Tag Archives: insulin

Newly discovered “insulin-like” molecule could change how we treat diabetes

Credit: Salk Institute.

Scientists at the prestigious Salk Institute have discovered a second insulin-like molecule produced by fat tissue that, like insulin, quickly regulates blood glucose. In a new study, they found that although the hormone has almost identical effects on the human body as insulin, it uses a different molecular pathway, thereby potentially circumventing insulin resistance. The remarkable findings could lead to novel treatments for diabetes and may even open the doors to new areas of metabolic research.

Before insulin was discovered in the 1920s at the University of Toronto, patients with type 1 diabetes rarely lived for more than a year or two. But after the hormone was successfully isolated it quickly saved lives, going on to become one of the most important medical breakthroughs of the 20th century. Today, millions of people across the world are diagnosed with type 1 or type 2 diabetes and benefit from insulin treatments. However, these treatments aren’t perfect due to problems arising from insulin resistance.

Insulin is released by your pancreas to lower blood sugar and keep it in the normal range. It achieves this goal by inhibiting the breakdown of fat cells into free fatty acids, a process known as lipolysis. In people with insulin resistance, glucose is not removed properly from the blood because the liver, fat, and muscles don’t respond well to insulin signaling. Furthermore, lipolysis occurs in excess, leading to increases in fatty acid levels, which prompt the liver to produce more glucose, compounding the already high blood sugar levels. This positive feedback loop can exacerbate insulin resistance, which characterizes diabetes and obesity.

The pancreas compensates by producing more insulin to help glucose from the food enter your cells. But if excess glucose in the blood remains high, the patient is at risk of developing prediabetes and, eventually, type 2 diabetes.

But insulin isn’t alone in regulating blood sugar in the body. In a new study published in the journal Cell Metabolism, Salk scientists showed that a hormone called FGF1 also regulates blood glucose through inhibiting lipolysis — a behavior that remarkably mirrors that of insulin.

“Finding a second hormone that suppresses lipolysis and lowers glucose is a scientific breakthrough,” says Professor Ronald Evans, co-senior author of the new study and Director of the Gene Expression Laboratory at Salk. “We have identified a new player in regulating fat lipolysis that will help us understand how energy stores are managed in the body.”

Previously, researchers injected FGF1 into mice with insulin resistance, resulting in dramatically lower blood sugar levels. However, why exactly this happens remained a mystery until Evans and colleagues showed that FGF1 suppresses lipolysis and regulates the production of glucose in the liver. That’s exactly what insulin does, which begs the question: do these molecules also share the same pathways to regulate blood sugar?

Turns out that they don’t and that’s actually fantastic news. Insulin suppresses lipolysis through PDE3B, an enzyme that initiates the signaling pathway, whereas the FGF1 hormone works through the PDE4 pathway.

“This mechanism is basically a second loop, with all the advantages of a parallel pathway. In insulin resistance, insulin signaling is impaired. However, with a different signaling cascade, if one is not working, the other can. That way you still have the control of lipolysis and blood glucose regulation,” says first author Gencer Sancar, a postdoctoral researcher in the Evans lab.

Since FGF1 uses a different pathway, the authors hope that the hormone will prove to be a new promising therapeutic route for diabetic patients.

Insulin injection.

Stem-cell implant prototypes pave the way towards life-long treatment for type 1 diabetes

New research is paving the way towards reliable, long-term treatments for type 1 diabetes. The work focused on developing implants based on stem cells that can deliver insulin directly into the bloodstream of diabetes patients.

Insulin injection.
Image credits Peter Stanic.

While the implants are not yet ready for use in a clinical role, the research does prove the viability of such systems for use in the future. The implants consist of pancreatic endoderm cells derived from human pluripotent stem cells (PSCs) and were tested with 26 patients. After more research and development, once such implants become able to secrete levels of insulin that will have a clinical effect on their recipients, they could become a viable alternative to current insulin-delivery systems and islet replacement therapies (pancreatic transplants).

Promising first steps

“The device is band-aid sized and designed to contain the lab grown islet cells for subcutaneous implant. It allows the cells within to become vascularized to permit delivery of oxygen and nutrients and release of insulin into the bloodstream. It is also readily retrievable”, said Dr. Timothy J. Kieffer of the University of British Columbia, corresponding author of the study, for ZME Science.

The team aims to provide an unlimited supply of insulin-producing cells for patients with type 1 diabetes, to mediate continuous, long-term treatment options while minimizing the invasiveness of the procedure.

Insulin is a hormone that keeps the levels of glucose (sugar) in our blood under control, and is produced by pancreatic β-cells. Type 1 diabetes is characterized by the destruction of these cells and leads to dangerously high levels of glucose building up in patients’ bloodstreams. Current treatments for this condition involve the administration of insulin directly into the bloodstream, either via manual injection or through automated systems that a patient can wear, which deliver the hormone periodically. Another possibility — although seen much more rarely in the grand scheme of things — is to treat the condition through islet transplant from donor organs.

Each of these treatment options comes with its own drawbacks. Direct injections require users to monitor their own state, remember to perform the procedure, and also carry the risk that they administer the shots imperfectly. Automated devices can be very burdensome to wear for long periods of time, are associated with long-term complications, and can malfunction. Transplants are very intrusive procedures and the supply of donor organs is very limited compared to the demand.

As such, an alternative is required, the team argues.

The current study reports on a phase I/II clinical trial involving the use of pancreatic endoderm cells as one such alternative. The team’s devices contain such cells in special capsules that allow for direct vascularization of the cells; these were implanted under the skin of the patients. The procedure did, however, run the risk of the participants’ bodies rejecting the implants, and thus involved an immunosuppressive treatment regimen that is commonly used in donor islet transplantation procedures. Possible side-effects of such treatments is an increased risk of cancer and infections in patients, as a direct consequence of their immune systems being suppressed.

That being said, the authors report that the devices worked as intended, and the cells within them started secreting insulin and delivering it directly into the participants’ bloodstreams in response to the glucose levels in their blood. Insulin expression (secretion) was recorded in 63% of the devices after they were explanted at time periods between 3 and 12 months after implantation. Insulin-secreting cells started accumulating progressively in these devices over a period of between 6 and 9 months after implantation.

Although not yet able to cover their full requirements for insulin, over a one-year study period, they reduced the amount of insulin participants needed to be administered by 20%. They also spent 13% more time in the target blood glucose range compared to pre-study periods.

“We found the implants were able to produce insulin in a meal regulated manner like normal healthy pancreatic islets, albeit at low levels,” Dr. Kieffer adds for ZME Science. “The sponsor company ViaCyte recently reported achieving clinically meaningful levels of insulin when more of these devices were implanted (8) that resulted in a dramatic reduction in the insulin injection requirements accompanied by vastly improved control of blood sugar.”

Overall, these devices were well-tolerated by their bodies and there were no severe adverse effects caused by the grafts. Two participants did experience serious adverse effects related to the immunosuppression treatment. Most of the adverse effects reported by participants, however, were related to the actual implantation/explantation surgeries, or to side-effects of the immunosuppressive treatment. All things considered, the team explains, the risk of local infection posed by the devices was very low, suggesting that the devices themselves are well-tolerated even in participants with a poor immune or healing response.

This does raise questions regarding the use of such devices over a patient’s whole life. An ideal solution to this would be an option to perform stem cell-based islet replacement therapy without the devices themselves, as this would bypass the need for immunosuppressive treatments altogether.

