Category: Metabolic Disorders

Categories : Injury & Trauma Metabolic DisordersTags :

Neurons Cause Metabolic Havoc after Spinal Injury

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Conditions such as diabetes, heart attack and vascular diseases commonly diagnosed in people with spinal cord injuries can be traced to abnormal post-injury neuronal activity that causes abdominal fat tissue compounds to leak and pool in the liver and other organs, a new animal study published in Cell Reports Medicine has found.

After discovering the connection between dysregulated neuron function and the breakdown of triglycerides in fat tissue in mice, researchers found that a short course of the drug gabapentin, commonly prescribed for nerve pain, prevented the damaging metabolic effects of the spinal cord injury – though not without side effects.

Gabapentin inhibits a neural protein that, after the nervous system is damaged, becomes overactive and causes communication problems – in this case, affecting sensory neurons and the abdominal fat tissue to which they’re sending signals.

“We believe there is maladaptive reorganisation of the sensory system that causes the fat to undergo changes, initiating a chain of reactions – triglycerides start breaking down into glycerol and free fatty acids that are released in circulation and taken up by the liver, the heart, the muscles, and accumulating, setting up conditions for insulin resistance,” said senior author Andrea Tedeschi, assistant professor of neuroscience in The Ohio State University College of Medicine.

“Through administration of gabapentin, we were able to normalise metabolic function.”

Previous research has found that cardiometabolic diseases are among the leading causes of death in people who have experienced a spinal cord injury. These often chronic disorders can be related to dysfunction in visceral white fat (or adipose tissue), which has a complex metabolic role of storing energy and releasing fatty acids as needed for fuel, but also helping keep blood sugar levels at an even keel.

Earlier investigations of these diseases in people with neuronal damage have focused on adipose tissue function and the role of the sympathetic nervous system, but also a regulator of adipose tissue that surrounds the abdominal organs.

Instead, Debasish Roy, a postdoctoral researcher in the Tedeschi lab and first author on the paper, decided to focus on sensory neurons in this context. Tedeschi and colleagues have previously shown that a neuronal receptor protein called alpha2delta1 is overexpressed after spinal cord injury, and its increased activation interferes with post-injury function of axons, the long, slender extensions of nerve cell bodies that transmit messages.

In this new work, researchers first observed how sensory neurons connect to adipose tissue under healthy conditions, and created a spinal cord injury mouse model that affected only those neurons – without interrupting the sympathetic nervous system.

Experiments revealed a cascade of abnormal activity within seven days after the injury in neurons – though only in their communication function, not their regrowth or structure – and in visceral fat tissue. Expression of the alpha2delta1 receptor in sensory neurons increased as they over-secreted a neuropeptide called CGRP, all while communicating through synaptic transmission to the fat tissue – which, in a state of dysregulation, drove up levels of a receptor protein that engaged with the CGRP.

“These are quite rapid changes. As soon as we disrupt sensory processing as a result of spinal cord injury, we see changes in the fat,” Tedeschi said. “A vicious cycle is established – it’s almost like you’re pressing the gas pedal so your car can run out of gas but someone else continues to refill the tank, so it never runs out.”

The result is the spillover of free fatty acids and glycerol from fat tissue, a process called lipolysis, that has gone out of control. Results also showed an increase in blood flow in fat tissue and recruitment of immune cells to the environment.

“The fat is responding to the presence of CGRP, and it’s activating lipolysis,” Tedeschi said. “CGRP is also a potent vasodilator, and we saw increased vascularisation of the fat – new blood vessels forming as a result of the spinal cord injury. And the recruitment of monocytes can help set up a chronic pro-inflammatory state.”

Silencing the genes that encode the alpha2delta1 receptor restored the fat tissue to normal function, indicating that gabapentin – which targets alpha2delta1 and its partner, alpha2delta2 – was a good treatment candidate. Tedeschi’s lab has previously shown in animal studies that gabapentin helped restore limb function after spinal cord injury and boosted functional recovery after stroke.

But in these experiments, Roy discovered something tricky about gabapentin: the drug prevented changes in abdominal fat tissue and lowered CGRP in the blood, in turn preventing spillover of fatty acids into the liver a month later, establishing normal metabolic conditions. But paradoxically, the mice developed insulin resistance, a known side effect of gabapentin.

