These capsules containing nano-carriers with insulin will be tested on humans in 2025. CREDIT Nicholas Hunt

There are approximately 425 million people worldwide with diabetes. Approximately 75 million of these inject themselves with insulin daily. Now they may soon have a new alternative to syringes or insulin pumps. Scientists have found a new way to supply the body with smart insulin.

The new insulin can be eaten by taking a capsule or, even better, within a piece of chocolate.

Inside these, we find tiny nano-carriers to which the insulin is encapsulated. The particles are 1/10,000th the width of a human hair and so small that you cannot even see them under a normal microscope.

“This way of taking insulin is more precise because it delivers it rapidly to the areas of the body that need it most. When you take insulin with a syringe, it is spread throughout the body where it can cause unwanted side effects,” explains Professor Peter McCourt at UiT Norway’s Arctic University. He is one of the researchers behind the study.

The research was recently published in Nature Nanotechnology.

Delivered to the liver

It was researchers at the University of Sydney and Sydney Local Health District who, in collaboration with UiT, discovered many years ago that it was possible to deliver medicines via nano-carriers to the liver. The method has then been further developed in Australia and in Europe.

Many medicines can be taken by mouth, but until now people have had to inject insulin into the body. McCourt explains that the problem with insulin with a nano-carrier is that it breaks down in the stomach and thus does not get to where it is needed in the body. This has been a major challenge in developing a diabetes medicine that can be taken orally.

But now the researchers have solved this challenge.

“We have created a coating to protect the insulin from being broken down by stomach acid and digestive enzymes on its way through the digestive system, keeping it safe until it reaches its destination, namely the liver,” says liver biologist McCourt.

The coating is then broken down in the liver by enzymes that are active only when the blood sugar levels are high, releasing the insulin where it can then act in the liver, muscle, and fat to remove sugar from the blood.

“This means that when blood sugar is high, there is a rapid release of insulin, and even more importantly when blood sugar is low, no insulin is released,” says Nicholas J. Hunt at the University of Sydney, who, together with Victoria Cogger, leads the project.

He explains that this is a more practical and patient-friendly method of managing diabetes because it greatly reduces the risk of a low blood sugar event occurring, namely hypoglycemia and allows for the controlled released of insulin depending on the patient’s needs, unlike injections where all the insulin is released in one shot.

Fewer side effects

The new method works similarly to how insulin works in healthy people. The pancreas produces insulin which first passes through the liver where a large portion of it is absorbed and maintains stable blood sugar levels. In the new insulin method, the nano-carrier releases insulin in the liver, where it can be taken up or enter the blood to circulate in the body.

“When you inject insulin under the skin with a syringe, far more of it goes to the muscles and to adipose tissues that would normally happen if it was released from the pancreas, which can lead to the accumulation of fats. It can also lead to hypoglycemia, which can potentially be dangerous for people with diabetes.

With the new method, there will be fewer such side effects.

In addition, you do not need to stab yourself with a needle and you can take the medicine you need in a slightly more discreet way. Also, this form of insulin does not need to be refrigerated.

Tested on baboons

The oral insulin has been tested on nematodes, on mice and rats. And lastly, the medicine has now been tested on baboons in the National Baboon Colony in Australia.

“In order to make the oral insulin palatable we incorporated it into sugar-free chocolate, this approach was well received” says Hunt.

He says that 20 baboons have taken part in this study. When they received the medicine, their blood sugar was lowered.

The baboons were normal, healthy baboons, but the oral insulin have also been tested on mice and rats that actually have diabetes. The mice and rats did not have low blood sugar events (hypoglycemia), gain weight or fat accumulation in the liver overcoming current challenges with injectable and other oral insulins.

What remains now is to test the new method on humans.

Ready for use in 2-3 years

“Trials on humans will start in 2025 led by the spin out company Endo Axiom Pty Ltd. Clinical trials are performed in 3 phases; in the phase I trial we will investigate the safety of the oral insulin and critically look at the incidence of hypoglycemia in healthy and type 1 diabetic patients. Our team is very excited to see if we can reproduce the absent hypoglycemia results seen in baboons in humans as this would be a huge step forward. The experiments follow strict quality requirements and must be carried out in collaboration with physicians to ensure that they are safe for the test subjects” says Hunt.