Still work to be done

One of the major limitations of the study was the lack of a control group, so the findings should not be used to draw any conclusion on how effective such devices would be at treating type 1 diabetes. However, the study does show that they are relatively safe to use and validate the working principle behind their design. More research will be needed to determine the quantity of cells such implants should contain in order to produce clinically-relevant benefits for patients.

“It was very exciting to see clear meal regulated insulin production in patients following the implants and also see islet cells in the retrieved devices that looked like normal healthy pancreatic islet cells. We now have clear proof of principle data that this stem cell-based approach can work,” Dr. Kieffer adds for ZME Science.

Currently, the cells survive an average of 59 weeks after implantation. The total percentage of insulin-positive cells they contained at maturation was below the team’s ideal target, however. The researchers are now working on solutions to promote vascularization between the grafts and the patients’ bodies, and on measures to improve the survival of the cells they contain.

“Our ultimate goal is to entirely free patients from the burden of glucose monitoring and insulin injections, and without the use of any immunosuppression,” Dr. Kieffer concluded in his email for ZME Science. “We are thus very excited by the recent ViaCyte / CRISPR Therapeutics announcement that Health Canada has approved clinical testing of genetically modified cells that have been engineered to evade detection by the immune system.”

“With protocol refinements and immune-evasive cells, we hope to reach this goal.

The paper “Implanted pluripotent stem-cell-derived pancreatic endoderm cells secrete glucose-responsive C-peptide in patients with type 1 diabetes” has been published in the journal Cell Stem Cell.

Why is insulin so outrageously expensive?

As any diabetic patient is painfully aware, insulin can be incredibly expensive — and that’s particularly true for Americans. But why is a drug that was discovered a century ago so costly?

Insulin is the definite poster child of drug price gouging. If people wonder why ‘Big Pharma’ is so hated across the world, look no further than the ridiculous pricing for insulin and the suspicious policies of the handful of companies that manufacture it.

Over the past decade, the cost of insulin had tripled in the United States, and the out-of-pocket prescription costs that patients have to pay have doubled just in the last five years.

How much is a bottle of insulin?

The cost of a single vial of insulin varies depending on the type of insulin and whether or not it is covered by insurance. Each insurance plan can cover insulin products differently.

In 2012, the average cost of insulin per diabetes patient was $2,864 per year. By 2016, just four years later, it had risen to $5,705.

Today, one vial of insulin can cost $250 and a pack of pens ranges from $375 to $500. Most patients require two vials of insulin per month or 1-2 packs of insulin pens, but some people need up to six vials per month.

Besides insulin, diabetic patients need other types of medication, which also tend to be high priced. According to a 2016 study, the total average out-of-pocket pharmacy and medical costs for patients with diabetes reached $18,500 in 2016 — a surge of $6,000 from 2012 costs, half of which are accounted for by spending on insulin.

As a result of these exorbitant prices, one in four patients say that they ration their insulin because they can’t afford full proper doses. In some cases, this practice can cost lives. For patients with type 1 diabetes, just a single day without insulin is enough to send them to the emergency room.

There are nearly 30 million people suffering from diabetes in the United States, 5% of whom — or about 1.5 million — suffer from type 1 diabetes, hence they require insulin to literally survive. Although people with type 2 diabetes can control their blood sugar with diet and exercising, many still need insulin shots, especially as their condition deteriorates.

The market is dominated by only a few manufacturers

Only three pharmaceutical giants — Novo Nordisk, Sanofi-Aventis, and Eli Lilly — produce 90% of the global insulin supply. Basically, these big three control the market. They also tend to mirror each other’s prices.

Here’s the thing though: insulin was invented in 1923 by Frederick Banting who immediately gave away the patent after it was clear that the drug would save millions of lives each year. Along with co-inventors James Collip and Charles Best, the patent was sold to the University of Toronto for a symbolic $1. Soon after, insulin from pigs and cattle was being produced and sold on a massive scale around the world.

“Insulin does not belong to me, it belongs to the world,” Banting once said.

Now, nearly 100 years later, insulin is inaccessible to thousands of Americans because of its high cost. Usually, when a drug has been on the market for decades, its patent expires, which means any manufacturer can produce a generic version that should drive the prices down by a high margin. But this expectation falls apart in the case of insulin — if anything, the reverse is true.

Part of the reason for this is something called ‘evergreening’, the practice involving various techniques to extend the protection on a drug and block competition that might lead to price reductions.

Early insulin was not ideal, requiring multiple injections for some patients. Some even developed potentially dangerous allergic reactions. Over the decades, manufacturers have introduced all sorts of new processes and technologies that vastly improved insulin, making the drug purer and safer.

In the 1970s, manufacturers stopped making insulin from animals. Instead, everyone now uses a technique based on recombinant DNA technology that basically produces human insulin from genetically modified bacteria.

That was great news for animals, but kinda bad news for patients. Although there’s no clear reason why a company would stop producing the animal-version of insulin, this cheap, older alternative has disappeared from the market — at least in the U.S. (you can still find animal-derived insulin in other countries, such as in Canada).

And by making minor modifications to their manufacturing process or packaging, manufacturers were also able to extend patent protections, thereby discouraging competitors and promoting a cartel-like business environment. This strategy is a win-win for big business but a lose-lose for patients who require life-saving therapy.

Unlike aspirin or adderall, which are chemical drugs which contain the same ingredients every time, insulin is a biologic drug. This means that the manufacturing is a lot more complicated since you have to work with live cells. It also means that the rules for generic drug patents don’t apply. For instance, the generic equivalent of a biologic drug is called a ‘biosimilar’.

In the US, there are only 17 FDA approved biosimilars for insulin. Many of these biosimilars are manufactured by one of the ‘big three’ manufacturers, which doesn’t help to bring the price down.

When asked how they explain the high price of insulin, manufacturers often cite the “complexity of the supply chain” as a reason high up their list. That may be true, but that doesn’t explain why cheaper, easy to manufacture animal-derived insulin isn’t offered as an alternative.

There is some progress but prices are still ‘too damn high’

Due to public outrage surrounding the prices of insulin and pressure from some members of Congress to keep prices under control, some insurance and pharmaceutical companies have taken measures to lower the monthly cost.

According to Singlecare, some of these measures include:

  • Cigna and Express Scripts capped the monthly out-of-pocket cost at $25/month, with an estimated 700,000 people with diabetes being eligible. However, employers must opt into this program. Cigna covers less than 1% of the millions of people with diabetes in the US.
  • Sanofi has a program for cash payers that costs $99/month and provides either 10 vials, 10 boxes of pens, or a combination of the two. People with Medicare, Medicaid, or other federal and state programs are not eligible for this program, however.
  • Eli Lilly developed a generic version of Humalog that is priced at half the normal rate, at $137.35/vial. They also launched their Insulin Value Program in April, which offers a $35 copay card for the uninsured or those with commercial insurance.
  • In April 2020, Novo Nordisk announced that it would offer a free 90-day supply of insulin to patients who had lost their health insurance as a result of the pandemic.
  • The state of Colorado has taken the unusual route of capping the price of the drug. People with diabetes in Colorado don’t have to pay more than $100/month copay for their insulin.

Such programs, although welcomed, don’t help every patient. For instance, you can’t use these discounts if you have Medicare and most often than not they’re capped at $100-$150.

The bottom line is that insulin is expensive because manufacturers control its price and since competition (or the competitive spirit) is almost non-existent. In other words, insulin is expensive because it can be.

Credit: Pixabay.

Could a combination of drug therapy and stem cells reverse type 2 diabetes?

