Genetic discovery may help better identify children at risk for type 1 diabetes

Six novel chromosomal regions identified by scientists leading a large, prospective study of children at risk for type 1 diabetes will enable the discovery of more genes that cause the disease and more targets for treating or even preventing it.

The TEDDY study’s international research team has identified the new gene regions in young people who have already developed type 1 diabetes or who have started making antibodies against their insulin-producing cells, often a precursor state to the full-blown disease that leads to a lifetime of insulin therapy.

Their analysis of 5,806 individuals published in the Journal of Autoimmunity also confirmed three regions already associated with one of those related conditions.

“We want to build a more precise profile of who will get this disease and when,” says Dr. Jin-Xiong She, director of the Center for Biotechnology and Genomic Medicine at the Medical College of Georgia at Augusta University, principal investigator of TEDDY’s Georgia/Florida site and the study’s corresponding author.

In keeping with their theory that two subtypes of type 1 diabetes will become clear from longitudinal studies of those at risk, the international TEDDY team also found different chromosomal regions were associated with which autoantibody shows up first in a patient, a sign his immune system is turning on his pancreas.

They looked at two top autoantibodies: one directly against insulin, called IAA, and one called GADA, against the enzyme glutamate decarboxylase, which regulates the insulin-producing beta cells in the pancreas. About 90 percent of patients with type 1 diabetes have one or the other autoantibody first and many eventually end up with both, She says. The second autoantibody may surface in a few days or even years later.

“There is mounting evidence that we have at least two major subtypes of type 1 diabetes, based on the autoantibodies children have. Now we have found a genetic basis that supports that,” says She, Georgia Research Alliance Eminent Scholar in Genomic Medicine.

TEDDY – The Environmental Determinants of Diabetes in the Young – is an international initiative following almost 9,000 children for 15 years in a strategic and rare opportunity to watch how genetics and environmental factors collide to cause disease, She says. An original goal of TEDDY was to better determine which genetic variations correlate with progression or lack of progression to type 1 diabetes.

For this particular pursuit, they focused on the 5,806 Caucasian TEDDY participants, because of genetic differences in different ethnic groups. They also focused on non-HLA genes, says Dr. Ashok Sharma, MCG bioinformatics expert and the study’s first author.

Most genes known to be associated with type 1 diabetes – including those currently considered the top two high-risk genes, which are the ones TEDDY screens for – are classified as human leukocyte antigen, or HLA genes. It’s a logical association since HLA genes regulate our immune system, says Sharma.

But in their comprehensive effort to better identify children at highest risk of disease – and ideally one day intervene – this particular search focused on non-HLA genes. “By study design we were looking for them,” Sharma says.

“With HLA genes you can achieve a certain level of accuracy in identifying high-risk individuals,” says She. “But if we can add additional genes into the screening, we can refine the prediction of the disease, we can increase the accuracy, we can probably even identify higher percentages of at-risk individuals.”

“It’s not monogenic, there are many genes involved,” Sharma says of type 1 diabetes, a condition that affects 1 in 300 people in the United States by age 18, according to the National Institutes of Health.

Which of those genes are involved also varies by individual. Sharma and She note the reality that not all patients with the high-risk genes even get the disease, although they still don’t know why.

One of the many points they hope TEDDY clarifies is if or how these genetics along with environmental factors – like childhood infections or even what children eat – conspire to cause actual disease. Genetic factors are comparatively easier to identify, and should also help identify environmental factors, they say.

For this study, the scientists also started with 176,586 SNPs, or single nucleotide polymorphisms. A nucleotide is a basic building block of our genetic information. In the case of DNA, those are A, C, T and G, chemical bases that can be arranged in seemingly endless potential orders. SNPs are genetic variations – one letter replaced by another – that scientists are using increasingly to figure out which occur more or less often in people with a certain condition or disease.

The SNPs examined by TEDDY scientists were already associated with other autoimmune diseases like rheumatoid arthritis or celiac disease, but not type 1 diabetes, Sharma says. They determined which of these SNPs are different in TEDDY participants who had developed type 1 diabetes versus those who had Islet cell autoantibodies versus those who still had neither.

