Maternal obesity impacts the eating behaviours of offspring via long-term overexpression of the microRNA miR-505-5p, according to a study publishing June 4 in the open-access journal PLOS Biology by Laura Dearden and Susan Ozanne from the MRC Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, UK, and colleagues.
Previous studies in both humans and animal models have shown that the offspring of obese mothers have a higher risk of obesity and type 2 diabetes.
While this relationship is likely the result of a complex relationship between genetics and environment, emerging evidence has implicated that maternal obesity can disrupt the hypothalamus – the region of the brain responsible for nutrition sensing and energy homeostasis.
In animal models, offspring exposed to overnutrition during key periods of development eat more, but little is known about the molecular mechanisms that lead to these changes in eating behaviour.
In this study, researchers found that mice born from obese mothers had higher levels of the microRNA miR-505-5p in their hypothalamus – from as early as the foetal stage into adulthood.
The researchers found that the mice ate more and showed a preference for high-fat foods.
Interestingly, the effect of maternal obesity on miR-505-5p and eating behaviours was mitigated if the mothers exercised during pregnancy.
Cell culture experiments showed that miR-505-5p expression could be induced by exposing hypothalamic neurons to long-chain fatty acids and insulin, which are both high in pregnancies complicated by obesity.
The researchers identified miR-505-5p as a novel regulator of pathways involved in fatty acid uptake and metabolism, therefore high levels of the miRNA make the offspring brain unable to sense when eating high fat foods.
Several of the genes that miR-505-5p regulates have been associated with high body mass index in human genetic studies.
The study is one of the first to demonstrate the molecular mechanism linking nutritional exposure in utero to eating behaviour.
The authors add, “Our results show that obesity during pregnancy causes changes to the baby’s brain that makes them eat more high fat food in adulthood and more likely to develop obesity. Importantly we showed that moderate exercise, without weight loss, during pregnancies complicated by obesity prevented the changes to the baby’s brain. This helps us understand why the children of mothers living with obesity are more likely to become obese themselves, with early life exposures, genetics and current environment all being contributing factors.”
As research continues to produce evidence about the underlying causes of obesity and optimal strategies to treat and manage obesity have evolved, there are disparities in application of the latest scientific advances in the clinical care for people with obesity. Widespread adoption of current findings, consistency of care and expertise in obesity care varies by health care professional and institution. These findings are detailed in a new American Heart Association scientific statement, “Implementation of Obesity Science Into Clinical Practice,” published in the journal Circulation.
“Obesity is undeniably a critical public health concern in the U.S. and around the world, affecting nearly all populations and straining our health care systems,” said Deepika Laddu, Ph.D., FAHA, chair of the statement writing committee and a senior research scientist at Arbor Research Collaborative for Health in Ann Arbor, Michigan. “As a major risk factor for heart disease, obesity has significantly hindered progress in reducing heart disease rates. Despite advancements in understanding the complexities of obesity and newer treatment options, major gaps remain between obesity research and real-world implementation in clinical practice.”
Studies show intensive lifestyle therapy is considerably more effective for weight loss than brief advice from a health care professional. However, general educational information is offered more frequently by health professionals rather than referrals to classes, programs or tangible resources for lifestyle changes. One study revealed that only 16% of health care professionals had working knowledge about evidence-based lifestyle treatments for obesity, including diet and nutrition, physical activity and intensive behavioral therapy referral. Other barriers to addressing weight loss are exacerbated by socioeconomic and racial or ethnic inequities. People of diverse races and ethnicities and people who are covered by Medicare or Medicaid are less likely to be referred to weight management programs or to have them covered by insurance.
For about 30 years, the prevalence of obesity in the US and around the world has been escalating. Recent estimates indicate more than 40% of US adults ages 20 and older are living with obesity, according to the US Centers for Disease Control and Prevention.
Research has led experts to unlock the multifactorial causes of obesity, including sociological and physiological determinants of health. Treatments for obesity have also evolved with more strategies for lifestyle modifications, medication therapy and bariatric surgery – but each treatment approach comes with challenges.
