new use in breast cancer therapy,” Prof Wang posited.

Source: University of California – San Diego

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20 Years of Data Proves Safety of Islet Cell Transplantation

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A 3D map of the islet density routes throughout the healthy human pancreas. Credit: MariusOrion/Wikimedia Commons

In a paper published in The Lancet Diabetes & Endocrinology, researchers report that their long-running islet cell transplant programme has shown that is safe and helps control diabetes for up to 20 years.

The researchers reported on patient survival, graft survival, insulin independence and protection from life-threatening hypoglycaemia for 255 patients who have received a total of more than 700 infusions of islets at the University of Alberta Hospital over the past two decades.

“We’ve shown very clearly that islet transplantation is an effective therapy for patients with difficult-to-control Type 1 diabetes,” said Professor James Shapiro at the University of Alberta. “This long-term safety data gives us confidence that we are doing the right thing.”

In Type 1 diabetes, the immune system mistakenly destroys the cells within the insulin-producing islets so patients have to take insulin by injection. Patients with hard-to-control diabetes face dangerous hypo- or hyperglycaemia and long-term complications.

Between March 1999 and October 2019, 255 patients received islet transplants by infusion into their livers. Seventy per cent of the grafts survived for a median time of nearly six years. The researchers reported that a combination of two anti-inflammatory medications given during the first two weeks following transplant significantly increased long-term islet function.

The transplant recipients have to take lifelong immunosuppression drugs, which in some cases lead to skin cancer or infection, but most such complications were not fatal during the study period.

After two or more islet infusions and a median time of 95 days following the first transplant, 79% of the recipients could go off insulin. A year later, 61% remained insulin-independent, 32% at five years and 8% after 20 years, the researchers reported. Even though most patients had to start taking insulin again, doses were generally much smaller and diabetes control was improved.

“Being completely free of insulin is not the main goal,” said Prof Shapiro. “It’s a big bonus, obviously, but the biggest goal for the patient — when their life has been incapacitated by wild, inadequate control of blood sugar and dangerous lows and highs — is being able to stabilise. It is transformational.”

With trials ongoing in other countries, Prof Shapiro will continue to focus on finding a more plentiful supply of islet cells to replace the current reliance on deceased donors. Human trials have already shown success using stem cells programmed to produce insulin. Trials have just started to transplant cells that have been gene edited to make them invisible to the immune system.

“Islet transplant as it exists today isn’t suitable for everybody, but it shows very clear proof of concept that if we can fix the supply problem and minimize or eliminate the anti-rejection drugs, we will be able to move this treatment forward and make it far more available for children and adults with Type 1 and Type 2 diabetes in the future,” said Shapiro.

Source: University of Alberta