Previous research has shown that the same genes are not always associated with IA and actual type 1 diabetes.

In fact, while Islet cell autoantibodies, or IA, are considered a red flag for type 1 diabetes, not every child with IA will progress to full-blown disease, She says, although multiple autoantibodies definitely increase that risk. In fact, different genes may play a role in IA development while others play a role in disease progression, the TEDDY scientists write.

While the SNPs themselves may or may not have a direct functional consequence, they are in close proximity to a gene that does, says She. “It’s a marker,” he says, that will enable the scientists to more efficiently and effectively identify causative genes.

“We are using SNPs but not as an endpoint,” Sharma notes. “We want to find out the genes which are there,” a focal point for the work now underway.

Key to the work already complete, is how closely and long TEDDY participants are followed. Normally gene identification starts with what is called a case-control design, in which genetic variations are compared between patients with a condition and healthy individuals, to look for differences that may contribute to the disease.

While standard cross-sectional, or case-control studies haven’t shown a huge impact from non-HLA genes, they only provide a “snapshot’ of what is happening with both patients and controls alike, the scientists say. With the prospective and longitudinal TEDDY, the scientists are literally watching the disease occur – or not – in high-risk young people.

In fact, this is the first major study regarding gene identification for any disease that uses this sort of longitudinal information, She says.

As with many things, timing is everything, and the TEDDY perspective sharpens the search, particularly for important non-HLA genes by adding the “time to disease” perspective, She says.

Photographed: Drs. Jin-Xiong She (left) and Ashok Sharma

Pain-Free Skin Patch Responds to Sugar Levels for Management of Type 2 Diabetes

Researchers with NIH’s National Institute of Biomedical Imaging and Bioengineering (NIBIB) have devised an innovative biochemical formula of mineralized compounds that interacts in the bloodstream to regulate blood sugar for days at a time. In a proof-of-concept study performed with mice, the researchers showed that the biochemically formulated patch of dissolvable microneedles can respond to blood chemistry to manage glucose automatically.

“This experimental approach could be a way to take advantage of the fact that persons with type 2 diabetes can still produce some insulin,” said Richard Leapman, Ph.D., NIBIB scientific director. “A weekly microneedle patch application would also be less complicated and painful than routines that require frequent blood testing.”

Insulin is a hormone made in the pancreas and secreted into the bloodstream to regulate glucose in response to food intake. It is needed to move glucose from the bloodstream into cells where the sugar can be converted to energy or stored. In type 1 diabetes, usually diagnosed in children and young adults, the body does not make insulin at all. Type 2 diabetes, which can be diagnosed at any age but more commonly as an adult, progressively lessens the body’s ability to make or use insulin. Untreated, diabetes can result in both vascular and nerve damage throughout the body, with debilitating impacts on the eyes, feet, kidneys, and heart.

Global incidence of all types of diabetes is about 285 million people, of which 90 percent have type 2 diabetes. Many require insulin therapy that is usually given by injection just under the skin in amounts that are calculated according to the deficit in naturally generated insulin in the blood. Insulin therapy is not managed well in half of all cases.

NIBIB researchers led by Xiaoyuan (Shawn) Chen, senior investigator in the Laboratory of Molecular Imaging and Nanomedicine, are working on an alternate therapy approach to regulate blood sugar levels in type 2 diabetes using a painless skin patch. In a Nov. 24, 2017, study published online in Nature Communications, the team applied the treatment to mice to demonstrate its potential effectiveness.

The base of the experimental patch is material called alginate, a gum-like natural substance extracted from brown algae. It is mixed with therapeutic agents and poured into a microneedle form to make the patch. “Alginate is a pliable material—it is soft, but not too soft,” Chen said. “It has to be able to poke the dermis, and while not a commonly used material for needles, it seems to work pretty well in this case.”

Chen’s team infused the alginate with a formula of biochemical particles that stimulates the body’s own insulin production when needed and curtails that stimulation when normal blood sugar concentration is reached. The responsive delivery system of the patch can meet the body’s need for days instead of being used up all at once.