The team instead tried starting with a high dose, tapering off and stopping after four weeks.

“This way, we were able to normalise metabolism to a condition much more similar to control mice,” Roy said. “This suggests that as we discontinue administration of the drug, we retain beneficial action and prevent spillover of lipids in the liver. That was really exciting.”

Finally, researchers examined how genes known to regulate white fat tissue were affected by targeting alpha2delta1 genetically or with gabapentin, and found both of these interventions after spinal cord injury suppress genes responsible for disrupting metabolic functions.

Tedeschi said the combined findings suggest starting gabapentin treatment early after a spinal cord injury may protect against detrimental conditions involving fat tissue that lead to cardiometabolic disease – and could enable discontinuing the drug while retaining its benefits and lowering the risk for side effects.

Source: Ohio State University

Categories : Injury & Trauma Metabolic DisordersTags :

Shoe Technology Reduces Risk of Diabetic Foot Ulcers

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Researchers have developed a new shoe insole technology that helps reduce the risk of diabetic foot ulcers, which can lead to hospitalisation and leg, foot or toe amputations. They describe the technology in The International Journal of Lower Extremity Wounds.

“The goal of this innovative insole technology is to mitigate the risk of diabetic foot ulcers by addressing one of their most significant causes: skin and soft tissue breakdown due to repetitive stress on the foot during walking,” said Muthu B.J. Wijesundara, principal research scientist at The University of Texas at Arlington Research Institute (UTARI).

Diabetes can damage the small blood vessels that supply blood to the nerves, leading to poor circulation and foot sores, also called ulcers. About one-third of people with diabetes develop foot ulcers during their lifetime. Those who have foot ulcers often die at younger ages than those without ulcers.

“Although many shoe insoles have been created over the years to try to alleviate the problem of foot ulcers, studies have shown that their success in preventing them is marginal,” Wijesundara said. “We took the research a step further by creating a pressure-alternating shoe insole that works by cyclically relieving pressure from different areas of the foot, thereby providing periods of rest to the soft tissues and improving blood flow. This approach aims to maintain the health of the skin and tissues, thereby reducing the risk of diabetic foot ulcers.”

In an article in the peer-reviewed International Journal of Lower Extremity Wounds, Wijesundara and UTA colleagues Veysel Erel, Aida Nasirian and Yixin Gu, along with Larry Lavery of UT Southwestern Medical Center, described their innovative insole technology. After this successful pilot project, the next step for the research team will be refining the technology to make it more accessible for users with varying weights and shoe sizes.

“Considering the impact of foot ulcers, it’s exciting that we may be able to make a real difference in the lives of so many people,” Wijesundara said.

Source: University of Texas at Arlington

Categories : Metabolic DisordersTags :

Study Links Emulsifiers and Type 2 Diabetes Risk

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Emulsifiers, commonly used additives for improving the texture of food products and extending their shelf life, may be associated with the onset of type 2 diabetes, according to a large cohort study of over 100 000 people in France.

Researchers from Inserm, INRAE, Université Sorbonne Paris Nord, Université Paris Cité and Cnam, as part of the Nutritional Epidemiology Research Team (CRESS-EREN), studied the possible links between the dietary intake of food additive emulsifiers and the onset of type 2 diabetes between 2009 and 2023. They analysed the dietary and health data of 104 139 adults participating in the French NutriNet-Santé cohort study, specifically evaluating their consumption of this type of food additive using dietary surveys conducted every six months. The findings suggest an association between the chronic consumption of certain emulsifier additives and a higher risk of diabetes. The study is published in Lancet Diabetes & Endocrinology.

In Europe and North America, 30 to 60% of dietary energy intake in adults comes from ultra-processed foods. An increasing number of epidemiological studies suggest a link between higher consumption levels of ultra-processed foods with higher risks of diabetes and other metabolic disorders.

Emulsifiers are among the most commonly used additives. They are often added to processed and packaged foods such as certain industrial cakes, biscuits and desserts, as well as yoghurts, ice creams, chocolate bars, industrial breads, margarines and ready-to-eat or ready-to-heat meals, in order to improve their appearance, taste and texture and lengthen shelf life. These emulsifiers include for instance mono- and diglycerides of fatty acids, carrageenans, modified starches, lecithins, phosphates, celluloses, gums and pectins.