“While significant strides have been made in advancing the science to help us understand obesity, there remains a considerable gap between what we know and what happens in the doctor’s office,” said Laddu. “Health care professionals and health care systems need to find better ways to put what we know about obesity into action so more people can get the right support and treatment. Adopting new technologies and telemedicine, making referrals to community-based weight management programs to encourage behavioural change, providing social support and increasing reach and access to treatments are just some of the promising methods we could implement to unlock successful, evidence-based obesity care.”
Weight loss medications
Glucagon-like peptide-1 (GLP-1) agonists, such as high-dose semaglutide and tirzepatide, are the most recently FDA-approved medications for long-term weight management, and both are associated with an average weight loss of more than 10% at six months in clinical studies. However, despite half of adults in the U.S. meeting the BMI criteria for obesity and being eligible for these medications, a small proportion of this population is currently taking them.
Weight loss surgery
In the decades since bariatric (weight loss) surgery was first introduced as an option for people with severe obesity, there have been advances in the expertise and safety of the procedures, as well as an increased understanding of the health benefits that often result after bariatric surgery. A comprehensive review of studies focused on weight loss surgeries showed that patients who underwent bariatric surgery had lower risks of cardiovascular disease and decreased risks for multiple other obesity-associated conditions, including Type 2 diabetes and high blood pressure. One challenge facing health care professionals is ensuring that the populations with the greatest needs have access to bariatric surgery in terms of costs, resources and social support.
The statement describes strategies that both address these challenges and improve how obesity-based research is incorporated into clinical care. The statement also identifies the need to develop solutions across populations in order to manage obesity at the community level. Potential improved public health policies and future research to expand patient care models and optimize the delivery and sustainability of equitable obesity-related care are suggested.
Specific approaches are highlighted in the statement to help bridge the gap between the science about obesity and clinical care, such as:
To reach and successfully impact populations in need, health care professionals may consider how social determinants of health, including insurance type, household income, race and ethnicity, environment, health literacy, access to health-promoting resources and social supports all influence the likelihood of successful patient treatment.
Education for health care professionals explaining the complex origins and clinical consequences of obesity is discussed. Such training should emphasize information about diagnosis, prevention and treatment of obesity. Despite the high prevalence of obesity around the world, there is a lack of education programs centered on obesity for medical professionals.
Further evaluation of health policy changes that health care systems and insurance plans can implement and scale in order to make obesity treatment affordable for patients, especially those at high risk for adverse outcomes such as cardiovascular disease.
A framework for delivering obesity care into clinical practice settings is reviewed, as well as efforts by some professional societies for developing interventions that make obesity treatment more accessible.
“The statement emphasises the importance of a comprehensive approach across different levels of health care delivery and public policy, along with the adoption of feasible, evidence-based strategies in clinical settings,” said Laddu. “It also underscores the need for future research and policy changes to improve current patient care models and ensure equitable access to obesity-related care for people in underrepresented groups.”
The scientific statement also provides possible solutions for how to help people in their day-to-day lives, including interventions with digital technology and access through telemedicine. However, more research is needed in obesity science and treatment. Limited understanding of the cost-effectiveness of obesity prevention and the long-term health outcomes for established therapies has hindered the implementation of obesity science into clinical settings. Cross-collaborative obesity science research between stakeholders and health economists may serve as the bridge to developing and scaling cost-effective prevention programs.
Depiction of multiple myeloma. Credit: Scientific Animations
People who use metformin are less likely to develop a myeloproliferative neoplasm (MPN) over time, indicating that the treatment may help prevent the development of certain types of cancers, according to a study published in Blood Advances.
Metformin is a therapy used to treat high blood sugar in people with type 2 diabetes that increases the effect of insulin, reduces how much glucose is released from the liver and helps the body absorb glucose. A meta-analysis of previous studies connected the therapy with a reduction in the risk of gastrointestinal, breast, and urologic cancers, while a retrospective study of US veterans found that metformin users have a reduced risk for solid and haematological cancers.
Metformin’s anti-inflammatory properties in focus
“Our team was interested in understanding what other effects we see with commonly prescribed treatments like metformin,” said Anne Stidsholt Roug, MD, PhD, chief physician at Aarhus University Hospital and clinical associate professor at Aalborg University Hospital in Denmark. “The anti-inflammatory effect of metformin interested us, as MPNs are very inflammatory diseases. This is the first study to investigate the association between metformin use and risk of MPN.”
