Scientists make a major breakthrough to treat fibrotic diseases that cause organ failure

Researchers from Duke-NUS Medical School (Duke-NUS) and the National Heart Centre Singapore (NHCS) have discovered that a critical protein, known as interleukin 11 (IL11) is responsible for fibrosis and causes organ damage. While it is surprising that the importance of IL11 has been overlooked and misunderstood for so long, it has now been very clearly demonstrated by this work.

A protein known as transforming growth factor beta 12 (“TGFB1”) has long been known as the major cause of fibrosis and scarring of body organs, but treatments based on switching off the protein have severe side effects. The scientists discovered that IL11, is even more important than TGFB1 for fibrosis and that IL11 is a much better drug target than TGFB1.

Fibrosis is the formation of excessive connective tissue, causing scarring and failure of bodily organs and the skin. It is a very common cause of cardiovascular and renal disease, where excessive connective tissue destroys the structure and function of the organ with scar tissue. Compared to other Asians, American, and Europeans, Singaporeans have a higher prevalence of coronary artery disease, hypertension, and diabetes, the three most common diseases that lead to heart failure. In addition, kidney failure is an epidemic in Singapore and around the world. Fibrosis of the heart and kidney eventually leads to heart and kidney failure, thus this breakthrough discovery — that inhibiting IL11 can prevent heart and kidney fibrosis — has the potential to transform the treatment of millions of people around the world.

The international team, led by Professor Stuart Cook, Tanoto Foundation Professor of Cardiovascular Medicine, along with Assistant Professor Sebastian Schäfer, both from NHCS and Duke-NUS’ Programme in Cardiovascular and Metabolic Disorders, carried out the translational research to identify the key drivers of chronic fibrotic disease in heart, kidney, and other tissues. The team also includes researchers from Harvard University and University of California, San Diego/UCSD (USA), Max Delbrück Center for Molecular Medicine/MDC-Berlin (Germany), London Institute of Medical Sciences/MRC-LMS and Imperial College London (the UK), and the University of Melbourne (Australia).

“Fibrotic diseases represent a major cause of illness and death around the world. The discovery that IL11 is a critical fibrotic factor represents a breakthrough for the field and for drug development. It is an incredibly exciting discovery,” explained the study’s senior author, Professor Cook, who is also Director, National Heart Research Institute Singapore.

“Currently, more than 225 million people worldwide suffer from heart and kidney failure and there is no treatment to prevent fibrosis. The team is at the stage of developing first-in-class therapies to inhibit IL11 and this offers hope to patients with heart and kidney disease,” shared Professor Terrance Chua, Medical Director, National Heart Centre Singapore.

“This therapeutic target for fibrotic diseases of the heart, kidney and other organs may be exactly what we need to fill the unmet pressing clinical gap for preventing fibrosis in patients. We are proud to announce that the suite of intellectual property arising from this research has been licensed to a newly launched Singapore-funded biotechnology start-up Enleofen Bio Pte Ltd, which is co-founded by Professor Cook and Assistant Professor Schäfer,” said Professor Thomas Coffman, Dean of Duke-NUS Medical School.

A step closer to a cure for adult-onset diabetes

In healthy people, exosomes – tiny structures secreted by cells to allow intercellular communication – prevent clumping of the protein that leads to type 2 diabetes. Exosomes in patients with the disease don’t have the same ability. This discovery by a research collaboration between Chalmers University of Technology and Astrazeneca takes us a step closer to a cure for type 2 diabetes.

Proteins are the body’s workhorses, carrying out all the tasks in our cells. A protein is a long chain of amino acids that must be folded into a specific three-dimensional structure to work. Sometimes, however, they behave incorrectly and aggregate – clump together – into long fibres called amyloids, which can cause diseases. It was previously known that type 2 diabetes is caused by a protein aggregating in the pancreas.

“What we’ve found is that exosomes secreted by the cells in the pancreas stop that process in healthy people and protect them from type 2 diabetes, while the exosomes of diabetes patients do not,” says Professor Pernilla Wittung Stafshede, who headed the study whose results were recently published in the Proceedings of the National Academy of SciencesPNAS.

What we know now is that “healthy” exosomes bind the protein that causes diabetes on the outside, preventing it from aggregating; however, the results do not explain why. We also don’t know if type 2 diabetes is caused by “sick” exosomes or if the disease itself causes them to malfunction.

“The next step is to make controlled models of the exosomes, whose membranes contain lipids and proteins, to understand exactly what component affects the diabetes protein. If we can find which lipid or protein in the exosome membrane leads to that effect, and can work out the mechanism, then we’ll have a good target for development of treatment for type 2 diabetes.”

The study is actually a part of industrial doctoral student Diana Ribeiro’s thesis work, and a collaboration between Chalmers and Astrazeneca.

“She came up with the idea for the project herself,” says Wittung Stafshede, who is also Ribeiro’s academic advisor at Chalmers. “She had done some research on exosomes before and I had read a bit about their potential. It’s a fairly new and unexplored field, and honestly I didn’t think the experiments would work. Diana had access to pancreatic cells through Astrazeneca – something we’d never had access to before – and she conducted the studies very thoroughly, and this led us to our discovery.”

This is the first time that Wittung Stafshede has worked with Astrazeneca.

“We ought to collaborate more. It’s beneficial to them to understand what molecular experiments we can carry out, and it’s valuable for us to be able to put our research into a wider medical-clinical perspective. In the search for a future cure for type 2 diabetes, it’s also good for us to already be working with a pharmaceutical company.”

Biomarkers Pinpoint the Effects of Thirdhand Smoke on Liver and Lung Found to Worsen Over Time

Researchers at the University of California, Riverside have found that thirdhand-smoke (THS) exposure has a significant effect on health as early as one month after initiation of exposure – an effect that worsens with time.

THS results when exhaled smoke and smoke emanating from the tip of burning cigarettes gets on surfaces such as clothing, hair, homes, and cars. THS has been shown, in mice, to cause type 2 diabetes, hyperactivity, liver and lung damage, and wound-healing complications.

Using a system in which the exposure of mice to THS mimics that of human exposure in the homes of smokers, the researchers investigated the effects of THS exposure on biological molecular markers – or “biomarkers” – found in serum, and in liver and brain tissues. The liver plays a major role in metabolism and detoxification; the brain plays significant roles in behavior.

Thirdhand smoke results when exhaled smoke and smoke emanating from the tip of burning cigarettes gets on surfaces such as clothing, hair, homes, and cars.Photo credit: UCR University Communications.

Our goal was to determine the minimum amount of time required to cause physiological changes in mice when they are exposed to THS, using an exposure system that mimics human exposure,” said Manuela Martins-Green, professor and chair of the Department of Molecular, Cell and Systems Biology, who led the research. “We found that THS exposure as early as one month resulted in liver damage. THS exposure for two months resulted in further molecular damage, and at four to six months caused even more such damage. We also found that the mice showed insulin resistance after long-term THS exposure.”

Damage to the liver can hinder its capability to detoxify the body, leading to more damage by THS toxins. Martins-Green and her team examined the brains of THS-exposed mice and found that stress hormones, such as epinephrine, increased in one month of exposure. Additional stress hormones are seen at two months, four months, and six months, eventually causing immune fatigue in the mice.

Study results appear in Clinical Science, a Portland Press journal.

“THS is a stealth toxin, a silent killer,” Martins-Green said. “Contaminants can be absorbed through the skin and through breathing. Although our research was not done on humans, people should be aware that hotel rooms, cars, and homes that were occupied by smokers are very likely to be contaminated with THS.”

Most people are either unaware they are being exposed to THS, or don’t believe in the damage THS can do, according to Martins-Green. THS toxins, which are invisible but can be smelled, remain on surfaces for many years, and are resistant to even strong cleaning agents. Further, they accumulate and age by reacting with the ambient air, and change into carcinogenic chemicals.

Because THS is absorbed through skin, children are especially vulnerable given their close contact with household surfaces. Children frequently ingest these toxins by putting their hands in their mouths. They also absorb them through the skin. Children living in the homes where smoking has occurred have been known to show tobacco metabolites in their urine as well as tobacco-derived carcinogens called tobacco specific nitrosamines.

“Exposure to tobacco smoke deposited on surfaces in homes and in house dust is an entirely newly recognized form of toxicity: THS,” said Stephen T. Holgate, the Medical Research Council Clinical Professor of Immunopharmacology and Honorary Consultant Physician within Medicine at the University of Southampton, England, who was not involved in the research. “The fact that noxious chemicals in tobacco smoke once deposited change in chemistry to become even more toxic and carcinogenic is of considerable importance to the health of all of us, but our children in particular. The studies of this Californian research team puts further pressure on those who continue to smoke in homes to realize what they are doing to the health of others, as well as mandating a search for methods to remove such products from furnishings and materials used in homes. This study adds to the increasing concerns of chemical exposures in the home and the serious adverse effects this may cause.”

