Tag Archives: pancreas

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.

Titanium dioxide nanoparticles.

White paint might be causing a lot of Type 2 diabetes, preliminary research finds

A pilot study from The University of Texas at Austin suggests white paint and Type 2 diabetes might be linked.

Titanium dioxide nanoparticles.

Titanium dioxide nanoparticles.
Image credits University of Turin.

In the mid-20th century, titanium dioxide (TiO2) overthrew lead-based compounds (which were really toxic) as the go-to white pigment. Today, it’s the most widely used white pigment, mixed into everything from food and medication to plastic and paper. We rely on this substance a lot, as we’re producing in excess of 9 million metric tons of the stuff per year.

However, the pigment may not be as harmless as we’ve believed. Preliminary research has found TiO2 crystals embedded in pancreas tissue afflicted with Type 2 diabetes (T2D).

The white tint of diabetes

The team worked with 11 pancreas specimens, 8 from donors with T2D and 3 from donors who didn’t have the condition. The specimens were provided by the Juvenile Diabetes Research Foundation nPOD at the University of Florida at Gainesville.

The last three samples didn’t contain any detectable levels of TiO2 crystals. The 8 specimens with T2D, however, all had TiO2 crystals embedded in their tissues. The researchers report finding over 200 million TiO2 crystallites per gram of TiO2 particles in the specimens of donors with diabetes.

It’s particularly suspicious to find TiO2 crystals in all of the T2D specimens since titanium dioxide doesn’t have any known role in human biology. Furthermore, while plenty of different salts and other metallic compounds have a role to play in our bodies, there is no known role for titanium salt or another type of titanium compound in our biochemistry.

“Our initial findings raise the possibility that Type 2 diabetes could be a chronic crystal-associated inflammatory disease of the pancreas, similar to chronic crystal-caused inflammatory diseases of the lung such as silicosis and asbestosis,” said Adam Heller, the study’s lead author.

Heller is a professor in the McKetta Department of Chemical Engineering in the Cockrell School of Engineering. He has had a life-long career of diabetes research, for which he received the National Medal of Technology and Innovation in 2007.

Statistics from the World Health Organization show that the number of diabetes patients has quadrupled over the past four decades, reaching some 425 million known cases today. T2D represents the majority of these cases.

Although rising obesity rates and higher average life expectancy (which means more people reach old age) are considered the main factors driving this increase in T2D, the team isn’t convinced. Heller suggests that the increased use of titanium dioxide during these past few decades may be a key, if overlooked, driver of the condition.

“The increased use of titanium dioxide over the last five decades could be a factor in the Type 2 diabetes epidemic,” he said.

“The dominant T2D-associated pancreatic particles consist of TiO2 crystals, which are used as a colorant in foods, medications and indoor wall paint, and they are transported to the pancreas in the bloodstream. The study raises the possibility that humanity’s increasing use of TiO2 pigment accounts for part of the global increase in the incidence of T2D.”

The findings, right now, are far from convincing — but they are, potentially, very far-reaching. This was only a pilot study, with a very limited sample; Heller will repeat the study using a larger sample.

The paper “Association of Type 2 Diabetes with Submicron Titanium Dioxide Crystals in the Pancreas” has been published in the journal Chemical Research in Toxicology.

3D map of the pancreas offers new tool in diabetes research

Researchers from the Umeå University in Sweden have created a 3D representation of the mouse pancreas, focusing especially on the distribution and volume of the insulin-producing cells. The wealth of quantitative and visual information could provide researchers with new very useful references in fighting diabetes sand other pancreas conditions.

Diabetes is one of the most common health conditions and while there are well-established treatment options out there, there’s still much to learn about it — and the key is insulin.

Insulin is a peptide hormone which regulates the metabolism of carbohydrates, fats, and protein, mostly by promoting the absorption of glucose from the blood into fat, liver and skeletal muscle cell. Insulin is produced by the pancreas in the so-called Islets of Langerhans (or pancreatic islets) — scattered by the thousands inside the pancreas.

In diabetes research, it’s often crucial to estimate the functioning and distribution of these cells. Generally, this is done by analyzing some thin sections of the pancreas and projecting the findings onto the entire organ. Yet that’s imperfect because you extrapolate from incomplete data.

“However, such analyses only provide limited information and are often ridden with relatively large margins of error since the conclusions are based only on two-dimensional data,” says Ulf Ahlgren, professor in molecular medicine at Umeå University and in charge of the publications.

The three-dimensional visualization, created with OPT, shows the pancreas of a healthy mouse. The individual pancreatic islets have been color-coded and their exact volume and 3-D-coordinates can be precisely determined throughout the pancreas. The exocrine pancreatic tissue (in grey) has partly been digitally removed. Image credits: Ulf Ahlgren.

Ahlgren and his research colleagues at the Umeå Centre for Molecular Medicine (UCMM) have now used optical projection tomography (OPT), the optical equivalent of X-ray computed tomography or the medical CT scan — but instead of X-rays, it uses regular light.

So far, they’ve only done this for mice, but it can already make a big difference.

“We believe that the current publication represents the most comprehensive anatomical and quantitative description of the insulin cell distribution in the pancreas. By making these datasets accessible to other researchers, the data will be available for use as a powerful tool for a great number of diabetes studies. Examples may include planning of stereological analyses, in the development of non-invasive imaging techniques or various types of computational modelling and statistical analyses,” says Ulf Ahlgren.