“Diabetes is a very serious disease and affects a lot of people,” Chen said, explaining that his group is part of a crowded field of drug research and developers with competing ideas. “Everybody is looking for a long-acting formula.”

Pain-free skin patch responds to sugar levels for management of type 2 diabetes | National Institute of Biomedical Imaging and Bioengineering

Chen’s formula puts two drug compounds—exendin-4 and glucose oxidase—into one patch. The two compounds react with the blood chemistry to trigger insulin secretion. Each is matched with a phosphate mineral particle, which stabilizes the compound until it is needed. Acidity that occurs when sugar concentrations rise weakens the bond with the drug being held by one, but not the other mineral.

Exendin-4 is similar in genetic makeup to a molecule the body produces and secretes in the intestine in response to food intake. Though it is somewhat weaker than the naturally occurring molecule, the team chose exendin-4 for its application because exendin-4 does not degrade in the bloodstream for an hour or more, so can have long-lasting effect after being released. However, it can induce nausea when too much is absorbed. To control how quickly it is absorbed, the researchers combined exendin-4 with mineral particles of calcium phosphate, which stabilize it until another chemical reaction occurs. That chemical reaction is caused by the second drug compound in the patch—glucose oxidase— that is held in its mineral buffer of copper phosphate.

Chen explained that when blood sugar is elevated beyond a precise point, it triggers a reaction with copper phosphate and glucose oxidase to produce slight acidity, which causes calcium phosphate to release some exendin-4. Rising glucose levels trigger the release of exendin-4; but exendin-4 then gets insulin flowing to reduce the glucose level, which slows down and stops release of exendin-4. “That’s why we call it responsive, or smart, release,” said Chen. “Most current approaches involve constant release. Our approach creates a wave of fast release when needed and then slows or even stops the release when the glucose level is stable.”

The researchers demonstrated that a patch about half an inch square contained sufficient drug to control blood sugar levels in mice for a week. For the approach to advance as an application that people with type-2 diabetes can use, the team will need to perform tests to treat larger animals with a patch that contains proportionately more therapeutic compound. In addition to its size, the patch would need to be altered for application on human skin, likely requiring longer needles.

“We would need to scale up the size of the patch and optimize the length, shape, and morphology of the needles,” Chen said. “Also, the patch needs to be compatible with daily life, for instance allowing for showering or sweating.”

Chen is encouraged by the success of his experiments, and by research reports of steady progress by other experimental microneedle patch developers.  For instance, others have completed early human studies with microneedle patch devices that contain insulin and that would benefit people with type 1 as well as type 2 diabetes. He hopes there will be lessons from development of those devices that can be applied to the microneedle patch that his team tested in this study.

Kidney Disease Increases Risk of Diabetes, Study Shows Elevated urea levels likely a culprit

Diabetes is known to increase a person’s risk of kidney disease. Now, a new study from Washington University School of Medicine in St. Louis suggests that the converse also is true: Kidney dysfunction increases the risk of diabetes.

Further, the researchers deduced that a likely culprit of the two-way relationship between kidney disease and diabetes is urea. The nitrogen-containing waste product in blood comes from the breakdown of protein in foods. Kidneys normally remove urea from the blood, but it can build up when kidney function slows down.

The findings are significant because urea levels can be lowered through medication, diet — for example, by eating less protein — and other means, thereby allowing for improved treatment and possible prevention of diabetes.

The epidemiological study, conducted in collaboration with the Veterans Affairs St.  Louis Health Care System, is published Dec. 11 in Kidney International.

“We have known for a long time that diabetes is a major risk factor for kidney disease, but now we have a better understanding that kidney disease, through elevated levels of urea, also raises the risk of diabetes,” said the study’s senior author Ziyad Al-Aly, MD, an assistant professor of medicine at Washington University. “When urea builds up in the blood because of kidney dysfunction, increased insulin resistance and impaired insulin secretion often result.”

In collaboration with scientists at the St. Louis Veterans Affairs’ Clinical Epidemiology Center, Washington University researchers examined medical records in national VA databases to dissect the relationship between kidney disease and diabetes. They evaluated the records of 1.3 million adults without diabetes over a five-year period, beginning in 2003.