Martins-Green and her team exposed mice to THS for up to six months, collecting brain, liver, and serum samples after one, two, four, and six months of exposure to test for hormonal alterations, insulin resistance, metabolic syndrome, and damage to the liver and brain. To produce THS, the researchers exposed common household fabrics such as curtain material, upholstery, and carpet to secondhand smoke (smoke that is exhaled and that leaves a burning cigarette) that was generated in the lab by a smoking machine devised to mimic the behavior of human smokers. These materials were then placed in cages housing the mice, which were never exposed to secondhand smoke). The researchers then tested 15 biomarkers of damage and disease associated with THS exposure in serum and nine biomarkers in liver and brain tissue of the mice in a time-dependent manner.

“We found a positive time-dependent significant correlation with increased time of THS exposure and the effects it had on all the variables we measured,” Martins-Green said. “These biomarkers, once validated in humans, can be used as critical indicators of exposure to THS, and how long this exposure has occurred.”

In other preliminary experiments, Martins-Green and her team found that mice exposed to THS are less social than unexposed mice. Insulin problems arising because of THS are seen to worsen with the Western diet. Further, the researchers found that over time the mice get addicted to THS.

“Clearly, THS is affecting the behavior of mice,” said Martins-Green, who plans to write a review paper on the health impacts of THS. “It’s not hard to imagine what the impact is on children who, unlike most adults, cannot remove themselves from these harmful environments. Although our work was done on mice, we are confident our results will apply to humans.”

Compounds in cocoa may help delay onset of type 2 diabetes

What if eating chocolate helped prevent and treat diabetes? It’s crazy enough to laugh off.

But here’s the thing: BYU researchers have discovered certain compounds found in cocoa can actually help your body release more insulin and respond to increased blood glucose better. Insulin is the hormone that manages glucose, the blood sugar that reaches unhealthy levels in diabetes.

Of course, there’s a catch.

“You probably have to eat a lot of cocoa, and you probably don’t want it to have a lot of sugar in it,” said study author Jeffery Tessem, assistant professor of nutrition, dietetics and food science at BYU. “It’s the compound in cocoa you’re after.”

When a person has diabetes, their body either doesn’t produce enough insulin or doesn’t process blood sugar properly. At the root of that is the failure of beta cells, whose job it is to produce insulin. The new study, published in the Journal of Nutritional Biochemistry, finds beta cells work better and remain stronger with an increased presence of epicatechin monomers, compounds found naturally in cocoa.

To discover this, collaborators at Virginia Tech first fed the cocoa compound to animals on a high-fat diet. They found that by adding it to the high-fat diet, the compound would decrease the level of obesity in the animals and would increase their ability to deal with increased blood glucose levels.

The BYU team, comprised of graduate and undergraduate students in Tessem’s lab and the labs of Ben Bikman and Jason Hansen (BYU professors of physiology and developmental biology), then dove in and dissected what was happening on the cellular level — specifically, the beta cell level. That’s when they learned cocoa compounds named epicatechin monomers enhanced beta cells’ ability to secrete insulin.

“What happens is it’s protecting the cells, it’s increasing their ability to deal with oxidative stress,” Tessem said. “The epicatechin monomers are making the mitochondria in the beta cells stronger, which produces more ATP (a cell’s energy source), which then results in more insulin being released.”

While there has been a lot of research on similar compounds over the past decade, no one has been able to pinpoint which ones are the most beneficial or how exactly they bring about any benefit — until now. This research shows the epicatechin monomers, the smallest of the compounds, are the most effective.

“These results will help us get closer to using these compounds more effectively in foods or supplements to maintain normal blood glucose control and potentially even delay or prevent the onset of type-2 diabetes,” said study co-author Andrew Neilson, assistant professor of food science at Virginia Tech.

But rather than stocking up on the sugar-rich chocolate bars at the checkout line, researchers believe the starting point is to look for ways to take the compound out of cocoa, make more of it and then use it as a potential treatment for current diabetes patients. This research was funded, in part, thanks to grants from the Diabetes Action Research and Education Foundation and the American Diabetes Association.

Scientists Discover Common Obesity and Diabetes Drug Reduces Rise in Brain Pressure

Research led by the University of Birmingham, published today in Science Translational Medicine, has discovered that a drug commonly used to treat patients with either obesity or Type II diabetes could be used as a novel new way to lower brain pressure.

Raised brain pressure is common in emergency situations such as traumatic brain injury, hydrocephalus and stroke, and is also the cardinal feature of Idiopathic Intracranial Hypertension (IIH). IHH causes disabling daily headaches and severely raised pressure around the nerves in the eye. It also causes permanent vision loss in 25% of untreated people.

Over a three-year period, researchers at the University of Birmingham examined whether GLP-1 agonist drugs – existing drugs used in the treatment of diabetes and obesity – could reduce intracranial pressure in an animal model of raised brain pressure.

Corresponding author Dr Alexandra Sinclair, of the University of Birmingham’s Institute of Metabolism and Systems Research, said: “Treatments to lower brain pressure are lacking and new treatments are desperately needed.

“The current primary treatment in IIH is acetazolamide and this does not work well for many patients, while also having such severe side effects that our previous trials have shown that 48 per cent of patients stop taking it.

“We have shown that the GLP-1 agonist extendin-4 significantly reduces brain pressure rapidly and dramatically, by around 44 per cent with significant effects from just 10minutes of dosing – the biggest reduction we have seen in anything we have previously tested. What’s more, we found that the effects last at least 24 hours.

“These findings are rapidly translatable into a new novel treatment strategy for IIH as GLP-1 agonists are safe and widely-used drugs used to treat diabetes and obesity. They are also potentially game-changing for other conditions featuring raised brain pressure, including stroke, hydrocephalus and traumatic brain injury.

“We are very excited that this novel treatment strategy could make a landmark change for future patient care.”

The findings are due to be presented on September 8th and 9th in Vancouver at the International Headache Society Meeting, followed by the British Endocrine Society meeting in the UK from November 6th to 8th.

The research was carried out in collaboration with Birmingham Health Partners, the University of Copenhagen, and the Department of Neurology at University Hospitals Birmingham NHS Foundation Trust.

The University of Birmingham is now due to begin a clinical trial to test GLP-1 agonist drug in patients with raised brain pressure.

  • The University of Birmingham is ranked amongst the world’s top 100 institutions. Its work brings people from across the world to Birmingham, including researchers, teachers and more than 5,000 international students from over 150 countries.
  • Botfield et al (2017). ‘Glucagon-like peptide-1 receptor agonists as a therapeutic to reduce intracranial pressure’. Science Translational Medicine.
  • The research was funded by a variety of supporters including the National Institute for Health Research, Medical Research Council, the West Midlands Neuroscience Teaching and Research Fund and the University of Birmingham Research Development Fund.
  • The cause of IIH is unknown and it mainly affects obese women in their 20s and 30s, and has been associated with hormone problems. IIH is becoming an increasingly frequent problem and now affects 20 per 100,000 of obese women.

Towards a safe and scalable cell therapy for type 1 diabetes by simplifying beta cell differentiation

More than 36 million people globally are affected by type 1 diabetes (T1D), a lifelong disorder where insulin producing cells are attacked and destroyed by the immune system resulting in deficient insulin production that requires daily blood glucose monitoring and administration of insulin. While successful outcomes from islet transplantations have been reported, very few patients can benefit from this therapeutic option due to limited access to cadaveric donor islets. Human pluripotent stem cell (hPSCs) could offer an unlimited and invariable source of insulin-producing beta cells for treatments of a larger population of T1D patients.

With the vision of providing a cell therapy for type 1 diabetes patients, scientists at the University of Copenhagen have identified a unique cell surface protein present on human pancreatic precursor cells providing for the first time a molecular handle to purify the cells whose fate is to become cells of the pancreas – including insulin producing cells. The work, outlined in a landmark study entitled ‘Efficient generation of glucose-responsive beta cells from isolated GP2+ human pancreatic progenitors’ has just been published in Cell Reports and is available here.

A biomarker to clearly separate cell populations is a holy grail of cell therapy research for the reasons of safety and end product consistency. By using this cell surface marker, the researchers have engineered a streamlined and simplified differentiation process to generate insulin-producing cells for future treatment of type 1 diabetes patients. The process enables cost-efficient manufacturing and exploits at its core an intermediate cell bank of purified pancreatic precursor cells.

