Researchers have identified a new mechanism that could improve the efficiency of diabetes treatments.

A study led by the University of Barcelona and the Biomedical Research Networking Center in Diabetes and Associated Metabolic Disorders (CIBERDEM) reveals how a new mechanism could improve the efficiency of currently available treatments for diabetes. The study on mice and cell cultures, may open up new ways of approaching metabolic diseases that are a global health problem.

The study, published in the journal Metabolism, focuses on the GDF15 protein, a factor that is expressed at high levels in many diseases, such as heart failure, cancer and fatty liver disease. Obese patients also have elevated levels of this protein, but its function is altered and those affected may develop resistance to GDF15 — that is, a reduction in the effectiveness of its activity.

The study is led by Professor Manuel Vázquez-Carrera, from the Faculty of Pharmacy and Food Sciences of the UB, the Institute of Biomedicine of the UB (IBUB), the Sant Joan de Déu Research Institute (IRSJD) and CIBERDEM. The study also highlights the participation of researchers Patricia Rada and Ángela María Valverde, also collaborators at CIBERDEM, the Spanish National Research Council (CSIC) and the Autonomous University of Madrid (UAM). The work has the collaboration of Professor Walter Wahli of the University of Lausanne (Switzerland), among other experts.

New alternatives to reduce glucose synthesis in the liver

“Our study reveals that GDF15 inhibits glucose synthesis in the liver. This pathway plays a decisive role in the generation of hyperglycaemia (increased blood glucose levels) in patients with type 2 diabetes mellitus”, says Professor Manuel Vázquez-Carrera.

“The action of the protein would also help reduce the presence of liver fibrosis, a condition associated with increased mortality in patients with fatty liver disease”, the researcher notes.

The study reveals that mice deficient in GDF15 have glucose intolerance and low levels of AMPK protein in the liver, which is a sensor of energy metabolism in the cell against type 2 diabetes.

Moreover, increased glucose synthesis in the liver (hepatic gluconeogenesis) was also detected in these study models, as well as increased liver fibrosis.

All indications are that all the described alterations were triggered by increased hepatic levels of transforming growth factor-beta 1 (TGF-β1) and an SMAD3mediator protein, which are the main inducers of liver fibrosis. Thus, treatment with recombinant CDF15 can activate AMPK and decrease levels of active SMAD3 in mouse liver and in primary hepatocyte cultures.

“In conclusion, the results indicate that GDF15 activates AMPK protein and inhibits hepatic gluconeogenesis and fibrosis through the reduction of the TGF-β1/SMAD3 pathway”, says Vázquez-Carrera.

“These results suggest that modulation of GDF15 levels could be useful to improve the effectiveness of current anti-diabetic treatments, as hepatic gluconeogenesis is key in hyperglycaemia in patients with type 2 diabetes mellitus, and serum TGF-β1 levels are also increased in these patients”, concludes the researcher.

New medicine can create a new life for diabetes patients – without needles!

Insulin capsules

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

RCSI research shows new benefits of weight loss for type 2 diabetes

Non-alcoholic fatty liver disease warning signs
Non-alcoholic fatty liver disease warning signs

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.  

A healthy plant-based diet reduces diabetes risk by 24 per cent – important for us all

Improvements in metabolism and liver and kidney function through a plant-based diet proven for the first time
Improvements in metabolism and liver and kidney function through a plant-based diet proven for the first time

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.

Researchers caution people’s use of fitness video games.

Researchers caution diabetes patients’ use of fitness video games
Researchers caution diabetes patients’ use of fitness video games

The authors of a new study warn people with type-1 diabetes to use fitness video games with caution.

The study by Staffordshire University and Federal University of Vale do Sao Francisco has found that ‘exergames’ can change people’s perceptions of how fatigued they are – which is potentially harmful for those with the condition.

Dr Pooya Soltani, Senior Lecturer in Games Technology at Staffordshire University, explained: “Type-1 diabetes patients need to control their blood glucose regularly, both before and after exercise, to prevent complications. As part of this, it is important to regulate the intensity of exercise, whether real or virtual.

“Most patients use a simple chart to measure how exerted they feel on a scale of 1 – 10, from hardly at all to using maximum effort. While this has proven to be effective for traditional exercise, we wanted to investigate whether this scale can also be used when exercising with video games.”

The trial assessed correlations between physiological measurements of exercise intensity, including metabolic equivalent (MET), oxygen consumption and heart rate in both real and virtual sessions.

Type-1 diabetes patients performed two 30-minute sessions of moderate-intensity exercise, either running or playing the Kinect Adventures! video game. A rate of perceived exertion (RPE) was measured on the 6 – 20 point Borg scale after the sessions.

The study’s co-author Jorge Luiz de Brito Gomes, from the Federal University of Vale do Sao Francisco, said: “The RPE and MET values were strongly correlated in real exercise but were moderately correlated during the virtual exercise session. Other metabolic and physiological variables were mostly low and lacked statistical significance during the virtual exercise.

“This highlights that it is crucial to exercise caution when extending use of the 6 – 20 point RPE scale to other types of exercise, especially virtual sessions, as they may not accurately reflect the physiological and metabolic intensity of the exercise.”

The researchers recommend that older measurement tools such as the 6 – 20 point RPE scale should be adapted to newer types of virtual game platforms.

Dr Soltani added: “Active video games and virtual reality are recent exercise trends that can provide motivation to participants and might increase their adherence to physical activity. Light to vigorous-intensity exergaming sessions may also benefit people with type-1 diabetes.

“But our research shows that the current 6 – 20 RPE scale needs to updated so that everyone can safely benefit from using immersive games. In the meantime, healthcare professionals who want to incorporate virtual sessions with exergames into their practice, should cautiously use methods like this which subjectively measure physical activity.”

Read the full article – Is rating of perceived exertion a valid method for monitoring exergaming intensity in type-1 diabetics?