A common blood test that measures the amount of urea nitrogen found in the blood showed that 117,000 of those without diabetes — or 9 percent — had elevated urea levels, signaling poor kidney function.

“That figure — 9 percent of people with high urea levels — remained relatively constant over time,” Al-Aly said. “It is also reflective of the general population.”

Overall, he said, those with high urea levels had a 23 percent higher risk of diabetes — a figure researchers determined by comparing risk between those with high and low urea levels. In each year studied, the researchers documented new cases of diabetes in 2,989 of every 100,000 people with low urea levels and 3,677 new cases of diabetes among those with high urea levels.

“The risk difference between high and low levels is 688 cases of diabetes per 100,000 people each year,” Al-Aly said. “This means that for every 100,000 people, there would be 688 more cases of diabetes each year in those with higher urea levels.”

Al-Aly said he was inspired to delve into the relationship between diabetes and kidney disease after reading a mouse study published in the August 2016 Journal of Clinical Investigation. As part of the study, researchers from the University of Montreal Hospital Research Centre in Canada induced kidney failure in mice. Subsequently, many of the animals experienced elevated urea levels, resulting in insulin resistance and impaired insulin secretion.

“I read the study with excitement and intrigue, and I thought, ‘We have to test this in humans,’ ” Al-Aly recalled. “Our results were almost an exact replica of the mouse study. The results showed a clear relationship between urea levels and risk of diabetes.”

Targeting a microRNA shows potential to enhance effectiveness of diabetes drugs

Over the past 15 years, University of Alabama at Birmingham endocrinologist Anath Shalev, M.D., has unraveled a crucial biological pathway that malfunctions in diabetes.

Her latest discovery in this beta-cell pathway, published in the journal Diabetes, shows the potential to enhance the effectiveness of existing diabetes drugs, as well as reduce some of the unwelcome side effects of those drugs.

The need for improved treatment is great. Diabetes is a disorder characterized by elevated blood sugar that afflicts one of every 10 U.S. adults and doubles the risk of early death. More than 30 million people in the United States have diabetes, which is the seventh-leading cause of death and also leads to blindness and lower-limb amputations.

In 2013, the UAB researchers found that either diabetes or elevated production of the protein TXNIP induced beta-cell expression of microRNA-204, or miR-204, and this microRNA, in turn, blocked insulin production. The Shalev group has now found another vital role for miR-204 — regulating the cell surface receptor that is the target of many of the newer type 2 diabetes drugs, such as Byetta, Victoza, Trulicity, Januvia, Onglyza and Tradjenta. This drug target is the glucagon-like peptide 1 receptor, or GLP1R. Activation of GLP1R with these drugs helps the beta cell produce and secrete more insulin.

Shalev’s new work was performed in rat beta cells, genetically modified mice, mouse pancreatic islets and human pancreatic islets. Healthy beta cells, which are found in the pancreatic islets, produce insulin to control blood sugar levels; in diabetes the beta cells are impaired and dysfunctional, and have lower GLP1R levels.

In the Diabetes study, Shalev and colleagues found that overexpression of miR-204 decreased expression of GLP1R in rat beta cells and in mouse and human pancreatic islets. Conversely, knock-down of miR-204 increased expression of GLP1R in those cells and pancreatic islets.

Greater GLP1R expression is beneficial because it helps transfer a signal to the beta cell to secrete more insulin, such as after a meal. Also, many of the newer diabetes drugs act as agonists to activate GLP1R. Higher expression can allow use of a lower-drug dose to treat diabetes, thus reducing dose-dependent side effects.

In mice, the UAB researchers found that a deletion of miR-204 caused enhanced GLP1R expression, and also better insulin secretion and glucose control. Furthermore, the knockout mice were more responsive to a GLP1R agonist in glucose tolerance tests. When the GLP1R knockout mice were used in a model of diabetes, where beta cells are damaged by low doses of the toxin streptozotocin, the diabetic mice showed improved glucose control and increased serum insulin levels.