The discovery of the new marker has also enabled the researchers to streamline and refine the process of producing hPSC-derived insulin cells.

“By starting with a purified population of pancreatic precursor cells instead of immature stem cells we eliminate the risk of having unwanted tumorigenic cells in the final cell preparation and thus generate a safer cell product for therapeutic purposes”, explains Assistant Professor Jacqueline Ameri, first author on the paper.

Professor Henrik Semb, Managing Director of the Danish stem cell centre (DanStem) explains:

“Although significant progress has been made towards making insulin producing beta cells in vitro (in the lab), we are still exploring how to mass-produce mature beta cells to meet the future clinical needs. Our current study contributes with valuable knowledge on how to address key technical challenges such as safety, purity and cost-effective manufacturing, aspects that if not confronted early on, could hinder stem cell therapy from becoming a clinically and commercially viable treatment in diabetes.”

Indeed, Semb’s group is among the first to directly address not only the therapeutic concept but to incorporate very early the manufacturing considerations in their process to ensure that future commercialization will be possible.

To translate the current findings into a potential treatment of type 1 diabetes, Ameri and Semb aim to commercialize their recent patent pending innovations by establishing the spin out company PanCryos. PanCryos has assembled a team with experts in stem cell biology, islet transplantations, business and regulatory guidance and is currently funded by a KU POC grant and a pre-seed funding from Novo Seeds.

“In parallel with other groups in this field, we have been working on a cell therapy for type 1 diabetes for many years. What is unique about our approach is the simplification of our protocol which acknowledges that eventually the process will need to be scaled up for manufacturing. PanCryos is being established to ensure the development of the first scalable allogenic cell therapy for type 1 diabetes so we can offer the route to an affordable therapy by providing a product that will not be too expensive to produce, as has occurred too often in the developing cell therapy field”, explains Jacqueline Ameri, co-founder and CEO for PanCryos.

Higher BMI linked with increased risk of high blood pressure, heart disease, type 2 diabetes

Results of a new study add to the evidence of an association between higher body mass index (BMI) and increased risk of cardiometabolic diseases such as hypertension, coronary heart disease, type 2 diabetes, according to a study published by JAMA Cardiology.

A connection between higher BMI and cardiometabolic disease risk usually arise from observational studies that are unable to fully account for confounding by shared risk factors. Mendelian randomization (a method of analysis using genetic information) is an approach that partially overcomes these limitations. Using mendelian randomization, Donald M. Lyall, Ph.D., of the University of Glasgow, Scotland, and colleagues conducted a study that included 119,859 participants in the UK Biobank (with medical, sociodemographic and genetic data) to examine the association between BMI and cardiometabolic diseases and traits.

Of the individuals in the study, 47 percent were men; average age was 57 years. The researchers found that higher BMI was associated with an increased risk of coronary heart disease, hypertension, and type 2 diabetes, as well as increased systolic and diastolic blood pressure.

These associations were independent of age, sex, alcohol intake, and smoking history.

The authors write that the results of this study has relevance for public health policies in many countries with increasing obesity levels. “Body mass index represents an important modifiable risk factor for ameliorating the risk of cardiometabolic disease in the general population.”

A limitation of the study was that the sample lacked data on a complete range of potential mediators, such as lipid traits and glucose levels.

Diabetes drug prevents stiffening of heart muscle in obese mouse model

Overconsumption of a Western diet high in fats and refined sugars has contributed to a global increase in obesity and Type 2 diabetes. Obese and diabetic premenopausal women are more at risk of developing heart disease — even more than men of similar age and with similar health issues. A study by researchers at the University of Missouri School of Medicine found that the diabetes medication linagliptin can protect against stiffening of the left ventricle of the heart in overweight female mice. The finding may have implications for management of cardiovascular diseases in humans.

“In previous studies, we showed that young, female mice consuming a Western diet, high in fat, sucrose and high fructose corn syrup, not only gained weight, but also exhibited vascular stiffening consistent with obese premenopausal women,” said Vincent DeMarco, Ph.D., a research associate professor of endocrinology at the MU School of Medicine and the lead author of the study. “Our current study sought to understand if linagliptin prevents cardiac stiffening caused by eating a Western-style diet.”

Linagliptin is a medication prescribed to lower blood glucose in patients with Type 2 diabetes. The medication works by blocking the enzyme dipeptidyl peptidase-4, or DPP-4. Previous studies have shown that DPP-4 inhibitors offer protection against vascular inflammation and oxidative stress — conditions associated with cardiovascular stiffening.

DeMarco’s team studied 34 female mice that were fed either a normal diet or a simulated Western diet for four months. Another group of mice were fed a Western diet containing a low dose of linagliptin. The team used an ultrasound system, similar to that used in humans, to evaluate the function of the left ventricle of the heart.

“A heartbeat actually is a two-part pumping action that takes less than a second in healthy humans,” DeMarco said. “The first part, known as diastole, involves relaxation of the left ventricle while it fills with oxygenated blood from the lungs. After the left ventricle fills with blood, it then contracts and pushes blood into the aorta. This part of the cardiac cycle is referred to as systole. If the left ventricle becomes stiffer it will not be able to relax normally, and diastole will be impaired. This form of heart disease is known as diastolic dysfunction, which is a risk factor for a more serious heart condition known as diastolic heart failure.”

The mice fed the Western diet alone gained weight, exhibited increased heart weight and developed diastolic dysfunction. However, the mice fed the Western diet along with linagliptin did not develop diastolic dysfunction. They also exhibited less oxidative stress and inflammation in their hearts compared to the mice fed the Western diet alone.

“Oxidative stress and inflammation are two factors that can promote excess accumulation of collagen, also known as fibrosis, in the walls of the left ventricle,” DeMarco said. “In our study, we found that Western diet-fed mice had increased fibrosis in the left ventricle that was prevented by linagliptin.”

The team also found that linagliptin suppressed not only DPP-4 activity, but also TRAF3IP2 production. TRAF3IP2 is a protein responsible for initiating tissue oxidative stress, inflammation and fibrosis in the heart.

“This was a major novel finding of our study,” DeMarco said. “However, further research is required to determine exactly how linagliptin affects the function of this important protein.”

DeMarco also cautioned that linagliptin, like other DPP-4 inhibitors, can be expensive without insurance coverage.

“Based on the results of this research and our previous studies, it is tempting to speculate that linagliptin could reduce the risk of cardiovascular complications associated with obesity and Type 2 diabetes,” DeMarco said. “However, ongoing clinical trials will help determine what, if any, cardio-protective role linagliptin could play in the management of obesity-related heart disease.”

Improved Options for Diabetics: Insurance Coverage Now Available for Dario’s New Glucose Monitoring Device and App

More than 387 million people are living with diabetes worldwide. This number is expected to grow to 592 million by 2035. Effective daily blood glucose monitoring is a huge factor in the health and wellbeing of diabetics. A new mobile health app and all-in-one blood glucose monitor system from DarioHealth Corp. (DRIO) can improve monitoring and outcomes for diabetics.

The Dario™ Smart Diabetes Management Solution is a platform for diabetes management that combines an all-in-one blood glucose meter, native smart phone app (iOS & Android), website portal and a wide variety of treatment tools to support more proactive and better informed decisions by users living with diabetes, their doctors and healthcare systems.

Users in the U.S. can take advantage of 3rd party insurance coverage to have the DarioHealth products reimbursed by insurance. DarioHealth signed strategic alliance agreements with partners across the U.S. who will be able to verify insurance coverage benefits, and if approved, will supply and bill the customer’s insurance for their Dario™ Blood Glucose Monitoring System and test strip supplies. During DarioHealth’s pilot phase of this insurance coverage option, partners were able to verify benefits for customers covered by Aetna and various Blue Cross Blue Shield plans.

DarioHealth plans to expand its reach and add additional providers and insurance coverage options for those who want to utilize the insurance benefits available to them.

Mobile health applications can significantly improve patient outcomes. Healthcare is one of the fastest growing categories in the app market. At present, 45,000 app publishers are responsible for some 165,000 mHealth apps available on the market. Mobile health app adoption has doubled in 2 years, from 2013 to 2015.

Urine Metabolites May Help Predict Which Obese Teens Will Develop Diabetes

Researchers have discovered a unique metabolic “signature” in the urine of diabetic, obese black teenagers that they say may become a way to predict the development of type 2 diabetes in people at risk. They will present their results Tuesday at the Endocrine Society’s 99th annual meeting in Orlando, Fla.