As with all food additives, the safety of emulsifiers had been previously evaluated by food safety and health agencies based on the scientific evidence that was available at the time of their evaluation.
However, some recent studies suggest that emulsifiers may disrupt the gut microbiota and increase the risk of inflammation and metabolic disruption, potentially leading to insulin resistance and the development of diabetes.

For the first time worldwide, a team of researchers in France has studied the relationships between the dietary intakes of emulsifiers, assessed over a follow-up period of maximum 14 years, and the risk of developing type 2 diabetes in a large study in the general population.

The results are based on the analysis of data from 104 139 adults in France (average age 43 years; 79% women) who participated in the NutriNet-Santé web-cohort study (see box below) between 2009 and 2023.

The participants completed at least two days of dietary records, collecting detailed information on all foods and drinks consumed and their commercial brands (in the case of industrial products). These dietary records were repeated every six months for 14 years, and were matched against databases in order to identify the presence and amount of food additives (including emulsifiers) in the products consumed. Laboratory assays were also performed in order to provide quantitative data. This allowed a measurement of chronic exposure to these emulsifiers over time.

During follow-up, participants reported the development of diabetes (1056 cases diagnosed), and reports were validated using a multi-source strategy (including data on diabetes medication use). Several well-known risk factors for diabetes, including age, sex, weight (BMI), educational level, family history, smoking, alcohol and levels of physical activity, as well as the overall nutritional quality of the diet (including sugar intake) were taken into account in the analysis.

After an average follow-up of seven years, the researchers observed that chronic exposure – evaluated by repeated data – to the following emulsifiers was associated with an increased risk of type 2 diabetes:

  • carrageenans (total carrageenans and E407; 3% increased risk per increment of 100 mg per day)
  • tripotassium phosphate (E340; 15% increased risk per increment of 500 mg per day)
  • mono- and diacetyltartaric acid esters of mono- and diglycerides of fatty acids (E472e; 4% increased risk per increment of 100 mg per day)
  • sodium citrate (E331; 4% increased risk per increment of 500 mg per day)
  • guar gum (E412; 11% increased risk per increment of 500 mg per day)
  • gum arabic (E414; 3% increased risk per increment of 1000 mg per day)
  • xanthan gum (E415; 8% increased risk per increment of 500 mg per day)

This study constitutes an initial exploration of these relationships, and further investigations are now needed to establish causal links. The researchers mentioned several limitations of their study, such as the predominance of women in the sample, a higher level of education than the general population, and generally more health-promoting behaviours among the NutriNet-Santé study participants. Therefore caution is needed when extrapolating the conclusions to the entire French population.

The study is nevertheless based on a large sample size, and the researchers have accounted for a large number of factors that could have led to confounding bias. They also used unique, detailed data on exposure to food additives, down to the commercial brand name of the industrial products consumed. In addition, the results remain consistent through various sensitivity analyses, which reinforces their reliability.

“These findings are issued from a single observational study for the moment, and cannot be used on their own to establish a causal relationship,”explain Mathilde Touvier, Research Director at Inserm, and Bernard Srour, Junior Professor at INRAE, lead authors of the study. “They need to be replicated in other epidemiological studies worldwide, and supplemented with toxicological and interventional experimental studies, to further inform the mechanisms linking these food additive emulsifiers and the onset of type 2 diabetes. However, our results represent key elements to enrich the debate on re-evaluating the regulations around the use of additives in the food industry, in order to better protect consumers.”

Among the next steps, the research team will be looking at variations in certain blood markers and the gut microbiota linked to the consumption of these additives, to better understand the underlying mechanisms. The researchers will also look at the health impact of additive mixtures and their potential ‘cocktail effects.’

They will also work in collaboration with toxicologists to test the impact of these exposures in in vitro and in vivo experiments, to gather more arguments in favour of a causal link.

Categories : Metabolic Disorders VaccinesTags :

Metabolic Health before Flu Vaccination Determines Its Effectiveness

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A four-week healthy diet improved the effectiveness of a flu vaccine given to obese mice

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Scientists at St. Jude Children’s Research Hospital have shown that improving metabolic health in obese mice before vaccination, but not after, protects against influenza virus.