These results suggest that downregulating miR-204, now revealed as an upstream regulator of GLP1R, could lead to better treatment of diabetes.

One key fact about miR-204 may further aid improved treatment. This microRNA is highly expressed in beta cells, but it is not highly expressed in the rest of the pancreas or in cells of the gastrointestinal tract that also express GLP1R and therefore respond to GLP1R agonists. Thus, an inhibitor of miR-204 would be relatively selective for beta cells.

“This novel concept of inhibiting a microRNA in a non-targeted manner, but taking advantage of its restricted tissue distribution and thereby selectively upregulating its target genes in that tissue, may have far reaching implications for microRNA biology and tissue-specific gene targeting in general,” Shalev said.

“Since miR-204 is expressed primarily in pancreatic beta cells, manipulating its levels allows for preferential upregulation of GLP1R in the beta cell, where it helps secrete insulin, rather than in the gastrointestinal system, where it can cause nausea and impaired gastric emptying, or in the pancreas, where it can increase the risk for pancreatitis,” Shalev said. “So by inhibiting miR-204, one could increase the effects of GLP1R agonist drugs on insulin secretion, thereby lowering the necessary dose and avoiding some of the dose-dependent adverse effects.”

The mechanism by which miR-204 downregulates expression of GLP1R is binding of the microRNA to the 3-prime-untranslated region of GLP1R messenger RNA. Such binding is a known method to control gene expression by microRNAs. The UAB researchers discovered this specific binding using microRNA target prediction software. They found two binding sites for miR-204 in the messenger RNA for human GLP1R and one binding site in the messenger RNA for mouse GLP1R. When they mutated those binding sites, it eliminated the regulatory effect of miR-204.

Additionally, the Shalev group showed a novel link between TXNIP and GLP1R signaling. Mice with a beta cell-specific knockout of the protein TXNIP had lower miR-204 levels and higher GLP1R expression, and the mice showed enhanced insulin secretion and glucose control in response to an agonist of GLP1R. Thus, through both control of insulin production and regulation of GLP1R, as well as regulation of the unfolded protein response and beta cell apoptosis, miR-204 appears to play a linchpin role to control the function of beta cells in the pancreas.

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.”

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.

Study reveals sweetened drinks during pregnancy puts infants at higher risk for obesity

A recent Danish study of children born to women with gestational diabetes, found that maternal daily consumption of artificially-sweetened beverages during pregnancy was associated with a higher body mass index score and increased risk of overweight/obesity at 7 years.

Artificial sweeteners are widely replacing caloric sweeteners, due to the health concern related to sugar-sweetened beverages (SSBs) within the general population. Artificially sweetened beverages have been considered as potential healthier alternatives, although this study suggests contrary. This study looks to investigate the long-term impact of ASBs consumption during pregnancy on offspring obesity risk in relation to offspring growth through age 7 years among children born to women with gestational diabetes .

In particular, children born to women with gestational diabetes –the most common pregnancy complication affecting approximately 16% of pregnancies worldwide–represent a high-risk phenotype, which may serve as a unique model to study the early origins of obesity. Further evidence has linked nutritional biological disruptions during pregnancy to fetal development and obesity risk in later life. Thus, the authors argue it is important to identify modifiable dietary factors that may prevent offspring obesity and maternal complications.

The study investigated 918 mother and child pairs from the Danish National Birth Cohort. Enrolled participants completed four telephone interviews at gestational weeks 12 and 30, and 6 and 18 months postpartum, which collected data on sociodemographic, perinatal, and clinical factors. In addition, maternal dietary intake was assessed by a food questionnaire during pregnancy. Offspring body mass index scores and overweight/obesity status were calculated using weight and length/height at birth, 5 and 12 months, and 7 years. When the children were 7 years old, a follow-up questionnaire about the child’s health and development was delivered to the parents.

Results showed that approximately half (45.4%) of women reported consuming artificially sweetened beverages during pregnancy. Whereas 68.7% reported consuming SSBs, artificially sweetened beverage consumption–compared to never consuming artificially sweetened beverages–by pregnant women with gestational diabetes was associated with a 1.57 increased risk of being overweight for gestational age babies and a 1.93-fold increase in overweight/obesity risk at 7 years after adjustment for major maternal and offspring risk factors.

