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Diabetes

An estimated 347 million people worldwide suffer from diabetesANCHOR,or nearly five per cent of the population, with approximately 3.4 million dying as a consequence per yearANCHOR. Currently eighty per cent of diabetes deaths occur in low- and middle-income countriesANCHOR, driving the need for cheaper, easier treatments. The World Health Organisation predicts that diabetes will be the 7th largest cause of death in 2030ANCHOR.

Symptoms include raging thirst, rapid weight loss, tiredness and passing large quantities of sugary urine. Diabetes also increases the risk of heart disease and stroke - 50% of people with diabetes die of cardiovascular disease (primarily heart disease and stroke), compared to 30% across the world populationANCHOR ANCHOR.

Type 1 diabetes (previously known as insulin-dependent, juvenile or childhood-onset) is characterized by deficient insulin production. Type 2 diabetes (formerly called non-insulin-dependent or adult-onset) results from the body’s ineffective use of insulin. Treatment of diabetes involves lowering blood glucose and the levels of other known risk factors that damage blood vessels. People with type 1 diabetes require insulin; people with type 2 diabetes can be treated with oral medication, but may also require insulin.


Discovery of insulin
Type 1 diabetes
Type 2 diabetes
Animal Models
Current treatments
Current research
References

Discovery of insulin

The discovery and purification of insulin has saved millions of livesThe discovery, isolation and purification of insulin in the 1920s was a significant medical advance, preventing premature deaths in many sufferers.

In 1889 Joseph von Mering and Oskar Minkowski showed that removing the pancreas from a dog produced diabetesANCHOR. This was the first demonstration that there was an anti-diabetic factor produced by the pancreas which enabled the body to use sugars in the blood properly. This factor was named insulin by Schafer in 1915, some years before it was actually identified or isolated through animal testing.

Following von Mering and Minkowski's discovery, there were several unsuccessful attempts to isolate insulin. One of the most important was by Georg Zülzer, who used alcohol rather than water to extract insulin and was able to obtain active preparationsANCHOR. In 1909 Forschbach used animal experiments with dogs whose pancreas had been removed as a model for diabetes, showing that one of these extracts could reduce their blood sugar by 90%. Unfortunately, impurities in the extract meant this preparation of insulin also raised the animal's temperature. There were attempts to produce purer extracts, and two diabetic patients were treated in these trials, but there were similar toxic effects, so the use of such extracts did not continue.

Working in Toronto, the surgeon Frederick Banting and medical student Charles Best began their attempts to produce insulin in 1921. By the end of that year, they had shown in classic animal experiments that pancreatic extracts reduced blood sugar, removing sugar from the urine of dogs whose pancreas had been removedANCHOR. However, these extracts, once again, produced an unacceptable fever when injected into diabetic patients.

When biochemist, James Collip, joined the Toronto team he soon prepared insulin from beef pancreas which was pure enough to treat diabetic patientsANCHOR. He did this using an alcohol extraction technique to produce solutions containing different proteins. To find whether insulin was present in each solution, and in what amount, he measured its activity, monitoring blood sugar levels of rabbits following injection of each solution. Collip developed a measure of activity based on the ability of the extract to lower blood sugar in the rabbit. This was used to standardise extracts, an essential step as insulin overdose can be fatalANCHOR. Collip's extracts were used successfully in dogs and then in patients in 1922 with dramatic results. The paper was described by the British Medical Journal as a "magnificent contribution to the treatment of diabetes"ANCHOR.

Banting went on to win a Nobel Prize in 1923 for his work on insulin and World Diabetes Day is held each year on Banting's birthday, 14 November.

Type 1 diabetes

Type 1 diabetes, also known as juvenile diabetes, affects people of any age. It is caused by the immune system attacking the insulin-producing cells in the pancreas, although the trigger for this is unknown. The body is unable to regulate blood glucose levels without insulin and so patients must take daily insulin-injections. If not properly regulated, sufferers can face complications due to irregular blood sugar levels. Low blood sugar levels can lead to seizures and unconsciousness. High blood sugar can cause long-term damage to organs such as the heart and kidneys.