Credit: Pixabay.

Credit: Pixabay.

Stem cells have opened a new range of possible treatments and recent studies suggest they could also deal with type 1 diabetes. This early-onset, less-common type of diabetes occurs when your body’s defense mechanisms harm insulin-producing cells in the pancreatic state, usually while preventing infections elsewhere in your body. With the help of stem cells, physicians have previously generated new insulin-producing cells in order to replace the ones that the pancreas has eliminated.

According to GenFollower, stem cells are also being used to tackle infertility and improve the reproductive system. 

On the other hand, type 2 diabetes — which makes up 90 % of diabetic issues globally — is more challenging to treat. It usually occurs in older people as a result of extra weight or hormonal instability.

Although people with type two diabetes do lose a few of their insulin-producing cells, their major issue is elsewhere. Their cells became immune to blood insulin. Although blood insulin is present in the entire body, the cells can’t use blood insulin to keep glucose levels under control.

Basically, restoring the lost insulin-producing cells isn’t enough to eliminate the problem.

But now, in a new study released in the journal Stem Cell Reports, researchers may have discovered a way.

A Bilateral Approach

In order to model type 2 diabetes, researchers at the University of British Colombia put mice on a high-carb, high-fat diet. The outward symptoms of type two diabetes quickly followed. The mouse became obese, intolerant to blood sugar (blood glucose), and immune to blood insulin. Their glucose levels increased.

Next followed the attempt to change the elicited diabetic state. The team of researchers cultured human embryonic stem cells and organized them to be properly implanted into the diabetic mouse.

As soon as they were transplanted, the stem cells slowly and gradually grew into insulin-producing cells during the period of a couple of months.

After three months, the rodents’ symptoms began to improve. Among various other changes, the mice recuperated some of their ability to regulate blood sugar levels. After six months, the improvements were considerable.

However, stem cells were not enough to reverse the diabetic state which is why the researchers also turned to antidiabetic medicines.

The authors used metformin (Glucophage), which decreases the rate at which the renal system produces blood sugar, and sitagliptin (Januvia), which reinforces blood insulin production and manages blood glucose.

The combination of antidiabetic medicines and stem cell transplants significantly boosted the mouse’s ability to process blood sugar.

The sitagliptin showed the best outcomes. Diabetic mice treated with sitagliptin and stem cells showed the same reactions after consuming carbohydrates as the non-diabetic mouse on the low-fat diet.

A New Pandemic

Diabetes mellitus affects about 385 million people around the world and at least 20 million people in the USA.

In the United States, diabetes mellitus treatment costs the healthcare industry about $612 billion, or 14 % of all healthcare budget for adults.

Without proper treatment and management, diabetes can lead to blindness, kidney failure, and gangrene resulting in arm or leg amputation. The WHO (World Health Organization) says that diabetes could be the 7th major cause of death by 2030.

Credit: Pixabay.

Insulin shortage to affect 40 million people by 2030

The rate at which people are developing diabetes has experts worried that we will not be able to keep up with the demand for insulin. According to a new study performed at Stanford University, 40 million people with type 2 diabetes won’t have access to the life-saving hormone by 2030.

Credit: Pixabay.

Credit: Pixabay.

In 1980, around 5% of adults around the globe had diabetes. Today, that figure almost doubled at roughly 9% — and global population has also swollen by another three billion individuals.

Sanjay Basu, Stanford Assistant Professor of Medicine, and colleagues, modeled the prevalence of type 2 diabetes in 221 countries between 2018 and 2030. The historical data that they used for their projections come from 14 studies that involved 60% of all people with type 2 diabetes around the world.

People with type 1 diabetes require supplemental insulin. Those with type 2 diabetes may eventually need insulin, but not necessarily. Type 2 diabetes is associated with obesity, poor diet, and physical inactivity.

The findings suggest that the total number of type 2 diabetes sufferers will increase by 20%, from 406 million in 2018 to 551 million in 2030. Half of these people would come from China (130 million), India (98 million), and the USA (32 million).

The researchers conclude in the journal The Lancet that of all these diabetes patients, 79 million would actually be in need of insulin to manage their diabetes. However, half of them won’t have access to an adequate supply of insulin, considering current trends.

“These estimates suggest that current levels of insulin access are highly inadequate compared to projected need, particularly in Africa and Asia, and more efforts should be devoted to overcoming this looming health challenge,” Basu said in a statement.

“Despite the UN’s commitment to treat non-communicable diseases and ensure universal access to drugs for diabetes, across much of the world insulin is scarce and unnecessarily difficult for patients to access. The number of adults with type 2 diabetes is expected to rise over the next 12 years due to ageing, urbanization, and associated changes in diet and physical activity. Unless governments begin initiatives to make insulin available and affordable, then its use is always going to be far from optimal.”

Having an accurate projection for insulin demand is important in order to mitigate healthcare risks. The issue is amplified by the fact that the treatment for diabetes is also highly costly — something that may be driven by business interests rather than free market forces. Only three manufacturers control most of the insulin supply of the world, all of which were accused of conspiring to hike prices intentionally. Between 2002 and 2013, the price of insulin tripled although there were only minimal increases in costs associated with the development of the treatment. The authors caution that unless governments intervene to make insulin more accessible and affordable, a huge number of people could risk not having access to life-saving treatment in the future.

“These comprehensive analyses explicitly accounted for a variety of circumstances. Nevertheless, they are based on mathematical models that are in turn based on other mathematical models. They are also based on a variety of assumptions… Such considerations suggest that predictions about the future need to be viewed cautiously. Regardless of these uncertainties, insulin is likely to maintain its place as a crucial therapy for type 2 diabetes, and as such a sufficient global supply needs to be estimated and ensured… Ongoing updates to models such as these that incorporate new data and trends as they accrue, may be the most reliable way of assuring their reliability and relevance to evidence-based care,” Dr. Hertzel Gerstein from McMaster University, who was not involved in the study, commented.

Pancreatic cells islets.

Pancreatic cells can naturally morph to combat diabetes, pointing to new avenues of treatment

An old cell can learn new tricks!

Pancreatic cells islets.

Dyed cells in a pancreatic islet.
Image credits Xiaojun Wang et al., (2013) PLOS One.

New research reveals a surprising level of plasticity in pancreatic cells, which morph to maintain proper hormone levels in the blood. The findings suggest that many other specialised cells could hold this ability, pointing the way to new treatment options for conditions that involve massive cellular death.

Class reroll

“What we are showing here is that the state of differentiation of a given cell is not carved in stone. Cell identity, at all stages of life, is modulated by the immediate cellular environment, particularly by inhibitory signals,” says lead author Professor Pedro Herrera from the Université de Genève (UNIGE) Faculty of Medicine. “Cell identity maintenance is therefore an active process of inhibition throughout the life of the cell, and not an intrinsic or passive state of differentiation.”

“This ability of specialized cells to change their function could prove crucial for treating other pathologies that are due to massive or inappropriate cell death, such as Alzheimer’s disease or myocardial infarction”.

The research was born of the team’s interest in diabetes, a disease that involves damage or destruction (through various means) of insulin-producing cells in the pancreas. This dismantles our bodies’ ability to regulate blood-sugar levels, leaving an excess in the blood over long periods of time, which leads to all sorts of complications: blindness, kidney failure, heart attacks, stroke, to name a few. Onset of diabetes is strongly linked to lifestyle. According to the WHO, over 8.5% of adults worldwide suffered from diabetes (both types combined, figures for 2014) and roughly 1.6 million deaths were directly caused by diabetes in 2015. Needless to say, it’s a wide-reaching condition with a severe quality of life impact — so there is a lot of interest in finding a cure.