Ahlgren published a series of 3D images, as well as information about the individual volume of the Islets of Langerhans and their 3D coordinates and appearance throughout the entire pancreas in both healthy mice and obese mice (ob/ob), at different ages. The datasets are freely available and could make a big difference for medical researchers all around the world, helping to improve and finesse their studies.

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.

 

diabetes

The artificial pancreas could automate insulin delivery for diabetics

In the lab, a team UC Santa Barbara demonstrated that an artificial pancreas that can automatically deliver insulin shots at a regular basis to diabetes patients. The biocompatible pancreas constantly monitors glucose levels and administers the insulin when its needed. This way there would be no need for cumbersome daily insulin injections. The researchers will soon start trials on animal models and if all goes well, clinical trials will follow shortly.

diabetes

Image: Telegraph

The more severe form of diabetes is type 1, or insulin-dependent diabetes. The disease typically onsets in childhood or adolescence, but can appear  later on in life. With Type 1 diabetes, the body’s immune cells attack the pancreas since they mistakenly see the insulin-producing cells in the pancreas as foreign. This is why it’s called an “autoimmune” disease. Scientists are yet unsure why this happens.

The hormone insulin is often referred to as a “key”, since it instructs cells to “open” and allow glucose in. Without insulin, the cells stay locked and the sugar builds up in the blood. This can cause a slew of health problems. First, the cells are starved of glucose. Secondly, the extra sugar in the blood  can damage eyes, kidneys, nerves, and the heart, and can also lead to coma and death. This is why diabetics shouldn’t consume sugary foods or drinks. They already have in their system as it is.

Despite active research, type 1 diabetes has no cure. However, diabetics can lead a healthy life with proper treatment. Two years ago, a group at Universitat Autònoma de Barcelona (UAB) cured type 1 diabetes in dogs by injecting them with gene therapy vectors. Those amazing findings at the time shinned a new glimmer of hope that decade-long efforts aimed at curing diabetes in humans weren’t for nothing. The breakthrough we’ve all been waiting for might not be that far away. Until then, though, we need to focus on making treatments better.

Francis J Doyle of UC Santa Barbara and colleagues found a way to design an artificial pancreas that makes hands-on treatment a thing of the past. As a diabetic, making sure you always get your insulin shots on time can be a nightmare. This can be even worse for parents who need to look after their diabetic toddlers or young children.

“I think one of the most important things we can do is alleviate parents’ fears of overnight hypoglycemia,” said Eyal Dassau, a research engineer in UCSB’s Department of Chemical Engineering and the principal investigator on this study. “As a result, parents can get a full night’s sleep without having to worry what might happen at 4 a.m., or who’s awake to check their child’s glucose. That would be a big success.”

The device constantly monitors glucose levels and delivers the insulin in the nick of the time, based on an algorithm developed by the researchers. The algorithm  simulates the rise and fall of glucose that would correspond to meals and an overnight period of sleep, but it also constantly re-tweaks itself based on current levels. The artificial pancreas maintained blood glucose within the target range nearly 80 percent of the time, as reported in the journal Industrial and Engineering Chemical Research. Soon, the device will be tested on animals.

Science ABC : Pancreatic Cancer

Pancreatic cancer, also known as pancreatic carcinoma, is an aggressive type of cancer that invades the pancreas, an important organ near the stomach and the liver. While some pancreatic cancers can be caught and treated early, the prognosis for this disease is usually not good; the National Institutes of Health report that about 80% of people with pancreatic cancer already have advanced and incurable disease at the time of diagnosis. Most people with pancreatic cancer can try surgery, chemotherapy, radiation, or some combination of the three, based on a doctor’s recommendation; however, the average survival time for people diagnosed with pancreatic cancer is usually less than a year. The National Cancer Institute reports that less than 5% of patients with pancreatic cancer survive for more than five years.

The main reason that pancreatic cancer is so deadly is because it does not have many obvious symptoms. People who do careful self exams can easily spot a suspicious mole that may be skin cancer or a strange lump that may be breast cancer; however, the pancreas is so deep inside your abdomen that it is very difficult to check by yourself for any signs that something may be wrong. Some early signs of pancreatic cancer include unexplained weight loss, fatigue, nausea and vomiting, and pain in the upper abdomen, or just under your ribcage. You may also notice jaundice, which is a yellowing of the skin or the whites of the eyes. None of these symptoms by themselves mean that you have pancreatic cancer; however, you should see your physician if you are concerned about your health and notice several of these symptoms.

Fortunately, you can make changes in your lifestyle to stay healthy and reduce your risk of pancreatic cancer. If you smoke, try to quit. The toxic chemicals that cigarettes add to your body definitely increase your risk of many cancers, including pancreatic cancer. In addition, you can add fresh fruit and vegetables to your diet to increase your antioxidant intake, which lowers your risk for many cancers. Losing those extra pounds that you carry may also help you; the Mayo Clinic reports that pancreatic cancer is more common in people who are overweight or obese. You may want to consult with a doctor to create a balanced diet and exercise regime for the weight loss plan that is good for your overall health.

If you have been diagnosed with pancreatic cancer, your doctor will discuss treatment options and prognoses with you based on your individual case. Many patients find valuable psychological support within the medical system. However, external organizations like the Pancreatic Cancer Action Network can also provide valuable support and company to patients and families with pancreatic cancer. This organization and others can greatly improve your quality of life and help you and your family to stay positive while dealing with pancreatic cancer.