Type 2 diabetes

In healthy people, glucose concentrations in the blood increase soon after they eat a meal. As a consequence, beta-cells of the pancreas release insulin, which helps to lower blood glucose levels. Type 2 diabetes can develop when the body cannot produce enough insulin to meet its needs. This is often triggered by excess body weight and physical inactivity. Approximately ninety per cent of the world’s diabetics have type 2 diabetesANCHOR. Many research efforts are focused on finding which mechanisms and biochemical pathways are responsible for triggering this.

In 2010, scientists studying the hormone GIP (glucose-dependent insulin-releasing polypeptide) in pigs showed that it could be a cause of type 2 diabetesANCHOR. The hormone helps in the production and release of insulin. In the past, diabetic patients have been found to be unresponsive to GIP as well as insulin, although it was unclear whether it was a cause or consequence of the disease. By studying the hormone in genetically modified pigs with defective GIP receptors, scientists showed that pigs which could not respond to GIP had fewer beta-cells, resulting in a lower release of insulin.

In 2012, experiments in mice suggested that the loss of beta cells is not due to cell death but instead due to the cells reverting back to immature formsANCHOR. Following the observation that levels of a protein called FoxO1 decrease in beta-cells during early diabetes, researchers created a strain of GM mouse whose beta-cells lack the FoxO1 gene. FoxO1 acts as a sensor of blood sugar levels and responds by activating insulin production. After being fed a high-sugar diet, pregnancy, or ageing, the mice’s beta cells regressed and the mice developed symptoms of type 2 diabetes.

Scientists are also studying animals to better understand how lifestyle factors influence the chances of developing diabetes.

Studies in rats have found that consuming fructose can lead to insulin resistance, resulting in diabetesANCHOR. There was also evidence showing signs of dyslipidemia, a condition where abnormally large quantities of fat are found within the body. These results have since been replicated in humans. Researchers found that the human trial volunteers with fructose in their diet had produced new fat cells around vital organs such as the heart and liver. There were also early signs of processing abnormalities which may give rise to heart disease and diabetes. None of these changes were observed in a group on a glucose-rich diet.

Researchers comparing normal and obese mice found that obese mice produced more than twice as much of a small microRNA molecule called microRNA-143 in their liversANCHOR. MicroRNA-143 silences genes linked to an enzyme called AKT and so stops insulin activating AKT. AKT is important for glucose transport into cells and for stopping glucose production in the liver. Researchers do not yet know why obese mice form more microRNA-143 than normal mice. This may explain why obesity increases the chances of developing diabetes and understanding this could lead to new treatments for diabetes.

Scientists studying mice found that fat in the bloodstream interferes with the body’s sugar sensors so that cells no longer know when to produce insulinANCHOR. Mice fed on a high-fat diet showed increased levels of free fatty acids in their blood. These interfered with the production of an enzyme (GnT-4a) involved in making GLUT1 transporters, which allow pancreatic beta cells to monitor sugar levels. As a result the beta-cells had fewer GLUT1 transporters and the mice showed signs of type 2 diabetes. The scientists were able to reverse the effect of a high fat diet by artificially increasing production of the GnT-4a enzyme which restored  GLUT1 levels. The scientists looked at beta cells taken from patients with type 2 diabetes and also saw that GnT-4a enzyme production was disrupted, linking their findings in mice to the disease in humans.

The impact of diet might not even be observed until the next generation. Rats fed a low protein diet produced offspring that were more likely to develop type-2 diabetes as they grew olderANCHOR. Offspring of rats fed a low protein diet had lower levels of HNF 4-alpha than those born to normally fed mothers. This decreases the ability of the pancreas to produce insulin and leads to early development of diabetes. HNF 4-alpha levels normally decrease with age, but the poor maternal diet speeds up these ageing effects in offspring.