Metabolic health (normal blood pressure, blood sugar and cholesterol levels, among other factors) influences the effectiveness of influenza vaccinations. Vaccination is known to be less effective in people with obesity compared to those with a healthier body mass index (BMI), but St. Jude Children’s Research Hospital scientists have found that the difference is attributable not to obesity itself, but rather metabolic dysfunction. In a study published in Nature Microbiology, the researchers found that switching obese mice to a healthy diet before flu vaccination, but not after, completely protected the models from a lethal dose of flu, despite BMI.

“We found that the vaccines worked effectively if at the time of vaccination an animal is metabolically healthy,” said corresponding author Stacey Schultz-Cherry, PhD, St. Jude Department of Host-Microbe Interactions and Center of Excellence for Influenza Research and Response co-director. “And the opposite was also true: regardless of what the mice looked like on the outside, if they had metabolic dysfunction, the vaccines did not work as well.”

Prior research has shown that 100% of obese mice succumbed to influenza after exposure, even after vaccination. Contrary to the scientists’ original expectations, when mice who were vaccinated while obese returned to a healthy weight, outcomes did not improve. These now outwardly healthy mice still all succumbed to disease when exposed to the real virus. Only switching to a healthy diet four weeks before vaccination improved survival, with drastic effect, despite high BMI.

“We were excited to see this effect because mice with obesity are so susceptible to severe disease and succumbing to the infection,” Schultz-Cherry said. “Getting 100% survival with the vaccine where we had only seen 0% survival was impressive.” The improved survival suggests the researchers have discovered a greater underlying principle determining influenza vaccine efficacy.

Metabolic dysfunction hinders the immune system

While studying how metabolic function influences influenza vaccine responses, the scientists found that poor metabolic health causes immune system dysfunction. T cells, the primary immune cells involved in anti-viral responses, failed to act in animals that had been in an unhealthy metabolic state at the time of vaccination, even during later viral exposure. Even when the animals ate a healthy diet after vaccination and maintained a normal BMI, the anti-flu T cells were “frozen” in that dysfunctional state.

However, a healthy diet before vaccination improved T-cell function, which resulted in a robust anti-flu response during later exposure.

“The T cells were better able to do their job in the metabolically healthy mice at the time of vaccination,” Schultz-Cherry said. “It wasn’t a matter of the numbers of them or the types of them. It was their functional activity. There were plenty of them in the lungs, not working. The healthy diet switched them from not working to functioning properly, but only if the switch occurred before vaccination.”

The earlier healthy diet also improved inflammation. Pro-inflammatory cytokines are upregulated in obese animals. Schultz-Cherry’s team found that models also returned to a lower basal cytokine level when switched to a healthy diet before vaccination.

“A healthy diet lowered some of the systemic meta-inflammation in these animals, and they regained some of the epithelial innate immune responses,” said Schultz-Cherry. “We started seeing better signalling of things like interferons, which we know is problematic in obesity and in general saw the immune system starting to function the way that it should.”

Improving metabolic health may improve influenza vaccine effectiveness

“What we found and are emphasising is that it’s not the phenotype of obesity that matters; it’s really about metabolic health,” Schultz-Cherry said. “It’s metabolic health at that moment of vaccination that really makes a difference.”

The study was restricted to mice, but it does open research opportunities to improve influenza vaccine efficacy in humans. The findings suggest methods of improving metabolic health may also improve subsequent influenza vaccinations. Given the recent introduction of metabolic improvement drugs, especially glucagon-like peptide 1 (GLP-1) agonists, there may be potential for a cooperative effect.

“We don’t know for sure, but if the outcome of using GLP-1 drugs is weight loss and improved metabolic health, we would hypothesise that it will help,” Schultz-Cherry said. “But we do know that we can do better protecting our vulnerable populations, and this study is a start for understanding how.”

Source: St. Jude Children’s Research Hospital

Categories : Metabolic DisordersTags :

Probing an Outdated Diabetes Drug’s Insulin Resistance Lowering Abilities

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Thiazolidinediones (TZDs) are a class of drug that can be used to treat type 2 diabetes by reversing insulin resistance, one of the main hallmarks of the disease. While TZDs were extremely popular in the 1990s and early 2000s, they have fallen out of use among physicians in recent decades because unwanted side effects emerged, including weight gain and excess fluid accumulation in body tissues.

Now, researchers at University of California San Diego School of Medicine are exploring how to isolate the positive effects of these drugs, which could help yield new treatments that don’t come with the old side effects.