Pancreatic cells involved in blood-sugar regulation come in three flavors: α (alpha) cells which produce glucagon, β (beta) cells which produce insulin, and δ (delta) cells which produce somatostatin. These cells bunch together in small clusters known as pancreatic islets. Glucagon raises sugar levels in the blood, insulin works to reduce it, and somatostatin is the hormonal equivalent of a manager’s email, governing activity in the pancreas. Diabetes is characterised by the absence of functional β cells, taking away the pancreas’ ability of reining in blood sugar.

In a study published back in 2014, however, Herrera and his colleagues showed that some pancreatic cells can switch their role to supplement the production of insulin if push comes to shove. In mice without β cells, they reported at the time, new insulin-producing cells appear spontaneously. However, it’s not a huge number — only “1 to 2% of α and δ cells”, Herrera explains, —  way too few to fix diabetes.

“Why do some cells do this conversion and others not? And above all, would it be possible to encourage it? These are the questions that are at the heart of our work,” Herrera adds.

To get to the bottom of things, the team analysed gene expression in pancreatic cells before and after the disappearance of β cells in pancreatic tissue. The first finding was that α cells suffer two key modifications: they start over-expressing some genes typically seen in β cells, and some that are characteristic for glucagon-producing α cells. Herrera’s team reports that insulin receptors on the surface of α cells suggests that their functions hinge on this hormone being present as well — hence, their activity is disrupted when β cells are destroyed.

Next, the team transplanted pancreatic islets into healthy mice to see what could coax these cells into morphing. Their hypothesis was that, when faced with hyperglycemia (high blood-sugar), α cells would change roles to address the lack of insulin.

In non-diabetic mice with functional β cells, and without hyperglycemia, some of the transplanted α cells started producing insulin when the β cells died in the grafted islets. This pretty much invalidated the team’s hypothesis, as a conversion was observed without hyperglycemia to act as a cue. The pancreatic environment itself was ruled out as a cause, too, as the grafts were placed in the renal capsule (i.e. outside of the pancreas). The only explanation, the team adds, is that the reprogramming capacity is intrinsic to the very pancreatic islet where these cells are located.

“Thus, in the same graft, only islets without β cells displayed reprogramming. No cell conversion occurred in neighbouring islets containing all their β cells,” says Herrera.

When the team blocked the insulin receptors of α cells in healthy mice, some of them started to produce insulin themselves — suggesting the hormone acts as a sort of ‘business as usual’ signal for α cells, preventing them from changing roles.

“By administering an insulin antagonist drug, we were able to increase the number of α cells that started producing insulin by 1 to 5%. In doing so, these cells became hybrids: they partially, but not fully changed their identity, and the phenomenon was reversible depending on the circumstances influencing the cells. Now that we are beginning to understand the mechanisms of this cellular plasticity, we believe that these adaptive cell identity changes could be exploited in future new treatments,” Herrera concludes.

While the work focused on pancreatic cells, there’s no reason why other specialised cells in the body couldn’t employ similar processes, the team says. More work will be needed to determine which cells can morph this way, and what would encourage them to do so — but, should we succeed, it could lead to new and very powerful treatments against conditions that involve cellular damage and death.

The paper has been published in the journal Nature Cell Biology.

Credit: Harvard SEAS.

Scientists come mighty close to delivering insulin in a pill

Credit: Harvard SEAS.

Credit: Harvard SEAS.

For decades, scientists have been looking for a holy grail of drug delivery: a method to give protein and peptide drugs like insulin by mouth, instead of injection. Harvard researchers have made huge stride forward by carrying insulin in an ionic liquid that prevents stomach enzymes from breaking down the drug. This approach more closely mimics the way in which a healthy person’s pancreas makes and delivers insulin to the liver, thereby mitigating some of the adverse effects of injecting insulin over a long time.

Doctors estimate that 40 million people worldwide have type 1 diabetes and depend on an insulin injection to keep their glucose levels in check. People diagnosed with type 1 diabetes usually start with two injections of insulin per day of two different types of insulin and gradually progress to three or four injections per day of different types of insulin. Many people fail to adhere to this very strict regime, which interferes with their normal day-to-day activities. Some have a phobia of needles or feel uncomfortable amounts of pain with each injection, making it an ordeal.

“The consequences of the resulting poor glycemic control can lead to serious health complications,” said senior author Samir Mitragotri, a Professor of Bioengineering at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS).

Delivering insulin orally would solve so many problems, making it as easy as popping any pill or tablet. The problem is that the protein is broken down by the stomach’s acidic environment and is poorly absorbed out of the intestines. Previously, scientists have attempted to navigate these obstacles by re-engineering the insulin molecule, coating it in protective polymers, and introducing additives to inhibit breakdown by enzymes or to enhance absorption. However, currently, no such treatment is clinically available.

Mitragotri and colleagues went a different route. They encapsulated an insulin-ionic liquid formulation in an enteric coating — a barrier that prevents the medication’s dissolution or disintegration in the gastric environment. The ionic liquid is comprised of choline and geranic acid, a biocompatible formulation that is easy and cheap to manufacture. What’s more, it can be stored for up to two months without degrading, which is longer than some injectable medications on the market.

Once it makes its way to the small intestine, where the environment is more alkaline, the ionic liquid carrying the insulin is automatically released. The implications of this work in the medical field could be huge — the approach could potentially be applied to many other proteins besides insulin.

“Insulin must navigate a challenging obstacle course before it can be effectively absorbed into the bloodstream,” said Mitragotri in a statement. “Our approach is like a Swiss Army knife, where one pill has tools for addressing each of the obstacles that are encountered.”

In the future, the Harvard researchers want to conduct more animal tests of the formulation in order to monitor the long-term toxicological effects. If all goes well, clinical trials in humans could gain approval faster than they normally would since the key ingredients of the ionic liquids are already considered safe. Choline is a vitamin-like essential nutrient and geranic acid, a widely used food additive, naturally occurs in cardamom and lemongrass.

The findings appeared in the journal Proceedings of the National Academy of Science.

Encapsulate

To HEK with diabetes: new cell capsule could treat the condition with 0 insulin shots

A new cell-based treatment for type 1 and 2 diabetes could eliminate the need for constant insulin injections for patients. The method showed its effectiveness in mice trials, and the team hopes to test in on human patients within two years.

Insulin Syringe

Image credits Melissa Wiesse.

The method uses a capsule of genetically engineered cells which is grafted under the patient’s skin. They monitor blood glucose levels and automatically secret and release insulin when needed. This would lead to more reliable and more efficient treatment to the condition than the ones we use now — where patients administer their own insulin. But we’re still a way off from that. The ETG University team behind the new capsule hopes they will obtain a human clinical trial license for the technology in the next two years, with potential commercialization in the next decade.

A growing issue

In 2013, some 24.4 million American adults were estimated to suffer from one form or another of diabetes, and as a rough estimate 10% of them had type 1. This condition usually begins developing in childhood as the body’s immune system starts systematically destroying all the pancreatic beta cells. These cells are the body’s sugar’o’meter, and release insulin to regulate glucose levels in the blood. So without them, patients have to get regular insulin shots or face the risk of hyperglicemia. Type 2 diabetes by contrast, is also usually associated with low levels of insulin but is characterized by high resistance to the hormone. Some type 2 patients also require shots of insulin to keep blood levels in check.