“After this phase I we will know that it is safe for humans and will investigate how it can replace injections for diabetic patients in phase 2 trials,” says the researcher.

The researchers hope that the new medicine can be ready for use by everyone in 2-3 year

Researchers in the School of Population Health at RCSI University of Medicine and Health Sciences have provided new evidence of the health benefits of weight loss efforts that lead to diabetes remission for type 2 diabetes patients.  

For participants in the weight-loss trial who were able to achieve remission i.e. reduce the need for medications and reduce their HbA1c levels (a measure of blood sugar control), the research found there was a 40% lower rate of cardiovascular disease and 33% lower rate of chronic kidney disease in this group. 

While previous trials have shown that substantial weight loss using diet and lifestyle can reverse type 2 diabetes, the new research published in Diabetologia is among the first to show that reversal of diabetes, in turn, affects cardiovascular and kidney disease outcomes. The research was led by Professor Edward Gregg, Head of the RCSI School of Population Health. 

The study called Look AHEAD (Action for Health in Diabetes) monitored over 5,000 patients during a period of 12 years. The magnitude of risk reduction was greatest for participants with evidence of at least four years of remission. 

“Using lessons learned from this study we can help inform diabetes treatment methods and improve quality of life for people with type 2 diabetes. It has highlighted the significance of weight loss for achieving remission from type 2 diabetes and then long-term positive cardiovascular and kidney disease outcomes” said Professor Gregg. 

Over the course of the study, the effect intensive lifestyle intervention was compared with that of diabetes support and education on cardiovascular disease and other long-term health conditions. It was noted that although 18% of participants achieved remission at some point during follow-up, the percentage of participants with current remission had decreased to 3% by the 8th year of the study, underlining the challenges of keeping weight off using lifestyle interventions.  

At least 75 per cent of type 2 diabetes cases could be avoided by adopting a healthy lifestyle. A plant-based diet has been shown to play a key role in this. With limitations – as demonstrated in a study led by Tilman Kühn from MedUni Vienna’s Center for Public Health: A more plant-based diet only develops its protective effects if not only the consumption of animal-based foods but also industrially processed and highly sugary foods is reduced. For the first time, the scientists identified improvements in metabolism and liver and kidney function as reasons for the positive effects of a healthy plant-based diet, in addition to the associated lower likelihood of obesity. The study results were recently published in the journal Diabetes & Metabolism.

According to analyses by the research team, a healthy plant-based diet with plenty of fresh fruit and vegetables and wholemeal products reduces the risk of diabetes by 24 per cent, even in the presence of a genetic predisposition and other diabetes risk factors such as obesity, advanced age or a lack of physical activity. Unhealthy plant-based diets with a high proportion of sweets, refined grains and sugary drinks, on the other hand, are associated with an increased risk of type 2 diabetes.  

Key biomarkers identified
The research was carried out with 113,097 participants in the large-scale British cohort study (UK Biobank) over an observation period of twelve years. According to their findings, the reasons behind the anti-diabetic effect of a healthy plant-based diet go far beyond the well-known lower body fat percentage and waist circumference. “Our study is the first to identify biomarkers of central metabolic processes and organ functions as mediators of the health effects of a plant-based diet,” says Tilman Kühn, Professor of Public Health Nutrition at MedUni Vienna and the University of Vienna, who led the study in close collaboration with researchers from Queen’s University Belfast. The investigations confirmed that normal values for blood lipids (triglycerides), blood sugar (HbA1c), inflammatory parameters (CRP) and the insulin-like growth factor (IGF1) are associated with a low risk of diabetes.

Further benefits discovered
It has also been demonstrated how important the full function of the liver and kidneys is in diabetes prevention. Both organs play a major role in people who already have diabetes. “However, our research has now shown that a healthy plant-based diet can improve liver and kidney function and thus reduce the risk of diabetes,” says Kühn, outlining a previously underestimated benefit of a conscious plant-based diet.