In a new study published in Nature Metabolism, the researchers discovered how one of the most well-known TZD drugs works at the molecular level and were able to replicate its positive effects in mice without giving them the drug itself.

“For decades, TZDs have been the only drugs we have that can reverse insulin resistance, but we seldom use them anymore because of their side effects profile,” said Jerrold Olefsky, MD, a professor of medicine and assistant vice chancellor for integrative research at UC San Diego Health Sciences.

“Impaired insulin sensitivity is the root cause of type 2 diabetes, so any treatment we can develop to safely restore this would be a major step forward for patients.”

The main driver of insulin resistance in type 2 diabetes is obesity. Obesity-related inflammation causes macrophages to accumulate in adipose tissue, where they can comprise up to 40% of the total number of cells in the tissue.

When adipose tissue is inflamed, these macrophages release tiny nanoparticles containing instructions for surrounding cells in the form of microRNAs. These microRNA-containing capsules, called exosomes, are released into the circulation and can travel through the bloodstream to be absorbed by other tissues, such as the liver and muscles. This can then lead to the varied metabolic changes associated with obesity, including insulin resistance.

To understand how TZD drugs, which restore insulin resistance, affect this exosome system, the researchers treated a group of obese mice with the TZD drug rosiglitazone. Those mice became more sensitive to insulin, but they also gained weight and retained excess fluid, known side effects of rosiglitazone.

However, by isolating exosomes from the adipose tissue macrophages of the mice who had received the drug and injecting them into another group of obese mice that had not received it, the researchers were able to deliver the positive effects of rosiglitazone without transferring the negative effects.

“The exosomes were just as effective in reversing insulin resistance as the drug itself but without the same side effects,” said Olefsky.

“This indicates that exosomes can ultimately link obesity-related inflammation and insulin resistance to diabetes. It also tells us that we may be able to leverage this system to boost insulin sensitivity.”

The researchers were also able to identify the specific microRNA within the exosomes that was responsible for the beneficial metabolic effects of rosiglitazone. This molecule, called miR-690, could eventually be leveraged into new therapies for type 2 diabetes.

“It’s likely not practical to develop exosomes themselves as a treatment because it would be difficult to produce and administer them, but learning what drives the beneficial effects of exosomes at the molecular level makes it possible to develop drugs that can mimic these effects,” said Olefsky. “There’s also plenty of precedent for using microRNAs themselves as drugs, so that’s the possibility we’re most excited about exploring for miR-690 going forward.”

Source: University of California – San Diego

Categories : Cancer Metabolic DisordersTags :

Study Shows no Thyroid Cancer Risk from GLP-1 Agonists

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GLP-1 analogues have become increasingly popular to treat diabetes and obesity, but there have been concerns that they might increase the risk of thyroid cancer. Now an extensive Scandinavian study led by researchers at Karolinska Institutet has found no evidence of such a link. The study is published in The BMJ.

GLP-1 receptor agonists, also known as GLP-1 analogues, reduce blood sugar levels and appetite. They are widely used in the treatment of type 2 diabetes and obesity, with their clinical use steadily increasing. Earlier studies and adverse event data have suggested that these drugs could be associated with an increased risk of thyroid tumours. However, due to limitations in data and methodology, clear conclusions could not be drawn, leading to uncertainty about this potential side effect.

“Many people take these medicines, so it is important to study potential risks associated with them,” says Björn Pasternak, principal researcher at the Department of Medicine, Solna, at Karolinska Institutet in Sweden. “Our study covers a broad group of patients and provides strong support that GLP-1 analogues are not associated with an increased risk of thyroid cancer.” 

The researchers analysed national register data from Denmark, Norway, and Sweden of about 145 000 patients treated with GLP-1 analogues, mainly liraglutide or semaglutide, and 290 000 patients treated with another diabetes drug (DPP4 inhibitors). The risk of thyroid cancer was compared between the groups over an average follow-up period of just under four years. 

GLP-1 treatment was not associated with an increased risk of thyroid cancer. The results were consistent also when compared to a third diabetes medication group (SGLT2 inhibitors).

“We cannot rule out that the risk of certain subtypes of thyroid cancer is increased in smaller patient groups that we could not study here, for example in people with a high congenital risk of medullary thyroid cancer who are advised against using these drugs,” says Peter Ueda, assistant professor at the Department of Medicine, Solna, at Karolinska Institutet.