But relying on insulin shots is already showing limitations, and the number of diabetes cases is expected to explode worldwide in the next few decades, according to the team. So a more efficient treatment is required.

“By 2040, every tenth human on the planet will suffer from some kind of diabetes, that’s dramatic. We should be able to do a lot better than people measuring their glucose,” said lead researcher Martin Fussenegger.

Fussengger added that if the technology is green-lighted for human use, diabetes patients could trade daily injections for the implant which would need to be replaced three times per year. It would do a much better job than than the shots which do not perfectly control blood glucose levels leading to complications such as eye, nerve, and heart damage associated with diabetes. Should it pass the trials, the capsule could do a lot of good by treating patients of type 1 diabetes as well as those with type 2 that require insulin shots.

Sweetening the deal

Previous efforts have tried to develop methods of artificially growing pancreatic cells from stem cells. Manufacturing these cells en masse has proven difficult, however, and the cells were prone to dying once introduced in the body.

“They are prima donnas in the cellular context,” he said.

Team thus looked at the more resilient kidney cells for a solution. A type known as HEK cells were grafted with two new genes allowing them to take on the role of pancreatic cells. One of them makes the cells sensitive to glucose levels and the other instructs them to release insulin into the blood after glucose levels rise get too high.

They were tested on mice (who were treated so that they lost all insulin-producing cells). The modified HEK cells were then implanted in porous capsules (think of a teabag) that protected the human cells from the mice’s immune response while allowing insulin to flow out.

The approach was found to be better at regulating blood-sugar levels than pancreatic cells and remained healthy three weeks after implantation.

Encapsulate

Even the Daleks are excited at the idea.
Image modified after Radio Times.

“It’s hard to understand why ours should be better than something that evolved for millions of years,” said . “It shows that as engineers, thinking rationally, we can also do a very good job.”

In the study, mice were treated such that they lost all their insulin-producing pancreatic cells. The cells were then implanted into the mice, enclosed in a teabag-like porous capsule that protected the human cells from the mouse immune system, but allowed the hormone to diffuse out. One advantage of this approach is that the cells don’t have to be genetically matched to the patient. Capsules could be produced and frozen on an industrial scale, to be used whenever needed.

The full paper “β-cell–mimetic designer cells provide closed-loop glycemic control” has been published in the journal Science.

New enzyme could be used as an insulin alternative, to treat diabetes and obesity

University of Montreal Hospital Research Centre (CRCHUM) scientists have identified a new enzyme that could protect the body from toxic levels of intra-cell sugar. When there is too much sugar in the body it gets processed into glycerol-3-phosphate, a buildup of which can damage internal organs. The team behind the study proved that G3PP is able to extract excess sugar from cells.

Their discovery should lead to the development of therapeutics for obesity and type 2 diabetes.

Image via pixlr

“When glucose is abnormally elevated in the body, glucose-derived glycerol-3 phosphate reaches excessive levels in cells, and exaggerated glycerol 3 phosphate metabolism can damage various tissues,” said Marc Prentki, principal investigator at the CRCHUM and professor at the University of Montreal.

“We found that G3PP is able to breakdown a great proportion of this excess glycerol phosphate to glycerol and divert it outside the cell, thus protecting the insulin producing beta cells of pancreas and various organs from toxic effects of high glucose levels.”

Mammalian cells derive the bulk of their energy from oxidizing glucose and fatty acids. These substances govern many physiological processes, from insulin and glucose production, all the way to fat accumulation and nutrient metabolization. But a too large intake of glucose disrupts these processes and can lead to obesity, type 2 diabetes and cardiovascular diseases.

Beta cells in the pancreas respond to changes in blood sugar levels, cracking up or toning down on insulin — a hormone that controls glucose and fat utilization. Usually this keeps blood sugar levels stable and cells happy and well supplied with fuel. As glucose is being used in cells, glycerol-3-phosphate is formed, a molecule central to metabolism since it is needed for both energy production and fat formation.

But when these nutrients are found in excess, they can actually damage beta cells, inhibiting their function. Blood sugar levels remain unchecked, skyrocket, and damage the beta cells even further. This leads to a vicious circle, shutting down the body’s system of managing its fuel. G3PP however isn’t produced by beta cells, and the team hopes it can be used to regulate formation and storage of fat as well as production of glucose in the liver.

“By diverting glucose as glycerol, G3PP prevents excessive formation and storage of fat” says Dr Murthy Madiraju, a scientist at CRCHUM.

Dr Prentki added: ‘It is extremely rare since the 1960s that a novel enzyme is discovered at the heart of metabolism of nutrients in all mammalian tissues, and likely this enzyme will be incorporated in biochemistry textbooks.’

The research team is currently in the process of discovering ‘small molecule activators of G3PP’ to treat cardio-metabolic disorders. These drugs will form a new class of drugs, being unique in the way they operate inside the body.

The treatment will first have to be confirmed in several animal trials before drugs for human use can be developed.

“This is an interesting paper and to some extent unusual as new enzymes involved in metabolic control are rare,” said Professor Iain Broom, Director of the Centre for Obesity Research & Epidemiology, Robert Gordon University.

But we should take great care as we develop this class of drugs, he adds”

“Care should be taken, however, in reading too much into the possibilities for treatment of disease by focusing on such individual enzymes, especially as the evidence for this control mechanism comes from isolated cells.”

“This paper does have an important finding, however, and should not be dismissed lightly – but I would draw the line at statements of ‘guilt-free sugary treats’,” he said, referring to the media’s take on the story. ”

This is not an accurate by-line for this interesting piece of science.”

The paper can be found online in the journal Proceedings of the National Academy of Sciences.

 

insulin diabetes

Why insulin is so prohibitively expensive to the 29 million diabetes patients in the US

Even if it was first discovered more than 90 years ago, insulin is still out of reach for a shocking 29 million diabetes patients in the United States. Yes, this is the 21st century, but even so a staggering number of human beings are forced to live in life threatening conditions. But why is insulin so prohibitively expensive? According to Jeremy Greene, M.D., Ph.D., and Kevin Riggs, M.D., M.P.H., it’s all because of a series of perverse updates to insulin treatments. While insulin made today is more effective in some instances, previous versions weren’t that bad. In fact, they saved lives. Yet, these were replaced with very expensive versions, while the older, much cheaper versions are nowhere to be found on the market anymore. The two authors explore all that’s wrong with today’s insulin big pharma.

A brief history of insulin

insulin diabetes

Image: CNN

In their study published in the  New England Journal of Medicinethe two authors outline the history of insulin manufacturing until present day to build up the context which describes the present state of affairs in the big pharma business. Diabetes is diagnosed when a person has too much glucose (sugar) in the blood. This happens because the pancreas cannot make enough insulin. Insulin is produced in the pancreas and has two jobs in the body – the first is to transport glucose from the blood supply into fat and muscle cells, where it can be used for energy. The second is to switch off the liver once the level of glucose in the blood is high enough.

In 1910, Sharpey-Shafer of Edinburgh suggested a single chemical was missing from the pancreas in diabetic people. He proposed calling this chemical “insulin”, and the name stuck and was later taken up by Frederick Banting and Charles Best, two Canadian researchers credited with the discovery of the hormone in 1921. They showed that removing the pancreas in dogs made them diabetic. Then, they isolated a fluid (the insulin in question) from the Islets of Langerhans-clusters of specialized cells within the pancreas and injected it in diabetes dogs.  This restored the dogs to normalcy – for as long as they had the extract. For their work, the two were awarded the  Nobel Prize in Medicine the very next year, in 1923. It might be worth mentioning that many credit R. C. Paulescu, a Romanian biologist, as the first to discover insulin.