In detailed metabolic analyses, the level of the main metabolite, or byproduct, of serotonin was “strikingly lower” in obese youth with type 2 diabetes than in nondiabetic obese adolescents, said Pinar Gumus Balikcioglu, M.D., the study’s lead investigator and an assistant professor of pediatric endocrinology at Duke University School of Medicine, Durham, N.C. Also, levels of several other metabolites were reportedly much higher than in the teenagers without diabetes.

“The major determinant of type 2 diabetes is obesity, which causes resistance to the effects of insulin. Yet many obese people do not become insulin resistant, and only a minority go on to develop Type 2 diabetes,” Gumus Balikcioglu said. “To identify those at highest risk, it is essential to find metabolic markers that predict the development of insulin resistance and diabetes.”

To attempt to do that, she and her colleagues have turned to the new field of studying the chemical “fingerprints” that small-molecule metabolites leave in blood and urine. In previous studies in obese teenagers, they analyzed hormone levels and metabolites in blood samples and identified several factors associated with the development of insulin resistance, she said.

In this study, they performed metabolic profiling of urine specimens obtained over a 24-hour period from 33 obese African-American teenagers ages 8 to 18: 13 with type 2 diabetes and 20 without. Both groups were comparable in age, sex and body mass index (an estimate of body fat). Participants who took the diabetes drug metformin were asked to stop taking it the day before the study, but those taking insulin were allowed to continue it for safety reasons.

Metabolic analysis, the researchers said, found that a much lower level of 5-hydroxy-indoleacetic acid (5-HIAA), the main metabolite of the neurotransmitter serotonin, was associated with diabetes. Although serotonin is perhaps best known for mood regulation, it has multiple functions, including controlling the development and function of the pancreatic beta cells that make insulin.

“A low level of serotonin or its byproducts could reduce insulin secretion, causing obese people to progress from insulin resistance to type 2 diabetes,” Gumus Balikcioglu said.

In addition, she said the diabetic teenagers had significantly higher levels of three metabolites than nondiabetic participants did. Among these were metabolites related to dysfunction of mitochondria, the “power unit” of the cell responsible for converting food to energy, and defects of the mitochondrial respiratory chain, which also lead to decreased energy production.

“Validation of our findings in larger clinical trials could provide a new noninvasive approach to identification of biomarkers for metabolic risk in in both children and adults,” she said. “More importantly, analysis of serotonin metabolism may provide new therapeutic targets for diabetes prevention and treatment.”

This study received funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; and the Children’s Miracle Network Hospitals partnerships and programs benefiting Duke Children’s Hospital and ENABLE career development program.

Study Suggests New Way to Prevent Vision Loss in Diabetics and Premature Babies

Researchers at Bascom Palmer Eye Institute, part of the University of Miami Miller School of Medicine, have identified a new molecule that induces the formation of abnormal blood vessels in the eyes of diabetic mice. The study, “Secretogranin III as a disease-associated ligand for antiangiogenic therapy of diabetic retinopathy,” which will be published March 22 in The Journal of Experimental Medicine, suggests that inhibiting this molecule may prevent similarly aberrant blood vessels from damaging the vision of not only diabetics, but also premature infants.

Changes in the vasculature of diabetes patients can cause long-term complications such as diabetic retinopathy, which affects around 93 million people worldwide. Many of these patients suffer a dramatic loss of vision as the blood vessels supplying the retina become leaky and new, abnormal blood vessels are formed to replace them. A molecule called vascular endothelial growth factor (VEGF) regulates blood vessel growth and leakiness, and two VEGF inhibitors, ranibizumab (Lucentis) and aflibercept (Eylea), have been approved to treat retinal vascular leakage, though they are only successful in about a third of patients.

The growth of abnormal new blood vessels also causes retinopathy of prematurity (ROP), the most common cause of vision loss in children that affects up to 16,000 premature infants per year in the US. VEGF inhibitors are not approved for use in these patients because VEGF is crucial for vascular development in newborn children.

Study lead-author Wei Li, Ph.D., research associate professor, and his colleagues at Bascom Palmer developed a technique called “comparative ligandomics” to identify additional molecules that regulate the behavior of blood vessels in diabetic mice. The approach allows the researchers to compare the signaling molecules that selectively bind to the surface of retinal blood vessel cells in diabetic but not healthy animals.

“It is estimated that between one third and one half of all marketed drugs act by binding to cell surface signaling molecules or their receptors,” says Li. “Our ligandomics approach can be applied to any type of cell or disease to efficiently identify signaling molecules with pathogenic roles and therapeutic potential.”

Using this technique, Li and colleagues discovered that a protein called secretogranin III (Scg3) efficiently binds to the surface of retinal blood vessel cells in diabetic, but not healthy, mice. Though Scg3 promotes the secretion of hormones and other signaling factors, it wasn’t thought to have a signaling function itself. Nevertheless, the researchers found that Scg3 increased vascular leakage, and, when administered to mice, it stimulated blood vessel growth in diabetic, but not healthy, animals.

VEGF, in contrast, stimulates blood vessel growth in both diabetic and healthy mice. Li and colleagues think that Scg3 binds to a distinct cell surface receptor that is specifically up-regulated in diabetes.

Treating diabetic mice with Scg3-neutralizing antibodies dramatically reduced the leakiness of their retinal blood vessels. Moreover, the antibodies significantly inhibited the growth of new blood vessels in mice with oxygen-induced retinopathy, a well-established animal model of human ROP.

Though the researchers still need to confirm the role of Scg3 in humans, inhibiting this protein could be an effective treatment for both diabetic retinopathy and ROP, especially as it appears to have no role in normal vascular development. “Scg3 inhibitors may offer advantages such as disease selectivity, high efficacy, and minimal side effects,” Li says. “Because they target a distinct signaling pathway, anti-Scg3 therapies could be used in combination with, or as an alternative to, VEGF inhibitors.”

Scientists Find Therapeutic Target for Diabetes-Related Blindness

Study reveals single cell type and surface molecule sufficient to cause common complication

Specific cells in the retina trigger inflammation and vision impairment associated with diabetes, according to new research out of Case Western Reserve University School of Medicine. The findings unexpectedly implicate Müller cells—which provide structural support in the retina—as key drivers of the process. Researchers now have a therapeutic target in hand and understand initial steps of diabetic retinopathy, one of the most common and debilitating side effects of diabetes.

Carlos Subauste, MD, Associate Professor of Medicine and Pathology and Timothy Kern, PhD, Professor of Medicine, Ophthalmology and Pharmacology at Case Western Reserve University School of Medicine led the research, recently published in Diabetes. Said Subauste, “Our studies uncovered a novel mechanism that explains the development of experimental diabetic retinopathy. Diabetic retinopathy is the leading cause of visual impairment in working age adults in the western world.”

In the study, Subauste and his team zeroed in on a receptor protein that sits on the surface of Müller cells. They discovered the receptor, CD40, sends signals to nearby cells called microglia and macrophages to initiate harmful inflammation in the retina. But, CD40 is a regular on the surfaces of many cells, so Subauste and his team had to devise a clever strategy to determine which cells initiate the harmful chain of events.

“From studies done with Dr. Kern, we knew mice with no CD40 are protected from diabetic retinopathy,” said Subauste. “We created transgenic mice that only express CD40 on Müller cells to further examine the role of the receptor.” The researchers discovered that mice with the receptor limited to Müller cells still developed retinopathy. A closer look revealed that CD40 also elicits pro-inflammatory molecules from bystander microglia and macrophages. The researchers found that CD40 makes Müller cells secrete a small energy molecule called ATP. In turn, ATP engages a specific receptor on the surface of microglia and macrophages triggering inflammatory responses in these cells.

The researchers had found their culprit. Their study provides direct evidence that a single receptor on the surface of Müller cells is sufficient to cause harmful inflammation that leads to experimental diabetic retinopathy.

Said Subauste, “Our study identifies CD40 as a therapeutic target against diabetic retinopathy.” The prevalence of the receptor throughout the body suggests the findings may also be applicable to inflammatory bowel disease, atherosclerosis, or lupus.

“Add-back of CD40 represents an elegant means of testing the hypothesis,” said a commentary in the journal featuring the study, calling the findings “unprecedented.”
Diabetic retinopathy is a major complication of diabetes that impairs the ability of the retina to sense light. For years, scientists have implicated inflammation as a primary driver of the complication, but it has been difficult to tease apart the many cells and signal molecules involved.