MPNs are a group of diseases that affect how bone marrow produces blood cells, resulting in an overproduction of red blood cells, white blood cells, or platelets that can lead to bleeding problems, a greater risk of stroke or heart attack, and organ damage.
Surprisingly strong association
The researchers compared metformin use among patients diagnosed with MPNs and a matched population from the Danish general population between 2010 and 2018. Of the 3816 MPN cases identified from the sample, a total of 268 (7.0%) individuals with MPN had taken metformin as compared to 8.2% (1573 out of 19 080) of the control group of people who had taken metformin but were not diagnosed with MPN. Just 1.1% of MPN cases had taken metformin for more than five years, as compared to 2.0% of controls. The protective effect of metformin was seen in all subtypes of MPN when adjusting for potential confounders.
“We were surprised by the magnitude of the association we saw in the data,” said Daniel Tuyet Kristensen, MD, PhD student, at Aalborg University Hospital and lead author of the study. “We saw the strongest effect in people who had taken metformin for more than five years as compared to those who had taken the treatment for less than a year.” Dr Kristensen added that this makes clinical sense, as MPNs are diseases that develop over a long period of time, like other types of cancer.
The researchers noted that while the protective effect of long-term metformin use was seen in all subtypes of MPN, the study was limited by its registry-based retrospective design. Further, they could not account for risk-modifying lifestyle factors, such as smoking, obesity, and dietary habits.
Dr Roug noted that while the study team were unable to assess exactly why metformin seems to protect against the development of MPN, they hope additional research will be conducted to better understand why this may be. Moving forward, the researchers aim to identify any similar trends with myelodysplastic syndromes and acute myeloid leukaemia in population-level data for future study.
Neuropathy, the nerve damage that causes pain and numbness in the feet and hands and can eventually lead to falls, infection and even amputation, is very common and underdiagnosed, according to a study published in Neurology®, the medical journal of the American Academy of Neurology.
“More than one-third of people with neuropathy experience sharp, prickling or shock-like pain, which increases their rates of depression and decreases quality of life,” said study author Melissa A. Elafros, MD, PhD, of the University of Michigan in Ann Arbor and a member of the American Academy of Neurology. “People with neuropathy also have an increased risk of earlier death, even when you take into account other conditions they have, so identifying and treating people with or at risk for neuropathy is essential.”
The study involved 169 people from an outpatient internal medicine clinic serving mainly Medicaid patients in Flint, Michigan. The participants had an average age of 58 years and 69% were Black people. One-half of the people had diabetes, which can cause neuropathy. A total of 67% had metabolic syndrome, which is defined as having excess belly fat plus two or more of the following risk factors: hypertension, elevated triglycerides, hyperglycaemia and low high-density lipoprotein (HDL) cholesterol. These risk factors are also associated with neuropathy.
All participants were tested for distal symmetric polyneuropathy. Information about other health conditions was also collected. A total of 73% of the people had neuropathy. Of those, 75% had not been previously diagnosed with the condition. Nearly 60% of those with neuropathy were experiencing pain. Of those with neuropathy, 74% had metabolic syndrome, compared to 54% of those who did not have neuropathy.
After adjusting for other factors that could affect the risk of neuropathy, researchers found that people with metabolic syndrome were more than four times more likely to have neuropathy than people who did not have the syndrome.
Risk differs according to race
Researchers were also looking for any relationship between race and income and neuropathy, as few studies have been done on those topics. There was no relationship between low income and neuropathy. For race, Black people had a decreased risk of neuropathy. Black people made up 60% of those with neuropathy and 91% of those without neuropathy.
“The amount of people with neuropathy in this study, particularly undiagnosed neuropathy, was extraordinarily high with almost three fourths of the study population,” Elafros said. “This highlights the urgent need for interventions that improve diagnosis and management of this condition, as well as the need for managing risk factors that can lead to this condition.” A limitation of the study is that it is a snapshot in time; it did not follow people to see who developed neuropathy over time. It also did not look at reasons why people were not able to manage risk factors that can lead to neuropathy.