The ongoing research program at Karolinska Institutet investigates the effects and potential side effects of newer diabetes medications such as GLP-1 analogues and SGLT2 inhibitors. These medications are now being used to treat broader patient groups, including those with obesity, heart failure, and kidney failure.

“We know from randomised clinical trials that they have positive effects, but clinical reality is different with patients varying in disease severity, comorbidities, and adherence to treatment recommendations,” says Björn Pasternak. “It’s therefore essential to investigate how these medicines perform in everyday clinical settings.”

Source: Karolinska Institutet

Categories : Metabolic Disorders Surgeries & ProceduresTags :

GLP-1 Agonists may Increase Risk of Aspiration Pneumonia after Endoscopy

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By HualinXMN – Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=133759262

New research from Cedars-Sinai found that glucagon-like peptide-1 receptor agonists (GLP-1RAs) are associated with an increased risk of aspiration pneumonia following endoscopy. The large, population-based study is published in the leading peer-reviewed journal Gastroenterology.

One way the new obesity medications work is by slowing digestion, so people feel full longer, causing them to eat less.

This also means that food sits in the stomach longer. As a result, the stomach may not empty completely during the usual duration of fasting that is recommended ahead of a surgical procedure to decrease risk of aspiration, explained the study’s corresponding author, Ali Rezaie, MD, medical director of the GI Motility Program and director of bioinformatics at the MAST Program at Cedars-Sinai.

“Aspiration during or after endoscopy can be devastating,” Rezaie said.

“If significant, it can lead to respiratory failure, ICU admission and even death. Even mild cases may require close monitoring, respiratory support and medications including antibiotics. It is important we take all possible precautions to prevent aspiration from occurring.”

The study analysed data from nearly 1 million de-identified U.S. patients who underwent upper or lower endoscopy procedures between January 2018 and December 2020.

Patients who were prescribed GLP-1RA medications had a 33% higher chance of experiencing aspiration pneumonia than those who did not take these medications before the procedure.

This comparison also considered other variables that could influence the outcome to ensure a fair comparison between the two groups.

“When we apply this risk to the more than 20 million endoscopies that are performed in the U.S. each year, there may actually be a large number of cases where aspiration could be avoided if the patient safely stops their GLP-1RA medication in advance,” Rezaie said.

“The results of this study could change clinical practice,” said Yee Hui Yeo, MD, first author of the study and a clinical fellow in the Karsh Division of Gastroenterology and Hepatology at Cedars-Sinai. “Patients taking these medications who are scheduled to undergo a procedure should communicate with their healthcare team well in advance to avoid unnecessary and unwanted complications.”

Source: Cedars-Sinai Medical Center

Categories : Injury & Trauma Metabolic DisordersTags :

Restoring Crucial Enzyme could Supercharge Chronic Wound Healing

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Scientists have uncovered a key step in the wound healing process that becomes disabled in diseases like diabetes and ageing. Importantly, the research published in Nature reveals a molecule involved in the healing of tissues that leads to a drastic acceleration of wound closure, up to 2.5 times faster, and 1.6 times more muscle regeneration.

The immune system has a critical role in orchestrating tissue healing. As a result, regenerative strategies that control immune components have proved effective. This is particularly relevant when immune dysregulation that results from conditions such as diabetes or advanced age impairs tissue healing following injury. Nociceptive sensory neurons have a crucial role as immunoregulators and exert both protective and harmful effects depending on the context. However, how neuro–immune interactions affect tissue repair and regeneration following acute injury was unclear.

Lead researcher, Associate Professor Mikaël Martino, from Monash University’s Australian Regenerative Medicine Institute (ARMI) in Melbourne, Australia, said the discovery “could transform regenerative medicine, because it sheds light on the crucial role of sensory neurons in orchestrating the repair and regeneration of tissues, offering promising implications for improving patient outcomes.”

The cost of managing poorly healing wounds costs around $250 billion a year.

“In adults with diabetes alone – where poor blood flow can lead to quickly worsening wounds that are often very slow or impossible to heal – the lifetime risk of developing a diabetic foot ulcer (DFU), the most common diabetes-related wound, is 20 to 35 per cent and this number is rising with increased longevity and medical complexity of people with diabetes,” co-lead author, ARMI’s Dr Yen-Zhen Lu said.