Said Subauste, “The choice of Müller cells was not obvious since it would have been logical to predict that CD40 expressed on microglia, macrophages, or endothelial cells, would have been the major driver of inflammation in the retina.” Instead, the researchers discovered CD40 on Müller cells activates these cell types, which are often implicated in inflammation.

Subauste teamed up not only with Timothy Kern, PhD but also with George Dubyak, PhD, Professor of Physiology and Pharmacology at Case Western Reserve University School of Medicine for the groundbreaking study. Subauste and Kern are now combining the mouse models with pharmacologic interventions identified by Subauste that block inflammatory processes induced by CD40, to ultimately prevent diabetic retinopathy.

A Pure Regenerative Medicine Play

by Richard (Rick) Mills, editor of aheadoftheherd.com

As a general rule, the most successful man in life is the man who has the best information

The promise of regenerative medicine is to treat disease and injury by replacing, regenerating or rejuvenating various parts of the human body that have been damaged by chronic disease, traumatic injury, heart attack, stroke, or aging. Treatments include both in vivo (studies and trials performed inside the living body) and in vitro (treatments applied to the body through implantation of a therapy studied inside the laboratory) procedures.

After many years of research the potential for regenerative medicine to redress the increasing prevalence of degenerative chronic diseases and acute injuries is beginning to receive huge scientific and public interest.

And no wonder! Look at some of the things we can already do…

  • Spina bifida suffers can now receive a bladder grown from their own cells.
  • Researchers have bioengineered a human liver that can be implanted into mice.
  • Heart disease affects the valves of the heart causing them to fail, we’ve already successfully grown heart valves from human cells.
  • Researchers have regenerated kidney tissue that is able to clear metabiolites, reabsorb nutrients and produce urine both in vitro and in vivo in rats.
  • Surgeons can now implant a tiny telescope within the eye helping restore some of the vision lost to end-stage age-related macular degeneration (AMD).
  • A material developed from the small intestines of pigs – small intestinal submucosa (SIS) – is used for everything from reconstructing ligaments, closing hard-to-heal wounds and treating incontinence.
  • Less complex organs such as the bladder and the trachea have been constructed from a patient’s cells and scaffolds and successfully transplanted.
  • Tissue-engineered vascular grafts for heart bypass surgery and cardiovascular disease treatment are at the pre-clinical trial stage.
  • New approaches to revitalizing worn-out body parts include removing all of the cells (decellularization) from an organ, and infusing new cells (recellularization) to integrate into the existing matrix and restore full functionality.

The first crop of simple stem cell therapies for regenerative medicine has reached widespread availability in the developed world. “Simple,” because these therapies are on the level of transfusions. In most cases stem cells are obtained from the patient, then grown in a cell culture and the greatly expanded number of cells injected back into the body. New medicine doesn’t get much simpler than that in this day and age. This is merely the start of a revolution in medicine, however, one will grow to become as large and as influential on health as the advent of blood transfusion or the control of common infectious diseases…Research continues, with a tone of excitement coming from the scientific community. They know they are onto something big.” Fightaging.org, Stem Cells, Regenerative Medicine, and Tissue Engineering

Some ongoing studies:

  • Diabetics treated with stem cell therapies that grow new insulin making cells.
  • Researchers are developing strategies to deliver proteins directly to the brain of stroke patients to stimulate stem cells and promote tissue repair.
  • Halting the progression of ALS, amyotrophic lateral sclerosis (also known as Motor Neuron disease and Lou Gehrig’s disease) and multiple sclerosis (MS).
  • Regrowing muscles in soldiers who were wounded in an explosion.
  • Restoration of Factor VIII in hemophiliacs.
  • The potential benefits of genetically enhanced stem cells in healing severe heart attacks.

It has to be pretty clear by now that regenerative medicine, although still in the early stages, is in the process of changing the practice of medicine.

These therapies will not only change healthcare, but will also lead to commercial success for the company and success in the market for investors.

One regenerative medicine company that’s currently off investors radar screens is Sernova Corp. (TSX-V: SVA, OTCQB: SEOVF, FSE: PSH).

However, with all Sernova has going on for it, the academic partnerships and R&D alliances, the company will begin to attract serious market attention, and possibly big pharma attention, in 2017.

Sernova Corp. is a clinical stage regenerative medicine company developing their Cell Pouch System™ for the treatment of chronic debilitating metabolic diseases such as diabetes, blood disorders including hemophilia and other diseases treated through replacement of proteins or hormones missing or in short supply within the body.

Sernova Corp. has developed the subcutaneous Cell Pouch™ and has specifically designed it to overcome the issues with previous implanted devices for cell transplantation.

Sernova’s implantable prevascularized macro-encapsulated Cell Pouch™ is a versatile and scalable, first-in-class medical device made entirely of FDA approved materials. The Cell Pouch System™ provides a natural “organ-like” environment rich in tissue matrix and micro-vessels. This is the ideal environment for therapeutic cells to thrive which then release proteins and/or hormones as required.

Sernova’s extensive preclinical safety and efficacy studies have shown this device to be both safe and effective, while being sparing of islets, supporting its design and function. The Cell Pouch™ being thin and typically smaller than a business card, fits easily under the skin with virtually no visibility.

Sernova Corp.’s Cell Pouch™, using human donor islet cells to produce insulin, should begin formal U.S. Food and Drug Administration (FDA) directed clinical testing in Type I/II diabetes early in 2017.

Phase I clinical human testing with porcine-derived islets and formal human studies using stem cell-derived islet cells will follow.

Sernova has entered into partnerships with the University of Toronto (a stem cell-derived diabetes technology licensing/alliance), Harvard University and the University of Chicago.

Sernova has also entered into R&D alliances with leading regenerative medicine and disease-specific organizations like the University of Toronto-affiliated Centre for Commercialization of Regenerative Medicine and the Juvenile Diabetes Research Foundation.

Sernova’s Cell Pouch™ potential is not limited to just islet cell transplantation in diabetes. Sernova has an R&D collaboration ongoing to develop cell therapies for treating hemophilia A (already funded from the European Commission’s Horizon 2020 program), and a separate alliance with the University of British Columbia focused on thyroid disorders.

Regenerative medicine could potentially provide lasting solutions to some of the world’s leading chronic diseases. That will massively impact the medical industry in coming years. The regenerative medicine market, still in its infancy, offers a genuine opportunity for investors.

Big pharmaceutical companies are beginning to show increased interest by making various acquisitions and engaging in partnership programs with startup research companies.

“The rapid aging of the global population and the increasing prevalence of obesity is leading to a significant and growing rate of inflammatory and degenerative diseases of all types. These demographically driven changes are generating significant interest from large, multi-national pharmaceutical companies now targeting small biotechnology start-ups engaged in developing diagnostics and treatments for these degenerative diseases.”

By the year 2020, baby boomers – people aged 65 and up –  will outnumber children under age 5 globally. Also, by the year 2020, the Department of Health and Human Services predicts the market for regenerative medicine will reach $300 billion.

Companies, such as Sernova Corp., are the leaders in preclinical research and many, like SVA is, are entering Phase I/II clinical trials. These company’s become significant targets once they successfully get their products to a stage warranting the attention of the big players.

The magnitude of the present opportunity for an investment into Sernova is equaled only by the enormous potential return once one of SVA’s therapies reaches the market, or more likely draws the attention of big pharma.

A new branch of medicine will develop that attempts to change the course of chronic disease and in many instances will regenerate tired and failing organ systems.” Leland Kaiser, recognized futurist and acknowledged authority on the changing American healthcare system

Conclusion

Harnessing the power of stem cells to repair or replace cells, tissues or organs that are damaged by trauma or disease means we are entering an era where treatments for some of the world’s most devastating diseases are developed.

Lab manufactured therapeutic cells hosted in the human body, in SVA’s prevascularized Cell Pouch System™ monitoring, regulating, manufacturing and secreting the necessary hormones, factors and proteins to control diabetes and hemophilia would be a major accomplishment.

The transformational potential of stem cells, placed within Sernova’s prevascularized Cell Pouch(TM) could:

  • Treat diseases in a much better way than traditional drugs/treatments
  • Significantly improve the quality of patient’s lives
  • Offer a faster, more complete recovery with significantly fewer side effects or risk of complications
  • Reduce the cost of healthcare
  • Prevent premature mortality
  • Bring significant indirect economic benefits not only to patients but society as a whole

It would be hard to argue against my position that Sernova Corp., and the regenerative medicine sector as a whole, will have taken a massive step forward if upcoming human Phase I/II clinical trials are successful.