Animal Models

The nonobese diabetic (NOD) mouse is a common model used for studying treatments for diabetes. This strain was created by researchers in Japan by selectively breeding the offspring of a laboratory mouse that had spontaneously developed symptoms resembling type 1 diabetes in humansANCHOR.

These NOD mice can be ‘humanised’ to make them more suitable for studying new treatments, particularly antibodiesANCHOR. Since antibodies need to fit very closely to the protein that they target, we cannot always directly apply mouse antibodies to human proteins and vice versa. By breeding NOD mice to produce a certain human protein of interest, e.g. CD3, researchers can test the effects of the antibody targeting this protein and refine the approach to make it more effective.

The biobreeding (BB) rat is another commonly used laboratory animal strain that is used for studying type 1 diabetesANCHOR. The symptoms of both the NOD1 mouse and BB rat are due to a complex interplay of many genes, as is seen in humans.

Models of obesity-induced type 2 diabetes include the KK mouse and the Zucker diabetic fatty (ZDF) ratANCHOR ANCHOR.

Current treatments

Metformin
Metformin is believed to be the most widely prescribed anti-diabetic drug in the worldANCHOR. It is the first-line drug of choice for the treatment of type 2 diabetes, particularly in overweight people and those with normal kidney functionANCHOR.

In 1929, Slotta and Tschesche discovered its sugar-lowering action in rabbits, noting it was the most potent of the range of compounds they studiedANCHOR. This result was completely forgotten, as other analogues became popular, which were themselves soon overshadowed by insulinANCHOR. It wasn’t until 1957 that French diabetologist Jean Sterne published the first trial of metformin on humans for the treatment of diabetes.

Insulin injection
Since Banting and Best developed a technique for purifying it sufficiently, insulin injections have saved millions of lives. Diabetics often need to inject themselves with insulin several times a day, as well as taking regular blood sugar level checks. The inconvenient and cumbersome nature of this has led to searches for new ways of delivering insulin to the body. Currently, the only main alternative to injections is an insulin pump, but there are several different approaches that are being developed. Insulin pumps slowly infuse insulin into the body and are good for patients who have trouble controlling their glucose levels. The small pumping device, worn outside the body was invented at Guy's Hospital in London and was based on the miniature infusion pump developed for infusing parathyroid hormone into dogs and other animalsANCHOR.

 
 

Islet transplants
Insulin is normally produced by islet or beta cells in the pancreas.  Currently, islet transplantation is the only curative therapy for late-stage type 1 diabetes. Successfully carried out in rats, dogs, monkeys and humans, this treatment requires the patient to take immune-suppressants to prevent rejection. Clinical islet transplantation is also restricted by a severe shortage of donor islets. The video on the right features Dr Aileen King discussing some of her research to improve this process.

Current research

Gene therapy
Gene therapy may be a way to tackle type 2 diabetes, which tends to hit older, overweight people.

In 2013 scientists cured diabetes in dogs using gene therapy, the first time this was achieved in a large animalANCHOR. The treatment delivers functional genes for insulin and glucokinase, which allow the dogs to sense and respond to changes in blood sugar levels. The two genes were delivered in viral “vectors” by injections. Once in the bloodstream, the vectors are absorbed into the animals’ muscle cells where the genes integrate with the genome. Following the gene therapy, the dogs' blood sugar levels were maintained at healthy levels. The health of the dogs was followed for four years without the symptoms reoccurring or any adverse side effects.

The research team had already shown that the technique worked in mice but needed a more accurate model of human diabetes and so used dogs. A gene therapy using the same vector delivery system has already been licensed by the European Medicines Agency, giving hope that patients might not need to wait too long for clinical trials of this new treatment to begin.

Insulin delivery
Researchers are also looking at new ways of administering insulin to avoid injections.