Stanford engineers have developed an injectable hydrogel depot technology that enables GLP-1 drugs to be administered once every four months, compared to repeated daily injections.  Photo courtesy of Andrea Ivana d’Aquino / Stanford University

Materials engineers at Stanford University have developed a novel hydrogel drug delivery system that transforms daily or weekly injections of diabetes and weight control drugs like Ozempic, Mounjaro, Trulicity, Victoza, and others to just once every four months. In a new study, published Nov. 21 in Cell Reports Medicine, researchers believe that such a system will greatly improve management of both diabetes and weight, improve patient drug compliance, and help those with Type 2 diabetes improve long-term health outcomes.

These drugs all work by mimicking the hormone glucagon-like peptide 1 (GLP-1). But, as good as they are at helping people manage their diets and their weight, the typical daily or weekly injections are a burden for many patients. 

“Adherence is one of the biggest challenges in Type 2 diabetes management,” said Eric Appel, associate professor of materials science and engineering at Stanford and principal investigator on the new hydrogel that allows the slow release of the diet control drugs over many months. “Needing only three shots a year would make it much easier for people with diabetes or obesity to stick with their drug regimens.”

Half a billion people worldwide suffer from Type 2 diabetes, including 130 million in America alone. Treatment is estimated to cost the United States upward of $400 billion each year. Introduced only recently, the GLP-1 drugs have been described as “miracle drugs” with few side effects and profound control of energy intake by helping patients feel more satiated and less hungry, and by targeting other reward-related dietary effects. 

Novel nanocomposite hydrogels
The secret of the hydrogel is in the unique physical characteristics of the nanoparticles at its heart. Hydrogels are not new – many people today wear contact lenses made of hydrogels, for instance – but these are engineered to resist tearing and to hold their shape. Appel’s hydrogel is instead engineered with polymers and nanoparticles that are weakly bound to one another, so as to hold together as a gel yet dissipate slowly over time. The hydrogel is formed from a mesh of polymer chains and nanoparticles that hold the drug molecules until the mesh dissolves away, releasing the drugs.

“Our hydrogel melts away over many months like a sugar cube dissolving in water, molecule by molecule,” Appel explained. “I often refer to the mesh being held together by a sort of molecular Velcro that sticks together quite well, but then can be easily pulled apart.” 

The new hydrogel, technically known as a polymer-nanoparticle (PNP) hydrogel, has a Goldilocks “just right” quality of fluidlike flow that can be easily injected using off-the-shelf needles, yet a gel-like stability durable enough in the body to last the full four-month period. Molecules of the GLP-1 drugs are formulated into the hydrogel and are similarly doled out over time as the hydrogel slowly melts away.

The physician injects a small dollop of gel, known as a “depot,” of the drug-laden hydrogel under the skin in a convenient location such as under the arm. The key for the engineer is to design the hydrogel in such a way as to make this depot small enough to be comfortable and inconspicuous to the patient, yet large enough and durable enough to last the full four months. Appel believes his team has achieved that measure of control.

“We chose four months to match the cadence that people actually meet with their physician or endocrinologist and why we were so specific with the release period,” Appel said.

Promising potential
So far, the team has tested the new drug delivery system in laboratory rats with high success. In rats, a single injection of this hydrogel-based therapy improves management of blood glucose and weight compared to daily injections of a leading commercial drug, Appel noted. 

While this particular hydrogel was engineered specifically for the GLP-1 four-month checkup regimen, Appel said that the team has successfully tuned the release timeframes to anywhere from days to upward of six months. He adds that such systems have been used with other proteins, vaccines, and even therapeutic cells, and there is evidence that GLP-1 drugs can also reduce risk of cardiovascular disease. 

All these signs point to the promising possibility that this drug delivery system can be applied to other drugs and other conditions.

“There’s even been really promising results with children with Type 1 diabetes,” Appel said of the promise ahead.

Next up will be tests in pigs, whose skin and endocrine systems are most similar to those in humans. If those trials go according to plan, Appel could see human clinical trials within a year and a half to two years.

“At the very least, we have laid a pathway for the prolonged release of therapeutic GLP-1–based anti-diabetic and anti-obesity treatments that could have beneficial impact on Type 2 diabetes management and, perhaps, other conditions as well,” Appel said.