Sernova is today a relatively unknown pure regenerative medicine play that has partnered their Cell Pouch™ with a network of academic cell therapy research and development partners.

For these two reasons Sernova, and a well timed investment in the regenerative medicine space, best be on your radar screen. Is it?

If not, it should be.

Richard (Rick) Mills

aheadoftheherd.com

Richard lives with his family on a 160 acre ranch in northern British Columbia. He invests in the resource and biotechnology/pharmaceutical sectors and is the owner of aheadoftheherd.com.

***

Legal Notice / Disclaimer

This document is not and should not be construed as an offer to sell or the solicitation of an offer to purchase or subscribe for any investment.

Richard Mills has based this document on information obtained from sources he believes to be reliable but which has not been independently verified.

Richard Mills makes no guarantee, representation or warranty and accepts no responsibility or liability as to its accuracy or completeness. Expressions of opinion are those of Richard Mills only and are subject to change without notice.

Richard Mills assumes no warranty, liability or guarantee for the current relevance, correctness or completeness of any information provided within this Report and will not be held liable for the consequence of reliance upon any opinion or statement contained herein or any omission.

Furthermore, I, Richard Mills, assume no liability for any direct or indirect loss or damage or, in particular, for lost profit, which you may incur as a result of the use and existence of the information provided within this Report.

Richard owns shares of Sernova Corp. (TSX-V: SVA, OTCQB: SEOVF, FSE: PSH). Sernova is an advertiser on Richard’s site – aheadoftheherd.com.

High-Impact Clinical Trials Yield Results That Could Improve Kidney Care

The results of numerous high-impact clinical trials that could affect kidney-related medical care will be presented at ASN Kidney Week 2016, November 15–20 at McCormick Place in Chicago, IL.

• In the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial, 9340 patients with type 2 diabetes and high cardiovascular risk were randomized liraglutide (a long-acting glucagon-like peptide-1 analog) or placebo. Over a median follow-up of 3.84 years, a composite outcome of kidney dysfunction or death due to kidney disease occurred in fewer participants treated with liraglutide (268 of 4668) than with placebo (337 of 4672), translating to a 21% reduced risk. “Liraglutide in addition to standard of care therapy reduced the progression of diabetic nephropathy,” the study’s investigators concluded.
Liraglutide and Renal Outcomes in Type 2 Diabetes: Results of the LEADER Trial

• In a trial that involved 406 adult live donor/recipient kidney transplant pairs, remote ischemic preconditioning (RIPC), a safe and virtually cost-free intervention, resulted in sustained improvement in kidney function after transplantation, reaching 13% by 5 years. “Given the resultant clinical, economic, and quality of life implications, we recommend that RIPC is adopted into routine care for these patients,” stated the trial’s investigators. The intervention involves reducing blood flow in both the donor and recipient as a preconditioning step before surgery, which can involve more significant and prolonged blood flow reductions. A blood pressure cuff placed on the upper arm that is inflated for short periods of time activates a reflex that makes internal organs more resistant to the harmful effects of low blood flow that occurs during transplantation.
Remote ischaemic preconditioning (RIPC) leads to sustained improvement in allograft function following live donor (LD) kidney transplantation: 5 year follow up in the REnal Protection Against Ischaemia Reperfusion in transplantation (REPAIR) study

• A study that randomized 615 kidney transplant recipients to receive either basiliximab induction with low dose tacrolimus, mycophenolate mofetil, and steroid maintenance therapy (arm A), or rapid corticosteroid withdrawal on day 8 (arm B), or rapid corticosteroid withdrawal on day 8 following rabbit antithymocyte globulin (ATG) instead of basiliximab (arm C), rejections at 12 months were similar in all groups (11.2%, 10.6%, and 9.9%, respectively). As a secondary endpoint, rapid steroid withdrawal reduced posttransplantation diabetes in arm B to 23.9% and in arm C to 22.7% compared with standard arm A with 39.2%. “Rabbit ATG failed to show superiority over basiliximab induction for the prevention of biopsy proven acute rejections after rapid steroid withdrawal within one year after renal transplantation. Nevertheless, rapid steroid withdrawal after induction therapy for patients with a low immunologic risk profile can be achieved without any loss of efficacy and is highly advantageous in regard to posttransplantation diabetes mellitus incidence,” the researchers wrote. Rabbit ATG, an infusion of rabbit-derived antibodies against human T cells, is used in the prevention and treatment of acute rejection in organ transplantation. Basiliximab is a monoclonal antibody that is an interleukin-2 receptor antagonist.
Rabbit-ATG or Basiliximab Induction for Rapid Steroid Withdrawal after Renal Transplantation: an Open-label, Multicentre, Randomized Controlled Trial

• In a trial of 99 individuals on hemodialysis, lower sodium levels in patients’ dialysate solutions did not effectively reduce their left ventricular mass, an indicator of heart health. Enlarged left ventricles, or left ventricular hypertrophy, contributes to premature cardiovascular mortality in dialysis patients. Other studies have shown benefits (such as reduced blood pressure) to lowering dialysate sodium concentrations.
The Sodium Lowering In Dialysate (SoLID) Trial: a Randomised Controlled Trial of Low Versus Standard Dialysate Sodium Concentration (DNa) During Hemodialysis (HD) for Regression of Left Ventricular (LV) Mass

• In a trial of 265 patients with lupus nephritis, 32.6% of patients receiving low dose voclosporin and 27.3% of patients receiving high dose voclosporin achieved complete remission at 24 weeks, compared with 19.3% of patients receiving placebo. Also, partial remissions were more common in patients receiving either low or high dose voclosporin than in those receiving placebo. Side effects were higher in the patients treated with voclosporin, consistent with increased immunosuppression. “These favorable data will help plan subsequent studies of voclosporin in lupus nephritis,” the study’s investigators wrote. Voclosporin is a novel calcineurin inhibitor, a type of immunosuppressant.
AURA-LV: Successful treatment of active lupus nephritis with Voclosporin

• In the phase 2 DUET trial that included 96 patients with focal segmental glomerulosclerosis (FSGS), which is characterized by scarring of the kidneys, sparsentan, a dual angiotensin II (Ang II) and endothelin type A receptor antagonist, reduced urinary protein excretion to a greater extent than blockade of Ang II alone. “In accord with prior studies in essential hypertension, sparsentan appears to be safe and well tolerated in patients with FSGS,” noted the study’s investigators.

Researching Proinsulin Misfolding to Understand Diabetes

  According to the World Health Organization, 422 million adults across the globe have diabetes. In fact, the number of adults with the disease continues to grow each year.

To help the growing patient population, researchers at the University of Michigan are going down to the molecular level. Here, they’re trying to determine what makes cells in the diabetic pancreas less efficient in generating insulin molecules.

Diabetes occurs when the body’s pancreas does not produce enough insulin to keep blood sugar levels under control.

“Ten years ago, we found that when insulin is being made in the pancreatic beta cells, a certain subfraction of new synthesized insulin molecules, called proinsulin, cannot fold properly,” says Ming Liu, Ph.D., research associate professor of internal medicine at U-M and co-investigator on a new study on the topic.

“This problem is known as proinsulin misfolding, and several different groups around the world have now come up with similar observations. We also found that in animals in which production of misfolded proinsulin molecules reaches 30 percent of total proinsulin, that is enough for these animals to develop diabetes from pancreatic beta cell failure.”

A four-member team of U-M faculty are currently zeroing in on misfolded proinsulin.

“When you are born, you receive two copies of the gene encoding proinsulin, one from your mom and one from your dad,” says Billy Tsai, Ph.D., co-investigator and professor of cell and developmental biology at U-M. “There is a special kind of diabetes, called Mutant Ins-gene Induced Diabetes of Youth (MIDY), in which the patients with diabetes have a mutation in one of the copies so that as much as half of all of their proinsulin may be misfolded.”

Tsai explains that in the pancreatic beta cell, proinsulin first is targeted, or delivered, to the endoplasmic reticulum (ER) compartment, in order to begin the process of making insulin. When proteins are made in the ER, if things go right, they acquire their natural folded three-dimensional shape that is needed in order to function as they should.

If they don’t acquire and retain that proper shape, then the cell recognizes them as being defective protein molecules and works to destroy them so that they don’t wreak havoc within the cell.

“In the MIDY disease, having that one mutated gene making proinsulin is bad news,” Tsai says. “The cell has to figure out a way to recognize the bad protein molecules that come from the mutant gene and destroy them. And if it doesn’t, it turns out that misfolded proinsulin can have a “dominant-interfering” effect on the normal bystander proinsulin molecules that are made from the other, good gene.”