An insulin patch called U-Strip that allows insulin to pass through the skin has been trialled in 100 type 1 diabetes patients, with larger trials expectedANCHOR. The patch relies on a sonic applicator which produces a burst of sound waves that open up the pores of the skin, allowing the insulin to pass through.

Inhaled insulin delivery systems give insulin as a dry powder, inhaled through the mouth directly into the lungs where it passes into the bloodstreamANCHOR. Extensive testing in dogs helped establish the relationship between the amounts of insulin inhaled and circulating in the bloodstream. Successful human trials have followed.

Despite the successful trials, these inhaled systems have not been popular with patients and doctors due to the high cost and bulkiness of the delivery system. The first product to market, Exubera by Pfizer, was withdrawn in 2007 because of this and several other companies shutdown their late-stage trials in response. Despite this, in October 2013 Mannkind applied for approval for their inhaled insulin system, AfrezzaANCHOR.

Researchers from De Montfort University, Leicester, UK are developing a device which would be implanted into the body between the lowest rib and the hip and would be topped up with insulin every few weeksANCHOR. The artificial pancreas is currently undergoing pre-clinical trials in rats and is made of a metal casing containing a supply of insulin which is kept in place by a gel. When glucose levels in the body rise, the gel barrier starts to liquefy and lets insulin out. The insulin then feeds into the veins around the gut and then into the vein to the liver, mimicking the normal process for a person with a healthy pancreas. As the insulin lowers the glucose level in the body, the gel reacts by hardening again and stopping the supply.

Stem cells
It is possible to transplant insulin-producing cells from donors, but sources are rare. Instead, doctors hope one day to be able to grow the specialised cells in the lab from human stem cells. Human embryonic stem cells (hESCs) are ideal for this as they can develop into any cell type.

Scientists have been able to successfully transform human embryonic stem cells into pre-pancreatic cellsANCHOR. They were then transplanted into mice where they developed further into insulin-producing cells, curing the mice of type 1 diabetes. Although the research showed that stem cells may one day provide a cure for diabetes, it also revealed hurdles. For example, some cells developed into bone or cartilage, an unacceptable side-effect that future experiments must resolve before clinical trials are attempted.

In 2011 scientists demonstrated that stem cells extracted from a rat's brain could be made to produce insulin and used to cure diabetes in the same ratANCHOR. After extracting tissue and isolating the stem cells, the researchers exposed the cells to Wnt3a – a human protein that switches on insulin production – and also to an antibody that blocks a natural inhibitor of insulin production. After growing enough cells, the scientists attached them to a thin natural membrane of collagen which they surgically placed onto the rat's pancreas without damaging the organ itself. Within a week, insulin and glucose levels in treated rats matched those in non-diabetic rats. Later, when the sheets of cells were removed from the pancreas, the diabetes returned.

Hormones
A hormone known as TLQP-21 that is found inside beta cells can improve both insulin production and blood glucose levels when given to rats predisposed to type 2 diabetesANCHOR. In addition, fewer beta cells died in treated animals compared to untreated controls. The hormone acts in a similar way to glucagon-like peptide-1, which is already targeted by existing type 2 diabetes drugs. Tests on human beta cells in the lab showed that the hormone had the same effect as in isolated rat beta cells. The whole animal studies suggest that the experimental drug could have fewer side-effects than current treatments.

In 2013, experiments in mice identified a hormone called betatrophin that increases the number of beta cells in the pancreasANCHOR. The scientists discovered that blocking insulin receptors with a chemical called S961 led to a dramatic increase in beta cell replication. This was found to be linked to increased activity of a previously unstudied gene named betatrophin in liver and fat tissue. Applying S961 directly to beta cells in a petri dish does not trigger this growth; it could only be observed in the animals. In addition, injecting artificial betatrophin into diabetic mice raised insulin levels through stimulating beta cell replication and treated the condition.


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