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Insulin-producing beta cells in the islet of Langerhans.  CREDIT Helmholtz Munich | ©Erik Bader

Research targeting the insulin-inhibitory receptor, called inceptor, unveils promising avenues for beta cell protection, offering hope for causal diabetes therapy. A novel study in mice with diet-induced obesity demonstrates that the knock-out of inceptor enhances glucose regulation, prompting its further exploration as a drug target for type 2 diabetes treatment. These findings, led by Helmholtz Munich in collaboration with the German Center for Diabetes Research, the Technical University of Munich, and the Ludwig-Maximilians-University Munich, drive advancements in diabetes research.

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Targeting Inceptor to Combat Insulin Resistance in Beta Cells

Insulin resistance, often linked to abdominal obesity, presents a significant healthcare dilemma in our era. More importantly, the insulin resistance of beta cells contributes to their dysfunction and the transition from obesity to overt type 2 diabetes. Currently, all pharmacotherapies, including insulin supplementation, focus on managing high blood sugar levels rather than addressing the underlying cause of diabetes: beta cell failure or loss. Therefore, research into beta cell protection and regeneration is crucial and holds promising prospects for addressing the root cause of diabetes, offering potential avenues for causal treatment.

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With the recent discovery of inceptor, the research group of beta cell expert Prof. Heiko Lickert has uncovered an interesting molecular target. Upregulated in diabetes, the insulin-inhibitory receptor inceptor may contribute to insulin resistance by acting as a negative regulator of this signaling pathway. Conversely, inhibiting the function of inceptor could enhance insulin signaling – which in turn is required for overall beta cell function, survival, and compensation upon stress.

In collaboration with Prof. Timo Müller, an expert in molecular pharmacology in obesity and diabetes, the researchers explored the effects of inceptor knock-out in diet-induced obese mice. Their study aimed to determine whether inhibiting inceptor function could also enhance glucose tolerance in diet-induced obesity and insulin resistance, both critical pre-clinical stages in the progression toward diabetes. The results were now published in Nature Metabolism.

Removing Inceptor Improves Blood Sugar Levels in Obese Mice

The researchers delved into the effects of removing inceptor from all body cells in diet-induced obese mice. Interestingly, they found that mice lacking inceptor exhibited improved glucose regulation without experiencing weight loss, which was linked to increased insulin secretion in response to glucose. Next, they investigated the distribution of inceptor in the central nervous system and discovered its widespread presence in neurons. Deleting inceptor from neuronal cells also improved glucose regulation in obese mice. Ultimately, the researchers selectively removed inceptor from the mice’s beta cells, resulting in enhanced glucose control and a slight increase in beta cell mass.

Research for Inceptor-Blocking Drugs

“Our findings support the idea that enhancing insulin sensitivity through targeting inceptor shows promise as a pharmacological intervention, especially concerning the health and function of beta cells,” says Timo Müller. Unlike intensive early-onset insulin treatments, utilizing inceptor to enhance beta cell function offers promise in alleviating the detrimental effects on blood sugar and metabolism induced by diet-induced obesity. This approach avoids the associated risks of hypoglycemia-associated unawareness and unwanted weight gain typically observed with intensive insulin therapy.

“Since inceptor is expressed on the surface of pancreatic beta cells, it becomes an accessible drug target. Currently, our laboratory is actively researching the potential of several inceptor-blocking drug classes to enhance beta cell health in pre-diabetic and diabetic mice. Looking forward, inceptor emerges as a novel and intriguing molecular target for enhancing beta cell health, not only in prediabetic obese individuals but also in patients diagnosed with type 2 diabetes,” explains Heiko Lickert.

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The researchers found that 670 nanometres (nm) of red light stimulated energy production within mitochondria, the tiny powerhouses within cells, leading to increased glucose consumption. In particular, it led to a 27.7% reduction in blood glucose levels following glucose intake, and it reduced maximum glucose spiking by 7.5%.

While the study was conducted in healthy individuals, the non-invasive, non-pharmacological technique can impact diabetes control after meals, as it can reduce damaging fluctuations of blood glucose in the body that contribute to ageing.

The study also highlights the significant long-term consequences for human health, including the potential dysregulation of blood sugars posed by lengthy exposure to blue light. Given the prominence of LED lighting and the fact that LEDs emit towards the blue end of the spectrum with very little red, the authors suggest this may be a potential public health issue. The research has been published in the Journal of Biophotonics.

Mitochondria provide energy for vital cellular processes, using oxygen and glucose to produce the energy-rich nucleoside adenosine triphosphate (ATP). Previous research has established that long-wavelength light between approximately 650-900 nm (spanning the visible through to the near-infrared range) can increase mitochondrial production of ATP, which reduces blood glucose and also improves health/lifespan in animals. 

The authors Dr Michael Powner, Senior Lecturer in Neurobiology in the School of Health & Psychological Sciences at City, and Professor Glen Jeffery, Professor of Neuroscience in the UCL Institute of Ophthalmology, also say that this improvement in ATP production can cause signalling changes that are transmitted throughout the body.