He adds that the normal proinsulin would ordinarily be made into insulin and that would help to lower blood sugar. But, when the misfolded proinsulin physically attaches itself to the normal bystander proinsulin, that blocks the ability of beta cells to make the normal proinsulin into insulin.

Liu and Tsai are joined in the study by U-M colleagues Peter Arvan, M.D., Ph.D., professor and chief of the Division of Metabolism, Endocrinology & Diabetes, and Ling Qi, Ph.D., professor of molecular and integrative physiology.

The team explains that the pancreatic cells have a way of rectifying the protein misfolding problems. The major way is by recognizing misfolded or damaged proteins and ejecting them from the ER to the cell’s proteosome, a major cellular garbage disposal that has the responsibility of chopping up proteins targeted for destruction. That process is called Endoplasmic Reticulum Associated Degradation (ERAD).

The idea is that if misfolded proinsulin is chopped up and degraded, then the remaining normal proinsulin can move through the beta cell and be successfully converted into biologically active insulin, to lower blood sugar.

The team is now researching if there is a way to stimulate the degradative pathway in order to get rid of more of the mutant protein.

“We think we can rectify this diabetic disease by manipulating the ERAD pathway so we can restore normal insulin secretion,” says Tsai.

“We’re trying to show proof of principle that if we manipulate the cells to have increased ability to degrade misfolded proinsulin, we can increase the amount of normal insulin that can be made and secreted. The hope is this would then help in the development of drugs that would stimulate ERAD to generate the same beneficial effect.”

The team explains this type of research has not been reported before in the diabetes field.

“There have been extensive studies on proteins undergoing ERAD,” says Qi. “Researchers know that protein misfolding is important for certain diseases, but we’re now focusing in on diabetes.”

Arvan agrees, “To understand protein misfolding diseases, we have to know more about protein folding. This is an exciting step in the field of diabetes research.”

The team has just received a four-year, multi-investigator grant from the National Institutes of Health, from which important new answers are expected.

New Data From Harvard & Yale Researchers Reveal Breakthrough Oral Fully Human Anti-CD3 Antibody, for the Treatment of NASH, Diabetes & Autoimmune Diseases

Immunotherapies have shown great promise to treat a wide range of diseases including auto-immune disease and NASH. However, they are typically administered through IV instead of orally because if taken orally, they would be degraded and inactivated by the harsh conditions in the gastrointestinal tract. New data from preclinical studies conducted by Prof. Kevan Herold of Yale University and Prof. Howard Weiner of Harvard University show that Foralumab, a drug from London-based Tiziana Life Sciences, has shown consistent efficacy via oral administration. Oral efficacy with Foralumab is a potential game-changer for the treatment of autoimmune diseases and NASH.

Foralumab is a long half-life therapeutic mAb candidate with high affinity and potency for CD3 epsilon. It is the only fully human engineered anti CD3 monoclonal antibody (mAb) in clinical development.  The unique oral technology stimulates the natural gut immune system and potentially provides a therapeutic effect in inflammatory and autoimmune diseases with virtually no toxicity.

According to Prof. Kevan Herold, a member of Tiziana’s Scientific Advisory Board at Yale University, “This study demonstrates that oral administration works consistently in our pre-clinical models with human immune cells. This suggests that oral CD3-specific mAb has the potential for treating NASH, diabetes, and other autoimmune diseases in humans – an entirely novel approach for the treatment of currently unmet needs.”

Further animal studies conducted in a member of Tiziana’s Scientific Advisory Board, Prof. Howard Weiner’s laboratory at Harvard University, supported the potential of oral treatment with Foralumab for autoimmune and inflammatory diseases. Prof. Weiner stated, “Our data suggest that oral treatment with anti-CD3 mAb induces an anti-inflammatory response through induction of regulatory T cells (Tregs). This proof of concept of foralumab in humanized mice demonstrates that this approach could be used successfully in humans as well.”

Foralumab has applications in chronic inflammatory and autoimmune diseases with high unmet medical needs such as ulcerative colitis, inflammatory bowel diseases, multiple sclerosis, lupus, as well as in non-alcoholic steatohepatitis (NASH) and type 1 diabetes.

Stealth Pig Cells May Hold The Key To Treating Diabetes In Humans

University of Alabama at Birmingham researchers are exploring ways to wrap pig tissue with a protective coating to ultimately fight diabetes in humans. The nano-thin bilayers of protective material are meant to deter or prevent immune rejection.

The ultimate goal: transplant insulin-producing cell-clusters from pigs into humans to treat Type 1 diabetes.

In preclinical work begun this year, these stealth insulin-producers — pancreatic islets from pigs or mice coated with thin bilayers of biomimetic material — are being tested in vivo in a mouse model of diabetes, say UAB investigators Hubert Tse, Ph.D., and Eugenia Kharlampieva, Ph.D. Tse is an immunologist and associate professor in the Department of Microbiology, UAB School of Medicine, and Kharlampieva is a polymer and materials chemist and associate professor in the Department of Chemistry, UAB College of Arts and Sciences.

Their research, supported by two new JDRF Diabetes Foundation grants, “is a nice example of a truly multidisciplinary project that encompasses distinct areas of expertise including engineering, nanomaterials, immunology and islet transplantation,” said Fran Lund, Ph.D., professor and chair of Microbiology at UAB. “The project also melds basic science and engineering with the goal of developing better treatments for diabetes.”

“Our collaboration works because we have the same mindset,” Kharlampieva said of her collaboration with Tse. “We want to do good science.”

One of the chief jobs of pancreatic islets is production of insulin to regulate levels of blood sugar. In Type 1 diabetes, the β-cells that produce insulin are destroyed by an autoimmune attack by the body’s own immune system. To protect transplanted donor islets, researchers elsewhere have tried to coat islets with thick gels, or with coatings that bind covalently or ionically to the islets. Those approaches have had limited success.

Tse and Kharlampieva have taken a different approach, applying a gentler and much thinner coating of just five bilayers of biomimetic material about 30 nanometers thick. These layers act as a physical barrier that dissipates reactive oxygen species, and they also dampen the immune response. The thinness of the coat allows nutrients and oxygen easy passage to the cells.

“We did not expect the multilayers would show such a large, potential benefit,” Kharlampieva said of the immunomodulation shown by the bilayers.

The Tse-Kharlampieva collaboration got its start out of efforts to solve a problem in a UAB service to provide islets to national researchers — the islets often died or stopped secreting insulin during the three to five days of shipping. Kharlampieva was asked whether her bilayers might somehow protect the islets and preserve viability and functionality.

The bilayers are held together by hydrogen bonding, through an attraction between polar groups in the layers, which Kharlampieva calls a “friendlier approach” than covalent or ionic bonds. One of the layers, tannic acid, is a polyphenol that can scavenge destructive free radicals, much like the polyphenols found in green tea. Tse — who studies how oxidative stress contributes to islet dysfunction and autoimmune responses in Type 1 diabetes — wondered whether tannic acid’s ability to defuse radical oxygen species might help to lessen autoimmune dysregulation.

In collaborative research over more than five years, the UAB researchers showed that the answer was yes.

In a 2012 Advanced Functional Materials paper, Tse, Kharlampieva and colleagues found that:
• The bilayers, which include tannic acid, were able to wrap smoothly around a variety of mammalian pancreatic islets, and they maintained high chemical stability
• The coated islets retained viability and β-cell function in vitro for at least 96 hours
• Hollow shells of the bilayers suppressed synthesis of the proinflammatory cytokines IL12-p70 by stimulated macrophages and interferon- γ by stimulated T cells

In a 2014 Advanced Healthcare Materials paper, the researchers further examined the immunomodulatory effect of the hydrogen-bonded multilayers, in the form of hollow shells. They showed that the bilayer shells have:
• Antioxidant properties, as demonstrated by the dissipation of proinflammatory reactive oxygen and nitrogen species
• Immunosuppressive properties, as demonstrated by attenuated production of proinflammatory cytokines interferon-γ and tumor necrosis factor-α by antigen-stimulated autoreactive CD4+ T cells

The next step for the UAB researchers is in vivo testing of xeno- and allotransplantation to see if the bilayer-coated pancreatic islets have decreased risk of graft rejection, while restoring control of blood sugar. Xenotransplantation is transplanting from one species to another, and allotransplantation is transplanting from one member of a species to a different member of the same species.

In a one-year, in vivo demonstration grant, the UAB researchers found that nano-coated mouse islets survived and functioned as long as 40 days in diabetic mice that lack working immune systems. “We showed that they do stay alive, and they function to regulate blood glucose,” Tse said.