Nociceptive sensory neurons, also called nociceptors, are the nerves in our body that sense pain.

These neurons alert us to potentially damaging stimuli in tissues by detecting dangers like tissue damage, inflammation, extremes in temperature, and pressure.

The researchers discovered that, during the healing process, sensory neuron endings grow into injured skin and muscle tissues, communicating with immune cells through a neuropeptide called calcitonin gene-related peptide (CGRP).

“Remarkably, this neuropeptide acts on immune cells to control them, facilitating tissue healing after injury,” Associate Professor Martino said.

Importantly they found that sensory neurons are crucial to the dissemination of CGRP because they showed that the selective removal of sensory neurons in mice reduce CGRP and significantly impairs skin wound healing and muscle regeneration following injury.

When the scientists administered an engineered version of CGRP to mice with neuropathy similar to that seen in diabetic patients, it led to rapid wound healing and muscle regeneration.

According to Associate Professor Martino, these findings hold significant promise for regenerative medicine, particularly for the treatment of poorly-healing tissues and chronic wounds.

“By harnessing neuro-immune interactions, the team aims to develop innovative therapies that address one of the root causes of impaired tissue healing, offering hope to millions,” he said.

“This study has uncovered significant implications for advancing our understanding of the tissue healing process after acute injury. Harnessing the potential of this neuro-immuno-regenerative axis opens new avenues for effective therapies, whether as standalone treatments or in combination with existing therapeutic approaches. “

Source: Monash University

Categories : Metabolic Disorders Obstetrics & GynaecologyTags :

Metformin for Gestational Diabetes may Negatively Impact Offspring

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With the rise in gestational diabetes and metabolic disorders during pregnancy, metformin is also being prescribed more frequently. Although it is known that the oral antidiabetic agent can cross the placental barrier, the impacts on the brain development of the child are largely unknown. Now, researchers have been able to demonstrate in a mouse model that although metformin has positive effects in pregnant animals, it does not in the offspring. The researchers, from German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), published their findings in Molecular Metabolism.

Around one in six pregnant women worldwide are affected by gestational diabetes. According to the Robert Koch Institute, 63 000 women in Germany were affected by the disease in 2021, and the trend is increasing. Excessively high blood sugar levels during pregnancy are associated with negative consequences for mother and child. It increases the risk of affected women developing type 2 diabetes later on and their children have a higher risk of developing metabolic disorders and being overweight.

Long-term effect of metformin on offspring is unclear

The placenta-crossing oral antidiabetic agent metformin has been gaining importance as an alternative to insulin administration when lifestyle changes fail to treat gestational diabetes. But there are currently only a few studies on the long-term effects of metformin on the health of offspring. It is known that metformin has an impact on the AMPK signaling pathway, which regulates the networking of nerve cells during brain development.

The interdisciplinary team of DIfE researchers led by Junior Research Group Leader Dr Rachel Lippert therefore grappled with two central questions:

Firstly, is metformin treatment only beneficial for the mother or also the child?

Secondly, does metformin treatment lead to long-term negative physiological changes in the offspring, especially in connection with the development of neuronal circuits in the hypothalamus, a critical region in the regulation of energy homeostasis?

Mouse models shed some light

To answer the key questions, the researchers used two mouse models with high-fat or control diets to represent the main causes of gestational diabetes, ie, severe obesity of the mother before pregnancy and excessive weight gain during pregnancy. The antidiabetic treatment of female mice and their offspring took place during the lactation period as this corresponds to the third trimester of a human pregnancy in terms of brain development.

The mice were treated with insulin, metformin, or a placebo, with dosage based on standard human treatments. The research team collected data on the body weight of the mice, analysed various metabolic parameters and hormones, and examined molecular signaling pathways in the hypothalamus.

Maternal metabolic state is crucial

“As a result of antidiabetic treatment in the early postnatal period, we were able to identify alterations in the weight gain and hormonal status of the offspring, which were critically dependent on the metabolic state of the mother,” explains Lippert. Furthermore, sex-specific changes in hypothalamic AMPK signalling in response to metformin exposure were also observed. Together with the metformin-induced shift in the examined hormone levels, the results indicate that the maternal metabolic state must be taken into account before starting the treatment of gestational diabetes.