Anyway, the University of Toronto was good enough to  immediately give pharmaceutical companies license to produce insulin free of royalties. Soon enough, it became widely available throughout the world saving millions of lives. In 1955, insulin became the first protein to be fully sequenced. This was very important since once a protein’s sequence is known, it is possible, in theory, to recreate it synthetically. In fact, insulin was the first protein to be chemically synthesized in a laboratory, in 1963, but at the time it wasn’t successful since scientists were unable to make much of it.

Girl injecting herself with insulin (Lilly Girl), 1930. Photograph. Courtesy of Eli Lilly and Company Archives.

Girl injecting herself with insulin (Lilly Girl), 1930. Photograph. Courtesy of Eli Lilly and Company Archives.

For 60 years since Banting’s group first isolated insulin, diabetics relied on hormone purified from animals, primarily cattle and pigs. In the meantime, the drug was made purer so fewer adverse reactions occurred. It was also made to last longer in the bloodstream, so fewer injections were required. The breakthrough came in 1978 when insulin became the first human protein to be manufactured through biotechnology. A team of researchers from the City of Hope National Medical Center and the fledgling biotechnology company Genentech managed to synthesize human insulin in the laboratory using a process that could produce large amounts. Basically, they inserted human DNA in bacteria and used these as miniature factories. The result was human insulin, without the problems animal insulin sometimes causes. Humulin, as the commercial product was called, revolutionized diabetes treatment when it became widely available in the early 1980s.

Our drugs, our rules

 

Today, almost all diabetic people use recombinant human insulin instead of animal insulin. Then, a funny thing happened, Greene says: “The older [animal] insulin, rather than remaining around on the market as a cheaper, older alternative, disappeared from the market.”

According to Dr. Kevin Riggs, a professor of medicine at Johns Hopkins and co-author of the new insulin study, Humulin launched a highly aggressive marketing campaign targeted to doctors to take up the new product. Left without demand, the animal variety would wither away.  Dr. Adriane Fugh-Berman, a professor of medicine and pharmacology at Georgetown University, says this is allowed because the FDA doesn’t require new drugs on the market to be proven better than older drugs – it only requires the drugs not be worse. ”In government-funded studies that have compared older drugs to newer drugs, often older drugs come out looking better or equal to newer drugs,” Fugh-Berman says.

For instance, he quotes studies which found animal-derived forms of insulin work better for some patients. He also notes that while animal-derived insulin isn’t available in the US anymore, it is elsewhere. “In Canada, there actually is still an animal-derived insulin on the market, and that was really due to the efforts of consumer advocates,” Fugh-Berman says.

A treatment with the newest version of Humulin can cost up to $400 a month, and many of the millions of diabetes patients in the US can’t afford it. Left without an alternative, they stop taking treatment altogether.  According to a 2010 Health Action International report, the price of insulin can vary wildly according to where you live: insulin prices for 10 ml  may cost from $1.55 a vial in Iran to $76.69 in Austria.

“When people can’t afford it, they often stop taking it altogether.”

Patients with diabetes who are not taking prescribed insulin come to Riggs’ and Greene’s Baltimore-area clinics complaining of blurred vision, weight loss and intolerable thirst — symptoms of uncontrolled diabetes, which can lead to blindness, kidney failure, gangrene and loss of limbs.

Biotech insulin is now the standard in the U.S., the authors say. This perverse status quo was maintained by companies like Sanofi or Novo Nordisk thanks to incremental improvements  that extend their patents for many decades. Riggs and Greene note that patents on the first synthetic insulin expired in 2014.

 

 

Sea Snails Paralyze Their Prey With Unique Type of Insulin

What do you do if you need to catch your own food… but you’re just not fast enough? That’s the problem cone snails had to face, and the solution they came up with is pretty amazing: they kill fish by lowering their sugar levels with a unique type of insulin, researchers found

Conus geographus, the cone snail used for this study.

Cone snails are found in marine environments. They are part of a large genus, and all the species from that genus are venomous capable of inflicting serious damage to humans; there have been many cases of divers being stung by cone snails, and even some lived were claims by the very powerful venom. Cone snails use a hypodermic-like modified radula tooth and a venom gland to attack and paralyze their prey before engulfing it. Their tooth is used like a dart or a harpoon, injecting the venom. But a group of researchers now believes we can actually use this venom for medical purposes.

The venom of cone snails contains hundreds of different compounds, and its exact composition varies widely from one species of cone snail to another. But they all have one thing in common – they kill fish by overdosing them with toxins.

“It looks like the fish is completely narced,” says Christopher Meyer, a cone snail specialist at the Smithsonian’s National Museum of Natural History, who wasn’t involved in the study.

When the insulin is injected into the prey, it causes the sugar levels to plummet, making the fish sluggish; once it gets slow enough, the snail closes in and injects another toxin which completely paralyzes them. The type of insulin they use for this is what scientists believe can be used.

“This is a unique type of insulin. It is shorter than any insulin that has been described in any animal,” Baldomero M. Olivera, a professor of biology at the University of Utah and a senior author of the study, said in a statement. “We found it in the venom in large amounts.”

In order to study this substance, researchers examined the gene sequences of all the proteins in the venom gland of Conus geographus, a cone snail with a very powerful venom. They detected two sequences which are similar to the insulin we humans use, but also spotted some differences. Studying it could provide new insight into how human metabolism works, and even help in concrete medical situations.

“The snail insulin consists of 43 amino acid building blocks, fewer than any known insulin. Its stripped down size and odd chemical modifications may have evolved as a way to make it better at causing hypoglycemia in prey,” the scientists said in the statement.

This is yet another proof that there are many secrets in the biological world still waiting to be discovered. The fact that this slow sea snail is able to develop such a complex chemical mechanism is truly spectacular.

“How brilliant is this,” says Meyer, who has observed a close cousin of the geographic cone snail—named Conus tulipa—hunting and killing fish in the same way in Guam. The fish almost look like they’re passed out drunk, he says, and now we know why.

Cone snail venom has also been proposed as a pain reliever and an antibiotic.

Journal Reference: Proceedings of the National Academy of Sciences.

 

 

Older diabetics face high over-treatment risk

The “one size fits all” approach to diabetics treatment may cause significant problems for older patients also suffering from other conditions. Attempting to aggressively control blood sugar with insulin and sulfonylurea drugs could lead to over-treatment and hypoglycemia (low blood sugar), Yale researchers report.

Diabetes overtreatment may threaten the health and lives of older patients. Image via Health Works.

The study, which was published in JAMA Internal Medicine, found that many older patients received the same treatment as their younger counterparts, despite having other health conditions to struggle with. In patients with diabetes aged 65 and older this raises major problems – potentially even life threatening ones.

[ALSO SEE] Diabetes cured in mice

“We treat diabetes to prevent complications of the disease by lowering blood sugar levels, but the problem with aggressively lowering blood sugars in older people — to a hemoglobin A1c below 7% — is that it is uncertain whether this approach provides a benefit, and it could, in fact, cause greater harm,” said lead author Dr. Kasia Lipska, assistant professor of internal medicine at Yale School of Medicine. “Our study suggests that we have a one-size-fits-all approach despite questionable benefits and known risks. We have been potentially over-treating a substantial proportion of the population.”

This study asks some very valid questions and shows that even though managing diabetes is very important, we need to find a way to tailor treatments for individual patients and needs.