Now Tse and Kharlampieva, supported by two new JDRF grants, are testing the survival and functioning of nano-coated islets from mice or pigs in diabetic mice with intact immune systems.

The pig islets come from their University of Alberta collaborator Greg Korbutt, Ph.D. Korbutt’s team in Edmonton, Canada, has shown that human islets transplanted into immunosuppressed patients with brittle diabetes can produce insulin independence. “They are the leader in islet transplantation and developed the Edmonton Protocol for novel immunosuppression,” Tse said.

Pig islets — in contrast to scarce supplies of human islets — offer an unlimited source of insulin-producing tissue.

In the UAB experiments, the mouse and pig islets are coated with four or five bilayers of tannic acid and either poly(N–vinylpyrrolidone) or poly(N–vinylcaprolactam) by UAB research scientist Veronika Kozlovskaya, Ph.D. Mouse islet collection and transplantation of mouse or pig islets into mice is performed by UAB research technician Michael Zeiger, who grew up in Indonesia learning surgical skills from his veterinarian father.

At UAB, Lund holds the Charles H. McCauley Chair of Microbiology.

Regenerative bandage heals diabetic wounds faster

At some point in their lives, 15 percent of people with diabetes will develop a painful and hard-to-treat foot ulcer. Twenty-four percent of those affected will require a lower-leg amputation because of it. And, in some instances, what seems like a harmless sore might even lead to death.

A Northwestern University team has developed a new treatment for this severe and potentially deadly complication of diabetes. Called a “regenerative bandage,” the novel material heals diabetic wounds four times faster than a standard bandage and has the added benefit of promoting healing without side effects.

“Foot ulcers cause many serious problems for diabetic patients,” said Guillermo Ameer, professor of biomedical engineering in Northwestern’s McCormick School of Engineering and surgery in the Feinberg School of Medicine. “Some sores don’t heal fast enough and are prone to infection. We thought that we could use some of our work in biomaterials for medical applications and controlled drug release to help heal those wounds.”

An expert in biomaterials and tissue engineering, Ameer’s research was published online last week in the Journal of Controlled Release. Yunxiao Zhu, a PhD student in Ameer’s laboratory, is the paper’s first author. Northwestern Engineering’s Hao F. Zhang, associate professor of biomedical engineering, and Feinberg’s Robert Galliano, associate professor of surgery, also contributed to the work.

Diabetes can cause nerve damage that leads to numbness in the feet. A diabetic person might experience something as simple as a blister or small scrape that goes unnoticed and untreated because they cannot feel it to know that its there. As high glucose also thickens capillary walls, blood circulation slows, making it more difficult for these wounds to heal. It’s a perfect storm for a small nick to become a life-threatening sore.

Some promising treatments for these chronic wounds exist, but they are costly and can come with significant side effects. One gel, for example, contains a growth factor that has been reported to increase cancer risk with overuse.

“It should not be acceptable for patients who are trying to heal an open sore to have to deal with an increased risk of cancer due to treating the wound,” Ameer said.

Ameer’s laboratory previously created a thermo-responsive material — with intrinsic antioxidant properties to counter inflammation — that is able to deliver therapeutic cells and proteins. His team used this material to slowly release into the wound a protein that hastens the body’s ability to repair itself by recruiting stem cells to the wound and creating new blood vessels to increase blood circulation.

“We incorporated a protein that our body naturally uses to attract repair cells to an injury site,” Ameer said. “When the protein is secreted, progenitor cells or stem cells come to the wound and make blood vessels, which is part of the repair process.”

The thermo-responsive material is applied to the wound bed as a liquid and solidifies into a gel when exposed to body temperature. When the same amount of the protein was directly applied all at once, no benefit was observed. This demonstrates the importance of slow release from the thermo-responsive material. Ameer believes that the inherent antioxidant properties within the material also reduce oxidative stress to help the wound heal.

“The ability of the material to reversibly go from liquid to solid with temperature changes protects the wound,” Ameer said. “Patients have to change the wound dressing often, which can rip off healing tissue and re-injure the site. Our material conforms to the shape and dimensions of the wound and can be rinsed off with cooled saline, if needed. This material characteristic can protect the regenerating tissue during dressing changes.”

In collaboration with Zhang, Ameer imaged diabetic wounds to discover that they were much healthier after application of the regenerative bandage. The blood flow to the wound was significantly higher than in those without Ameer’s bandage.

“The repair process is impaired in people with diabetes,” Ameer said. “By mimicking the repair process that happens in a healthy body, we have demonstrated a promising new way to treat diabetic wounds.”

Genetics Of Type 2 Diabetes Revealed In Unprecedented Detail

The largest study of its kind into type 2 diabetes has produced the most detailed picture to date of the genetics underlying the condition.
More than 300 scientists from 22 countries collaborated on the study, which analysed the genomes of more than 120,000 people with ancestral origins in Europe, South and East Asia, the Americas and Africa.

The findings, published today in Nature, identify several potential targets for new diabetes treatments, but also reveal the complexity of the disease that needs to be addressed by efforts to develop more personalised strategies for treatment and prevention.

Type 2 diabetes is a growing threat to global health, with one in 10 people either having the disease or predicted to develop it during their lifetime. For any given individual, the risk of developing this form of diabetes is influenced by the pattern of genetic changes inherited from their parents, and environmental factors such as levels of exercise and choice of diet.

A better understanding of precisely how these factors contribute to type 2 diabetes will enable researchers to develop new ways of treating and preventing this condition, as well as offering the prospect for targeting those treatments towards those most likely to benefit, and those least likely to suffer harm.

Previous studies have identified over 80 areas in the genome that are associated with type 2 diabetes. However, these studies focused on the role of common DNA differences that appear frequently in the population, and they generally stopped short of identifying exactly which DNA sequence changes, or which specific genes, were responsible for this risk.

Today’s study explored the impact of changes in the DNA sequence on diabetes risk at a more detailed level. Some individuals had their entire genome sequenced while for others, sequencing was restricted to the part of the genome that codes directly for proteins (the exome).

Scientists compared the genetic variation between individuals who had type 2 diabetes and those who did not. This allowed them to test the contribution made by rare, ‘private’ DNA differences, as well as those that are common and shared between people.

They found that most of the genetic risk of type 2 diabetes can be attributed to common, shared differences in the genetic code, each of which contributes a small amount to an individual’s risk of disease. Some researchers had thought that genetic risk would instead be dominated by rare changes, unique to an individual and their relatives.

This finding means that future efforts to develop a personalised approach to treatment and prevention will need to be tailored toward an individual’s broader genetic profile, non-genetic risk factors and clinical features.

Researchers also identified over a dozen type 2 diabetes risk genes where the DNA sequence changes altered the composition of the proteins they encode. This implicates those specific genes and proteins directly in the development of type 2 diabetes.

One such variant – in the TM6SF2 gene – has been shown to alter the amount of fat stored in the liver, which in turn results in an increase in the risk of type 2 diabetes. Discoveries such as these point to new opportunities for developing drugs that might interrupt the development of the disease.

Mark McCarthy, from the Wellcome Trust Centre for Human Genetics at the University of Oxford, one of three senior authors on the paper, said: “This study highlights both the challenges we face, and the opportunities that exist, in resolving the complex processes underlying a disease such as type 2 diabetes. In this study, we have been able to highlight, with unprecedented precision, a number of genes directly involved in the development of type 2 diabetes. These represent promising avenues for efforts to design new ways to treat or prevent the disease.”

Joint senior author Professor Michael Boehnke, Richard G Cornell Distinguished University Professor of Biostatistics, Director, Center for Statistical Genetics, University of Michigan School of Public Health, added: “Our study has taken us to the most complete understanding yet of the genetic architecture of type 2 diabetes. With this in-depth analysis we have obtained a more complete picture of the number and characteristics of the genetic variants that influence type 2 diabetes risk.”

Data and discoveries generated through this project are available through the type 2 diabetes genetics portal (www.type2diabetesgenetics.org) developed as part of the Accelerating Medicines Partnership.

Jason Flannick, co-lead author and Senior Group Leader at the Broad Institute of Harvard and MIT and Research Associate at the Massachusetts General Hospital, said: “Our study tells us that genetic risk for type 2 diabetes reflects hundreds or even thousands of different genetic variants, most of them shared across populations. This large range of genetic effects may challenge efforts to deliver personalised (or precision) medicine. However, to ensure that these challenges can be taken up by the wider research community, we have made the data from our study publicly accessible for researchers around the world in the hope that this will accelerate efforts to understand, prevent and treat this condition.”