Associations were more pronounced in male than female offspring. Substituting SSBs with artificially sweetened beverages was associated with an increased risk of offspring overweight/obesity at 7 years whereas substitution of artificially sweetened beverage with water was associated with a 17% reduced risk. The findings illustrated a positive association between uterus exposure to artificially sweetened beverages and birth size and risk of overweight/obesity at 7 years.

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.

Liver Cancer Drug Shows Promise in Preventing Liver Fibrosis and Treating NASH

Namodenoson, a Phase II drug developed by Can-Fite BioPharma Ltd. (NYSE MKT: CANF), has shown in newly published data that it prevents liver (hepatic) fibrosis progression in preclinical studies.

“These latest study results add to the growing body of data that demonstrate Namodenoson’s potential efficacy in combating non-alcoholic fatty liver disease (NAFLD), the precursor to non-alcoholic steatohepatitis (NASH), indications for which there is currently no FDA approved drug. We are advancing Namodenoson into a Phase II trial in NAFLD and expect to commence patient enrollment in the coming months through leading medical institutions in Israel,” stated Can-Fite CEO Dr. Pnina Fishman.

NAFLD is characterized by excess fat accumulation in the form of triglycerides (steatosis) in the liver. According to a recent study published in Hepatology, an estimated 25% of the population in the U.S. has NAFLD, with a higher prevalence in people with type II diabetes. Incidence is increasing based on rising obesity rates. NAFLD includes a range of liver diseases, with NASH being the more advanced form, manifesting as hepatic injury and inflammation. According to the NIH, the incidence of NASH in the U.S. is believed to affect 2-5% of the population. The spectrum of NAFLDs resembles alcoholic liver disease; however, they occur in people who drink little or no alcohol. If untreated, NASH can lead to cirrhosis and liver cancer.

By 2025, the addressable pharmaceutical market for NASH is estimated to reach $35-40 billion.

Liver fibrosis is the excessive accumulation of scar tissue resulting from ongoing inflammation. It can result in diminished blood flow throughout the liver and is associated with NAFLD.

Recent preclinical studies in a mouse model of liver fibrosis demonstrated the anti-fibrotic effects of Namodenoson. The Namodenoson treated group exhibited normal liver under macroscopic view, no accumulation of fluid (ascites), a low fibrosis profile, and lower serum levels of transaminases as compared to the control group. In addition, liver protein extracts and mRNA for the alpha smooth muscle actin showed a significant anti-fibrotic effect in the Namodenoson treated group as compared to the control group.

These studies were conducted under the supervision of Prof. Rifaat Safadi M.D., a Key Opinion Leader in the field of liver diseases, and Director of Liver Unit, Institute of Gastroenterology and Liver Diseases, Hadassah University Hospital, Ein Kerem.

Prof. Safadi commented, “Lowering liver fat content and fibrosis are the main unmet needs in NASH. Today there is a huge market need for drugs that fight the worldwide NASH epidemic.”

“Namodenoson is uniquely compelling for its potential to treat NAFLD and NASH because its safety profile has already been de-risked, increasing the likelihood it can advance through late stage trials and into clinical use for this large and unmet need,” Dr. Safadi added. “In general, there is significant development risk for new potential drugs in development due to safety risks including drug induced liver injury (DILI), drug-to-drug interactions (DDI), and metabolites in safety testing (MIST). Namodenoson, however, has demonstrated a good safety profile and is low or negative for DILI, DDI and MIST.”

“In addition, Namodenoson recognizes the difference between diseased and normal cells, and targets only the diseased cells through the specific A3 adenosine receptor. This precision targeting is designed to lead to higher efficacy and safety by leaving healthy cells unaffected. We are all looking for drugs with this profile to treat NASH,” concluded Dr. Safari.

Can-Fite plans to commence patient recruitment for its Phase II trial of Namodenoson in NASH/NAFLD in the second quarter of 2017.