Focusing on prevention

According to Rachel Lippert, treatment of gestational diabetes in future could entail developing a medication that is available for all and does not cross the placenta. “Given the increasing prevalence, education about gestational diabetes and preventive measures are of vital importance. If we can find a way to manage lifestyle and diet more proactively, we are in a better position to exploit the potential of gestational diabetes treatment,” says Lippert.

Source: Deutsches Zentrum fuer Diabetesforschung DZD

Categories : Exercise Metabolic DisordersTags :

Metformin’s Weight Loss Tied to “Anti-hunger” Molecule

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A new study finds that the modest weight loss from taking metformin is attributable to an appetite-suppressing molecule that is abundant after exercise

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An “anti-hunger” molecule produced after vigorous exercise is responsible for the moderate weight loss caused by the diabetes medication metformin, according to a new study in mice and humans. The anti-hunger molecule, lac-phe, was discovered by Stanford Medicine researchers in 2022.

The finding, made jointly by researchers at Stanford Medicine and at Harvard Medical School and published in Nature Metabolism, further cements the critical role the molecule, called lac-phe, plays in metabolism, exercise and appetite. It may pave the way to a new class of weight loss drugs.

“Until now, the way metformin, which is prescribed to control blood sugar levels, also brings about weight loss has been unclear,” said Jonathan Long, PhD, an assistant professor of pathology. “Now we know that it is acting through the same pathway as vigorous exercise to reduce hunger. Understanding how these pathways are controlled may lead to viable strategies to lower body mass and improve health in millions of people.”

Many people with diabetes who are prescribed metformin lose around 2% to 3% of their body weight within the first year of starting the drug. Although this amount of weight loss is modest when compared with the 15% or more often seen by people taking semaglutide, the discoveries that led to those drugs also grew from observations of relatively minor, but reproducible, weight loss in people taking first-generation versions of the medications.

Post-workout appetite loss

When Long and colleagues at Baylor University discovered lac-phe in 2022, they were on the hunt for small molecules responsible for curtailing hunger after vigorous exercise. What they found was a mishmash of lactate and an amino acid called phenylalanine. They dubbed the hybrid molecule lac-phe and went on to show that it’s not only more abundant after exercise but it also causes people (as well as mice and even racehorses) to feel less hungry immediately after a hard workout.

“There is an intimate connection between lac-phe production and lactate generation,” Long said. “Once we understood this relationship, we started to think about other aspects of lactate metabolism.”

Metformin was an obvious candidate because as it stimulates the breakdown of glucose (thus reducing blood sugar levels) it can trigger the generation of lactate.

The researchers found that obese laboratory mice given metformin had increased levels of lac-phe in their blood. They ate less than their peers and lost about 2 grams of body weight during the nine-day experiment.

Long and his colleagues also analysed stored blood plasma samples from people with Type 2 diabetes before and 12 weeks after they had begun taking metformin to control their blood sugar. They saw significant increases in the levels of lac-phe in people after metformin compared with their levels before treatment. Finally, 79 participants in a large, multi-ethnic study of atherosclerosis who were also taking metformin had significantly higher levels of lac-phe circulating in their blood than those who were not taking the drug.

“It was nice to confirm our hunch experimentally,” Long said. “The magnitude of effect of metformin on lac-phe production in mice was as great as or greater than what we previously observed with exercise. If you give a mouse metformin at levels comparable to what we prescribe for humans, their lac-phe levels go through the roof and stay high for many hours.”

Further research revealed that lac-phe is produced by intestinal epithelial cells in the animals; blocking the ability of mice to make lac-phe erased the appetite suppression and weight loss previously observed.

Finally, a statistical analysis of the people in the atherosclerosis study who lost weight during the several-year study and follow-up period found a meaningful association between metformin use, lac-phe production and weight loss.

“The fact that metformin and sprint exercise affect your body weight through the same pathway is both weird and interesting,” Long said. “And the involvement of the intestinal epithelial cells suggests a layer of gut-to-brain communication that deserves further exploration. Are there other signals involved?”

Long noted that, while semaglutide drugs are injected into the bloodstream, metformin is an oral drug that is already prescribed to millions of people. “These findings suggest there may be a way to optimize oral medications to affect these hunger and energy balance pathways to control body weight, cholesterol and blood pressure. I think what we’re seeing now is just the beginning of new types of weight loss drugs.”

Source: Stanford Medicine