They suggest that it may be mediating the abscopal effect, which refers to the phenomenon in cancer treatment where specific irradiation of a primary tumour can result in shrinkage of secondary tumours located in a different part of the body. Likewise, 670 nm light shone selectively on to the backs of mice in previous studies has been shown to result in improvements in ATP that improve symptoms in both a model of Parkinson’s disease and a model of diabetic retinopathy.

To explore the impact of 670 nm red light on blood glucose, the researchers recruited 30 healthy participants, who were then randomised into two groups: 15 in the 670 nm red light group, and 15 in the placebo (no light) group. They had no known metabolic conditions and were not taking medication.

Participants were then asked to do an oral glucose tolerance test and record their blood glucose levels every 15 minutes over the next two hours. People who received red light exposure 45 minutes prior to drinking glucose exhibited a reduced peak blood glucose level and reduced total blood glucose during the two hours. 

Dr Powner, who was the lead author of the study, said:

“It is clear that light affects the way mitochondria function and this impacts our bodies at a cellular and physiological level. Our study has shown that we can use a single, 15-minute exposure to red light to reduce blood sugar levels after eating.

“While this has only been done in healthy individuals in this paper, it has the potential to impact diabetes control going forward, as it could help to reduce potentially damaging glucose spikes in the body after meals.”

Professor Jeffery said:

“Sunlight has a balance between red and blue, but we now live in a world where blue light is dominant because although we do not see it, LED lights are dominant in blue and have almost no red in them. This reduces mitochondrial function and ATP production. Hence our internal environments are red-starved. Long-term exposure to blue light is potentially toxic without red. Blue light on its own impacts badly on physiology and can drive disrupted blood sugars that may in the long run contribute to diabetes and undermine health spans.

“Pre-1990, we all had incandescent lighting which was OK because it had the balance of blue and red similar to sunlight, but there is a potential health span time bomb in the change to LEDs in an ageing population. This can partly be corrected by spending more time in sunlight.”

Healthcare providers who treat diabetes need to think beyond the clinical numbers, such as solely focusing on a person’s glucose goals. Taking the patient experience into account can improve the quality of care and facilitate the attainment of treatment goals, according to a new position statement published in the Endocrine Society’s Journal of Clinical Endocrinology & Metabolism.

The position statement reflects the consensus of two virtual roundtables the Endocrine Society held in 2022. Participants included representatives from the American College of Cardiology, American College of Physicians, American Diabetes Association^®, Association of Diabetes Care & Education Specialists, Diabetes Technology Society, the U.S. Centers for Disease Control and Prevention, diabetes research organization dQ&A, and patient advocacy organizations DiabetesSisters, Close Concerns, and Taking Control of Your Diabetes.

More than 500 million people worldwide have diabetes, which occurs when the pancreas doesn’t make enough insulin or when the body can’t respond to insulin properly, resulting in high levels of glucose in the blood (blood glucose). Managing this chronic disease requires making lifestyle changes throughout life, which can be burdensome for people living with diabetes and their caregivers. Daily tasks such as blood glucose monitoring, dietary and exercise management, routine preventive care scheduling, and medication management must be overseen by people living with diabetes themselves.

Effective two-way communication between people with diabetes and their healthcare providers helps establish a shared understanding of the treatment plan and goals. Healthcare providers who take the time to explain treatment options and discuss potential barriers can improve patient satisfaction and clinical outcomes. In addition, healthcare providers need to consider each patient’s level of health literacy and cultural background when discussing treatment options.

“Many existing educational resources are available to help health care providers think through ways they can discuss diabetes treatment in a neutral and nonjudgmental way and practice using those strategies,” said Rita R. Kalyani, M.D., M.H.S., Professor of Medicine in the Division of Endocrinology, Diabetes, & Metabolism at Johns Hopkins University School of Medicine, who chaired the position statement and represented the Endocrine Society during the consensus roundtables. “However, in the ever-changing landscape of diabetes and its management, both health care providers and people with diabetes will continue to need new and evolving tools to help address the common challenges they face.”

People with diabetes face an elevated risk of developing depression, anxiety, and other mental disorders. This makes understanding the psychosocial impact of diabetes important. Addressing stressors in the health care setting and ensuring timely mental health referrals, when appropriate, can help individuals with diabetes feel more comfortable and help them participate more fully in their appointments and care.

Each section in the position statement begins with a common clinical scenario that illustrates key gaps in diabetes care. Readily accessible graphics and tools that health care providers can use to deliver patient-centred care are also included.

The position statement offers a framework for leveraging the experiences of people with diabetes to optimize health outcomes in several important areas, including:

• Use of person-centred language in the health care setting
• Ensuring referrals to diabetes self-management and support service programs are timely and accessible to all people with diabetes.
• Effectively navigating available therapeutic options together and explaining complex regimens to people with diabetes to encourage them to take medication as prescribed.
• Consider ways to adjust an individual’s treatment plan promptly if they aren’t meeting therapeutic goals to prevent therapeutic inertia.
• Discussing strategies for assessment of hypoglycemia—low blood glucose episodes that can be dangerous—as well as prevention and treatment of hypoglycemia.
• Improving cardiovascular and renal outcomes using newer therapeutic options.
• Using telehealth in the appropriate clinical setting.
• Using and incorporating diabetes technologies such as insulin pumps and continuous glucose monitoring systems into the diabetes management plan, when appropriate.

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.

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