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.

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.

Microbes In Your Gut Influence Major Eye Disease

Age-related Macular Degeneration (AMD) is the leading cause of irreversible blindness in the industrialized world, affecting over 10 million individuals in North America. A study lead by Dr. Przemyslaw (Mike) Sapieha, researcher at Hôpital Maisonneuve-Rosemont (CIUSSS de l’Est-de-l’Île-de-Montréal) and professor at the University of Montreal, published in EMBO Molecular Medicine, uncovered that bacteria in your intestines may play an important role in determining if you will develop blinding wet AMD.

AMD is characterized by a heightened immune response, sizeable deposits of fat debris at the back of the eye called soft drusen (early AMD), destruction of nerve cells, and growth of new diseased blood vessels (wet AMD, late form). While only accounting for roughly 10% of cases of AMD, wet AMD is the primary form leading to blindness. Current treatments becomes less effective with time. It is therefore important to find new ways to prevent the onset of this debilitating disease.

While many studies on the genetics of AMD have identified several genes that predispose to AMD, no single gene can account for development of the disease. Epidemiological data suggests that in men, overall abdominal obesity is the second most important environmental risk factor, after smoking, for progression to late-stage blinding AMD. Until now, the mechanisms that underscore this observation remained ill defined. Elisabeth Andriessen, a PhD student in the lab of Professor Sapieha found that changes in the bacterial communities of your gut, such as those brought on by a diet rich in fat, can cause long-term low-grade inflammation in your whole body and eventually promote diseases such as wet AMD. Among the series of experiments conducted as part of this study, the group performed fecal transfers from mice receiving regular fat diets, compared to those receiving a high fat diet, and found a significant amelioration of wet AMD.

“Our study suggests that diets rich in fat alter the gut microbiome in a way that aggravates wet AMD, a vascular disease of the aging eye. Influencing the types of microbes that reside in your gut either through diet or by other means may thus affect the chances of developing AMD and progression of this blinding disease”, says Dr Sapieha. Professor Sapieha holds the Wolfe Professorship in Translational Vision Research and a Canada Research Chair in retinal cell biology.

Fatty Liver: Turning Off TAZ Reverses Disease

Scientists at Columbia University Medical Center (CUMC) have identified a factor in liver cells that is responsible for turning a relatively benign liver condition, present in 30 percent of U.S. adults, into a serious disease that can lead to liver failure.

The study was published online today in Cell Metabolism.

With the rise of obesity in the U.S., the incidence of nonalcoholic fatty liver disease (NAFLD)—in which excess fat fills the liver—has risen to epidemic levels. The extra liver fat is generally benign, but in one in five people, NAFLD evolves into a more serious condition, nonalcoholic steatohepatitis (NASH).

In NASH, the liver becomes inflamed and criss-crossed by fibrous scar tissue, and liver cells start dying. Patients with NASH are at risk of liver failure and liver cancer, but there are no drugs on the market that can slow or stop the disease.

Because the amount of fibrosis in the liver is associated with a greater risk of death from NASH, Xiaobo Wang, PhD, associate research scientist in the Department of Medicine at CUMC working in the lab of Ira Tabas, MD, PhD, looked for ways to stop fibrosis in a mouse model of NASH.

He found that in liver cells, TAZ, a previously unknown factor in NASH, plays a critical role in initiating fibrosis, and that fibrosis stops in mice with NASH when TAZ is inactivated in liver cells. With TAZ shut down, existing fibers in the liver also dissolved, essentially reversing the disease. Two other critical features of NASH, inflammation and cell death, were also reduced when TAZ was turned off. Fat accumulation in the liver was unaffected.

Based on their examination of liver biopsies from NAFLD and NASH patients, Drs. Wang and Tabas believe that TAZ works in the same way in people.

“We think that by stopping fibrosis through TAZ and its partners, we may be able to prevent the serious consequences of NASH, including liver failure and liver cancer,” said Ira Tabas, Richard J. Stock Professor and vice-chair of research in the Department of Medicine and professor of pathology & cell biology (in physiology and cellular biophysics) at CUMC.

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.