South Africa has seen the quickest and most alarming rise of diabetes on the continent; from an estimated 1.9 million people living with the condition in 2011 to 4.2 million by 2021 – with 7.5 million predicted to be afflicted by 20451. South Africa also has the fastest rising prevalence on the continent with an estimated 20% of the adult population either diabetic or pre-diabetic1. Globally, diabetes prevalence is predicted to rise by 46% between 2019 and 20452. It currently stands at some 537 million people worldwide1.
This emerged at the recently held annual Sanofi medical meeting, the Cardio-Metabolic Axis Forum from April 19th–21st in Cape Town. This was a meeting of leading endocrinologists, specialist physicians, nephrologists, diabetes-treating doctors, academics and Patient Advocacy Groups (PAGs).
Speaking at the conference, specialist physician and endocrinologist, Dr Landi Lombard – former editor of the South Africa Journal of Diabetes and Vascular Disease – told delegates that the risk of death associated with diabetes in cardiovascular conditions is more than twice that of people with non-diabetes, while in all-cause mortality, it’s just under twice that of a person living without diabetes. Of the estimated 537 million people living with diabetes globally, only about half are diagnosed, of whom 25% receive care, 12.5% achieve treatment targets, and 6% live a life free of diabetes-related complications1.
Dr Lombard said that the pandemic is being driven by poor lifestyle choices and diet, lack of exercise and widespread obesity in the population, so better healthcare worker communication and education of patients is vital to stem the tide of diabetes.
Professor Robert Ritzel of the Department of Endocrinology, Diabetology and Angiology at Schwabing Hospital in Munich, said the Pacific Islands and the Middle East led the world with diabetes prevalence at between 25 % and 40 %. He said what precipitated a surge in diabetes was the speed at which a nation changed from a traditional to a modern lifestyle. When this happened within a few years, diabetes prevalence was likely to range between 20% and 40%. However, when change occurred over many generations, it gave epidemiologists and clinicians time to adapt.
Lombard said one of the biggest challenges was what diabetologists called ‘therapeutic inertia’ which contributes to a patient living with sub-optimal blood sugar control for many years. This term embraced physician, patient and healthcare system factors, patient injection related factors, time and resource constraints among physicians and the lack of a proper healthcare system plan. He said that in people with Type 2 diabetes, the median time it takes for the disease to intensify while taking one or more anti-diabetic drugs is 2.9 years. However, the use of an injectable slowed intensification down to 7.2 years or more.
Reasons for failure to intensify treatment or progress to injectable therapies varied between specialist and primary care physicians but were mainly because of a patient fear of injection, too many injections, perceptions of this being a ‘last resort’ treatment, fear of weight gain, fear of low blood sugar, and poor communication with patients.
Lombard said even 1 year of poor blood sugar control in people with Type 2 diabetes could result in an increase in the cumulative incidence of kidney disease of 18%, neuropathy of 8%, retinopathy of 7% and a significantly increased risk of heart attack (67%), heart failure (64%), stroke (51%) and composite cardiovascular events (62%).
Professor Naomi ‘Dinky’ Levitt, former Head of Endocrinology and Diabetic Medicine at the University of Cape Town and Groote Schuur Hospital and Director of the Chronic Disease Initiative for Africa, highlighted gestational diabetes as one of the greatest challenges.
Described as the “doyenne” of endocrinology in South Africa (SA), Levitt said one third of women who have gestational diabetes go on to develop diabetes within 6 years of giving birth, so post-partum intervention is crucial.
According to Levitt, lifestyle interventions had about a 20% positive effect, mainly because new mothers were pulled in all directions by family, the baby, husband, and domestic and work needs.
She said that with 31.4% of SA women estimated to have developed gestational diabetes, it would be ideal to screen all pregnant women at 24 and 28 weeks. However, this would collapse the healthcare system because of the healthcare staffing demands, so the alternative was to focus on risk factors such as being over 30 years old or being overweight.
She said that focusing on women with gestational diabetes would have the greatest impact on the pandemic, as treatment can help avoid pre-eclampsia and improve foetal development, resulting in fewer admissions to the neonatal ICU.
Speaking on behalf of Sanofi the conference sponsor, Dr Asafika Mbangata said: “Sanofi puts patients first and the aim of the conference was to empower stakeholders with the right information to help make critical care decisions for patients by sharing the latest data on advancements in treatments and technologies, along with insights into global and local policy changes impacting diabetes care.”