For this study, patients were divided into three groups depending on their relative health – poor, intermediate and good. Blood sugar was considered controlled if it fell below 7%. About 62% of the patients had blood sugar levels less than 7%. Out of them, 55% were treated with either insulin or sulfonylureas medications.

“We should use an individualized therapy approach when treating older diabetes patients,” said Lipska. “Older patients who are relatively healthy may benefit if they are treated in a similar way to younger diabetes patients, but this approach might not work in older patients who often have other health issues.”

Diabetes is a term denoting a group of metabolic diseases in which there are high blood sugar levels over a prolonged period. As at 2013, 382 million people have diabetes worldwide, with type 2 diabetes making for 90% of all cases.

Journal Reference: Kasia J. Lipska, Joseph S. Ross, Yinghui Miao, Nilay D. Shah, Sei J. Lee, Michael A. Steinman. Potential Overtreatment of Diabetes Mellitus in Older Adults With Tight Glycemic Control. doi:10.1001/jamainternmed.2014.7345

small-intestine

Nanoparticle pill delivers insulin orally with 11-fold efficiency

Drug delivery encapsulated in tiny nanoparticles are thoroughly studied with great interest because they offer the chance to deliver treatments more efficiently. That’s not all though – with nanoparticle pills you can selectively target key areas and deliver drugs which otherwise wouldn’t be possible without using invasive methods. Take diabetes  for instance – patients need to take shots of insulin on a regular basis and this is the only way the drug can be delivered effectively so far. A team of researchers at MIT have demonstrated, however, insulin absorption in the bloodstream of mice through nanoparticle pill oral ingestion. The findings could pave the way for other kinds of drugs becoming orally ingestistable, which are currently delivered only through invasive methods, like those targeting cancer.

“If you were a patient and you had a choice, there’s just no question: Patients would always prefer drugs they can take orally,” says Robert Langer, the David H. Koch Institute Professor at MIT, a member of MIT’s Koch Institute for Integrative Cancer Research, and an author of the Science Translational Medicine paper.

Of course, this is not the first research we’ve reported that discusses oral nanoparticle delivery. The key finding from MIT lies in the way the drugs bind to the intestinal inner wall. Previously, it was shown that when feeding on their mother’s milk, babies absorb antibodies contained in the milk to boost their own immune defense. These antibodies are absorbed through  cell surface receptor called the FcR, which allows them to enter the blood stream.

The nano-pills of the future

Exploiting this biophysical processes, the researchers coated their nanoparticles containing the drug payload (insulin) with Fc proteins which attach themselves to the FcR receptors. Once attached to the receptors, the particles bring along the bio-compatible nanoparticles along with them.

After administering the nanoparticles oral to mice, the researchers measured 11-fold efficiency of insulin absorption in the bloodstream than nanoparticles devoid of the Fc protein coating.

“It illustrates a very general concept where we can use these receptors to traffic nanoparticles that could contain pretty much anything. Any molecule that has difficulty crossing the barrier could be loaded in the nanoparticle and trafficked across,” says  Rohit Karnik, an MIT associate professor of mechanical engineering.

small-intestine

image source: diet777.com

That’s very interesting, but it gets even more promising when you consider nanoparticle drug delivery can be used for treating all kinds of diseases that currently rely on invasive operations; i.e. cancer. The are numerous challenges to orally ingested nanoparticles though. Like a biological wall, the intestinal lining typically keeps drugs from reaching tumors via the blood stream.

“The key challenge is how to make a nanoparticle get through this barrier of cells. Whenever cells want to form a barrier, they make these attachments from cell to cell, analogous to a brick wall where the bricks are the cells and the mortar is the attachments, and nothing can penetrate that wall,” said  Omid Farokhzad, director of the Laboratory of Nanomedicine and Biomaterials at BWH.

The present research illustrates that intestinal cells can be breached, proving oral nanoparticle delivery can be attained. Further animal tests and experiments using other types of drugs are planned.

“If you can penetrate the mucosa in the intestine, maybe next you can penetrate the mucosa in the lungs, maybe the blood-brain barrier, maybe the placental barrier,” said Farokhzad.

(c) Bill David Brooks/Flickr

Bioadhesive coating might allow insulin oral administration instead of injections

(c) Bill David Brooks/Flickr

(c) Bill David Brooks/Flickr

The reason why some drugs can only be taken by injecting them, instead of less intrusive solutions like oral ingestion, is because otherwise these drugs can not reach the bloodstream effectively. For people suffering from chronic diseases that require a lifetime treatment of drugs administered by injection, like those suffering from diabetes who need an insulin shot every other day, this can be most cumbersome to  say the least. Bioengineers at Brown University, however, have developed a novel adhesive coating that can protect proteins like insulin on their way through the stomach to the small intestine where they can be effectively absorbed. Initial results have so far been extremely promising.

For years scientists have been trying to develop ways of delivering protein-based drugs safely through the stomach to the small intestine where they can be absorbed and distributed by the bloodstream. Progress has been slow in this direction, but recently Brown University researchers led by Edith Mathiowitz, professor of medical science at Brown University, reported they have developed a “bioadhesive” coating that significantly increased the intestinal uptake of polymer nanoparticles in rats and that the nanoparticles were delivered to tissues around the body in a way that could potentially be controlled.

“The results of these studies provide strong support for the use of bioadhesive polymers to enhance nano- and microparticle uptake from the small intestine for oral drug delivery,” wrote the researchers in the Journal of Controlled Release, led by corresponding author Edith Mathiowitz, professor of medical science at Brown University.

Adhesion/Absorption of protein-based drugs

The promising coating in question is a chemical called PBMAD. This chemical was subjected to tests both in the lab and on animal models to verify its potential as a protective coating for protein-based drugs. The experiments were made using  particles about 500 nanometers in diameter made of two different materials: polystyrene, which adheres pretty well to the intestine’s mucosal lining, and another plastic called PMMA, that does not. The PMMA plastic was most interesting to follow, so in their experiments the Brown researchers used the particle under two scenarios: bare and coated.

[RELATED] Type 1 diabetes cured in animals, humans might lag far behind

Basic benchtop tests were performed to see how well each kind of particles adhered, and it was found PBMAD-coated had the strongest adherence  to intestinal tissue, binding more than twice as strongly as the uncoated PMMA particles and about 1.5 times as strongly as the polystyrene particles. In the second part of the experiments, various doses of each type of particle were injected into the intestines of lab rats. Measurements showed that the rats absorbed 66.9 percent of the PBMAD-coated particles, 45.8 percent of the polystyrene particles and only 1.9 percent of the uncoated PMMA partcles.

Controlling the drugs

What’s maybe even more important to note is that each particle had its own unique distribution profiles around the body. For instance, 80 percent of the polystyrene particles that were absorbed went to the liver and another 10 percent went to the kidneys. The PBMAD-coated particles on the other hand were much more likely to reach the heart, while the uncoated ones were much more likely to reach the brain. What this means is that researchers can control where and how protein-based drugs reach specific parts of the body, essentially targeting doses of medicines taken orally, Mathiowitz said.

“The distribution in the body can be somehow controlled with the type of polymer that you use,” she said.

The whole idea is that protein-based medicines would be carried in the nanoparticles, however more work is required to demonstrate actual delivery of protein-based medicines in sufficient quantity to tissues where they are needed. For now, Mathiowitz and her team are busy understanding the biophysics of how the PBMAD-coated particles are taken up by the intestines.