“As we chase the miracles of science to improve people’s lives, we know we cannot shape the future of diabetes management without partnerships with healthcare professionals and other stakeholders. Collaboration across all medical disciplines is essential if we are to overcome this pandemic, and we’re hopeful the conference opened the door to future robust collaborative actions that improve patient outcomes,” concluded Dr Mbangata.
References
Adapted from IDF Diabetes Atlas (10th edition). International Diabetes Federation. 2022. http://www.diabetesatlas.org/. Accessed 23 April, 2024.
A 3D map of the islet density routes throughout the healthy human pancreas. Source: Wikimedia CC0
An experimental monoclonal antibody drug called mAb43 appears to prevent and reverse the onset of clinical type 1 diabetes in mice, in some cases lengthening the animals’ lifespan, report scientists at Johns Hopkins Medicine.
The drug is unique, according to the researchers, because it targets insulin-making beta cells in the pancreas directly and is designed to shield those cells from attacks by the body’s own immune system cells. The drug’s specificity for such cells may enable long-term use in humans with few side effects, say the researchers. Monoclonal antibodies are made by cloning, or making identical replicas of, an animal (including human) cell line.
The findings, published in Diabetes, raise the possibility of a new drug for type 1 diabetes, an autoimmune condition which has no cure or means of prevention. Unlike type 2 diabetes, in which the pancreas makes too little insulin, in type 1 diabetes, the pancreas makes no insulin because the immune system attacks the pancreatic cells that make it.
The lack of insulin interferes with the body’s ability to regulate blood sugar levels.
According to Dax Fu, PhD, associate professor of physiology at the Johns Hopkins University School of Medicine and leader of the research team, mAb43 binds to a small protein on the surface of beta cells, which dwell in clusters called islets. The drug was designed to provide a kind of shield or cloak to hide beta cells from immune system cells that attack them as “invaders.” The researchers used a mouse version of the monoclonal antibody, and will need to develop a humanised version for studies in people.
For the current study, the researchers gave 64 non-obese mice bred to develop type 1 diabetes a weekly dose of mAb43 via intravenous injection when they were 10 weeks old. After 35 weeks, all mice were non-diabetic. One of the mice developed diabetes for a period of time, but it recovered at 35 weeks, and that mouse had early signs of diabetes before the antibody was administered.
In five of the same type of diabetes-prone mice, the researchers held off giving weekly mAb43 doses until they were 14 weeks old, and then continued dosages and monitoring for up to 75 weeks. One of the five in the group developed diabetes, but no adverse events were found, say the researchers.
In the experiments in which mAb43 was given early on, the mice lived for the duration of the monitoring period of 75 weeks, compared with the control group of mice that did not receive the drug and lived about 18-40 weeks.
Next, the researchers, including postdoctoral fellows Devi Kasinathan and Zheng Guo, looked more closely at the mice that received mAb43 and used a biological marker called Ki67 to see if beta cells were multiplying in the pancreas. They said, after treatment with the antibody, immune cells retreated from beta cells, reducing the amount of inflammation in the area. In addition, beta cells slowly began reproducing.
“mAb43 in combination with insulin therapy may have the potential to gradually reduce insulin use while beta cells regenerate, ultimately eliminating the need to use insulin supplementation for glycaemic control,” says Kasinathan.
The research team found that mAb43 specifically bound to beta cells, which make up about 1% or 2% of pancreas cells.
Another monoclonal antibody drug, teplizumab, received US Food and Drug Administration approval in 2022. Teplizumab binds to T cells, making them less harmful to insulin-producing beta cells. The drug has been shown to delay the onset of clinical (stage 3) type 1 diabetes by about two years, giving young children who get the disease time to mature and learn to manage lifelong insulin injections and dietary restrictions.
“It’s possible that mAb43 could be used for longer than teplizumab and delay diabetes onset for a much longer time, potentially for as long as it’s administered,” says Fu.
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.
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.
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.
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.
A four-week healthy diet improved the effectiveness of a flu vaccine given to obese mice
Photo by Gustavo Fring on Pexels
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.”