“What this means now is that if I coat bioerodible nanoparticles correctly, I can enhance their uptake,” she said. “Bioerodible nanoparticles are what we would ultimately like to use to deliver proteins. The question we address in this paper is how much can we deliver. The numbers we saw make the goal more feasible.”

source: Brown Uni

Universitat Autònoma de Barcelona researchers have successfully cured type 1 diabetes in dogs, a breakthrough that gives hope that the same effects might be achieved for humans as well.

Type 1 diabetes cured in animals, humans might not lag far behind

In what can only be considered a remarkable medical breakthrough, researchers at  Universitat Autònoma de Barcelona (UAB) have completely cured type 1 diabetes in dogs after they were injected during a single gene therapy session. The injected gene therapy vectors ensure a healthy expression of glucose, thus the regular insulin shots and associated side effects with the disease are no longer required.

Universitat Autònoma de Barcelona researchers have successfully cured type 1 diabetes in dogs, a breakthrough that gives hope that the same effects might be achieved for humans as well.

Universitat Autònoma de Barcelona researchers have successfully cured type 1 diabetes in dogs, a breakthrough that gives hope that the same effects might be achieved for humans as well.

The therapy consists of a single session of minimally invasive injections to the dog’s rear leg with gene therapy vectors, known as adeno-associated vectors (AAV). These vectors, derived from non-pathogenic viruses, are widely used in gene therapy and have been successful in treating several diseases. In the treated dogs,  two genes are targeted to the muscle of adult animals  – insulin and glucokinase genes. The latter  is an enzyme that regulates the uptake of glucose from the blood, and is typically the one that can cause hyperglycemia (excess of blood sugar associated) in diabetes patients.

When the two genes act simultaneously, they work as a glucose sensor automatically regulating the glucose uptake to healthy levels. Multiple clinical trials have been from which it was observed that the diseased dogs recovered their health and no longer showed symptoms of the disease. In one case, one dog was monitored for four years after therapy and still didn’t show any signs of the disease returning.

While human trials might still be a long way, this sounding success in large animals gives hope that type 1 diabetes may be cured for human patients as well using the same therapy.

The study was led by the head of the UAB’s Centre for Animal Biotechnology and Gene Therapy (CBATEG) Fàtima Bosch, and involved the Department of Biochemistry and Molecular Biology of the UAB, the Department of Medicine and Animal Surgery of the UAB, the Faculty of Veterinary Science of the UAB, the Department of Animal Health and Anatomy of the UAB, the Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), the Children’s Hospital of Philadelphia (USA) and the Howard Hughes Medical Institute of Philadelphia (USA).

Findings were published in the journal Diabetes. 

source: press release

obesity

Gene mutation leads to insatiable eating disorder causing obesity

There are a number of factors that lead to obesity, the most obvious of which is of course eating too much, without burning the excess fat by exercising. Fact is, there are some people in the world who no matter how much they’d  eat, they never seem to be satisfied, constantly consumed by a sense of hunger and a voracious appetite. These individuals have a problem, and it’s genetic in nature. A recent research made by scientists at Georgetown University Medical Center have found that a gene mutation causes one to uncontrollably eat, as a result of a malfunctioned appetite quenching signal from the body to the right place in the brain.

obesityHunger is a an indispensable biological mechanisms, which signals a healthy individual that it’s time to ingest food and nourish the body by fluctuation of leptin and ghrelin hormone levels. Increasing levels of leptin result in a reduction of one’s motivation to eat. In humans, leptin and insulin hormones are released into to the body such that the brain may know that it’s time to stop eating, however researchers have found that mutations in the brain-derived neurotrophic factor (Bdnf) gene does not allow brain neurons to effectively pass leptin and insulin chemical signals through the brain.

A gene mutation that makes you eat continuously

The BDNF gene is crucial to the formation and maturation of the synapses, structures that link neurons with one another and allow chemical signal transmission between them. The gene generates one long and one short transcript. Researchers observed that mice which lacked the long-form Bdnf transcript had many immature synapses, resulting in deficits in learning and memory. Mice suffering from the same Bdnf mutation were also severely obese.

“This is the first time protein synthesis in dendrites, tree-like extensions of neurons, has been found to be critical for control of weight,” says the study’s senior investigator, Baoji Xu, Ph.D., an associate professor of pharmacology and physiology at Georgetown.

“This discovery may open up novel strategies to help the brain control body weight,” he says.

Other researchers began to look at the Bdnf gene in humans, and large-scale genome-wide association studies showed Bdnf gene variants are, in fact, linked to obesity.

Other large-scale genome-wide association studies have shown than the Bdnf gene variants are indeed linked to obesity in humans, as well – this is a fact that’s been well known for some time, but the mechanics weren’t understood before this study. Xu’s research shows that leptin and insulin chemical signals need to be moving along the neuronal highway to the correct brain locations, where appetite might be quenched, however when the Bdnf gene is mutated, neurons can’t communicated very well with each other anymore.

“If there is a problem with the Bdnf gene, neurons can’t talk to each other, and the leptin and insulin signals are ineffective, and appetite is not modified,” Xu says.

Hope for a cure to obesity

Scientists are now looking for way to regulate the leptin and insulin signal movements though the brain neurons. One immediate way to make this happen might be to introduce adeno-associated virus-based gene therapy such that additional long-form Bdnf transcript might be produced. Though this is a safe procedure, the researchers believe gene therapy might be ineffective, compared to a drug which can stimulate Bdnf expression in the hypothalamus.

The researchers’ findings were reported on March 18th in journal Nature Medicine.

Georgetown Press Release

Enzyme allows mice to eat more, and gain less weight

Mice altered to express the IKKbeta enzyme (right column) in their fat had smaller globules of fat in their subcutaneous adipose tissue (top row) and in their liver (bottom row) than normal mice (left column). (Credit: Xu Lab)

Scientists have genetically engineered mice able to express a certain enzyme, which allows for an increased metabolic rate. The lab mice infussed with this enzyme in their fat tissue were able to eat more, but gain far less weight than their naturally bred brethren.

It’s generally acknowledged that obesity and inflammation cause insulin resistance, however it’s not perfectly understood why this happens. Embarking on a research that seeks to clarify how obesity and inflammation affect insulin resistance, Brown University researchers changed the sequence of events for transgenically engineered mice by inducing inflammation via the IKKbeta enzyme in their fatty tissue before they were obese.

They then procedeed in administrating a fatty diet to two groups of mice, one altered, the other natural, with all mice starting at the same weight. They observed that 22 weeks on a high-fat diet, however, altered male mice weighed less than 38 grams while unaltered male mice weighed more than 45 grams. After switching to a less fatty diet, the weight differences between the two groups weren’t as evident, however they remained statistically significant.

“Turning on this molecule has a very dramatic impact on lipid metabolism,” says Haiyan Xu, assistant professor of medicine at Brown University and corresponding author of a paper describing the research published online in the journal Endocrinology.

The altered mice not only managed to eat more and gain less weight, but due to their accelerated metabolism, researchers could observe they had lower sugar levels in their blood, after a glucose shot, than those of the control mice. An insulin shot was also administered, and researchers also remarkably observed how insulin was more effective.

Scientists are now trying to figure out the mechanisms through which IKKbeta enzyme can increase metabolic performance. One thing’s for certain for the researchers responsible for the study: obesity and inflammation are both promoters of insulin resistance, and obesity seems to be the worse one, Xu says. “Lower body weight is always a beneficial thing for influencing insulin sensitivity. Reduced adiposity wins over increased inflammation.”

source