Category: Metabolic Disorders

Probing an Outdated Diabetes Drug’s Insulin Resistance Lowering Abilities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

Study Shows no Thyroid Cancer Risk from GLP-1 Agonists

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

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

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

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

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

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

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

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

Smart Moo-ve for Diabetes Treatment: Insulin Produced in Cow’s Milk

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An unassuming brown bovine from the south of Brazil has made history as the first transgenic cow capable of producing human insulin in her milk. The advancement, led by researchers from the University of Illinois Urbana-Champaign and the Universidade de São Paulo, could herald a new era in insulin production, one day eliminating drug scarcity and high costs for people living with diabetes.

“Mother Nature designed the mammary gland as a factory to make protein really, really efficiently. We can take advantage of that system to produce a protein that can help hundreds of millions of people worldwide,” said Matt Wheeler, professor in the Department of Animal Sciences, part of the College of Agricultural, Consumer and Environmental Sciences (ACES) at U. of I.

Wheeler is lead author on a new Biotechnology Journal study describing the development of the insulin-producing cow, a proof-of-concept achievement that could be scaled up after additional testing and FDA approval.

Precise insertion of DNA

Wheeler’s colleagues in Brazil inserted a segment of human DNA coding for proinsulin – the protein precursor of the active form of insulin – into cell nuclei of 10 cow embryos. These were implanted in the uteruses of normal cows in Brazil, and one transgenic calf was born. Thanks to updated genetic engineering technology, the human DNA was targeted for expression – the process whereby gene sequences are read and translated into protein products – in mammary tissue only.

“In the old days, we used to just slam DNA in and hope it got expressed where you wanted it to,” Wheeler said. “We can be much more strategic and targeted these days. Using a DNA construct specific to mammary tissue means there’s no human insulin circulating in the cow’s blood or other tissues. It also takes advantage of the mammary gland’s capabilities for producing large quantities of protein.”

When the cow reached maturity, the team unsuccessfully attempted to impregnate her using standard artificial insemination techniques. Instead, they stimulated her first lactation using hormones. The lactation yielded milk, but a smaller quantity than would occur after a successful pregnancy. Still, human proinsulin and, surprisingly, insulin were detectable in the milk.

“Our goal was to make proinsulin, purify it out to insulin, and go from there. But the cow basically processed it herself. She makes about three to one biologically active insulin to proinsulin,” Wheeler said. “The mammary gland is a magical thing.”

The insulin and proinsulin, which would need to be extracted and purified for use, were expressed at a few grams per liter in the milk. But because the lactation was induced hormonally and the milk volume was smaller than expected, the team can’t say exactly how much insulin would be made in a typical lactation.

Conservatively, Wheeler says if a cow could make 1 gram of insulin per liter and a typical Holstein makes 40 to 50 litres per day, that’s a lot of insulin. Especially since the typical unit of insulin equals 0.0347 milligrams.

“That means each gram is equivalent to 28,818 units of insulin,” Wheeler said. “And that’s just one liter; Holsteins can produce 50 liters per day. You can do the math.”

The team plans to re-clone the cow, and is optimistic they’ll achieve greater success with pregnancy and full lactation cycles in the next generation. Eventually, they hope to create transgenic bulls to mate with the females, creating transgenic offspring that can be used to establish a purpose-built herd. Wheeler says even a small herd could quickly outcompete existing methods – transgenic yeast and bacteria – for producing insulin, and could do so without having to create highly technical facilities or infrastructure.

“With regard to mass-producing insulin in milk, you’d need specialized, high-health-status facilities for the cattle, but it’s nothing too out of the ordinary for our well-established dairy industry,” Wheeler said. “We know what we’re doing with cows.”

An efficient system to collect and purify insulin products would be needed, as well as FDA approval, before transgenic cows could supply insulin for the world’s diabetics. But Wheeler is confident that day is coming.

“I could see a future where a 100-head herd, equivalent to a small Illinois or Wisconsin dairy, could produce all the insulin needed for the country,” he said. “And a larger herd? You could make the whole world’s supply in a year.

Source: University of Illinois College of Agricultural, Consumer and Environmental Sciences

Liver Immune System Quickly ‘Eats up’ LDL Cholesterol

Colourised electron micrograph image of a macrophage. Credit: NIH

A new study reveals that immune cells in the liver react to high cholesterol levels and eat up excess cholesterol that can otherwise cause damage to arteries. The findings, published in Nature Cardiovascular Research, suggest that the response to the onset of atherosclerosis begins in the liver.

Immediate response from the liver

In the current study, researchers from Karolinska Institutet wanted to understand how different tissues in the body react to high levels of LDL, commonly called ‘bad cholesterol’, in the blood.

To test this, they created a system where they could quickly increase the cholesterol in the blood of mice.

“Essentially, we wanted to detonate a cholesterol bomb and see what happened next,” says Stephen Malin, lead author of the study and principal researcher at the Department of Medicine, Solna, Karolinska Institutet.

“We found that the liver responded almost immediately and removed some of the excess cholesterol.”

However, it wasn’t the typical liver cells that responded, but a type of immune cell called Kupffer cells that are known for recognising foreign or harmful substances and eating them up. The discovery made in mice was also validated in human tissue samples.

“We were surprised to see that the liver seems to be the first line of defence against excess cholesterol and that the Kupffer cells were the ones doing the job,” says Stephen Malin.

“This shows that the liver immune system is an active player in regulating cholesterol levels, and suggests that atherosclerosis is a systemic disease that affects multiple organs and not just the arteries.”

Several organs could be involved

The researchers hope that by understanding how the liver and other tissues communicate with each other after being exposed to high cholesterol, they can find new ways to prevent or treat cardiovascular and liver diseases.

“Our next step is to look at how other organs respond to excess cholesterol, and how they interact with the liver and the blood vessels in atherosclerosis,” says Stephen Malin. “This could help us develop more holistic and effective strategies to combat this common and deadly disease.”

Source: Karolinska Institutet

Worsening Metabolic Syndrome Exacerbates Cancer Risk

Study reveals a significant link, suggesting that managing metabolic syndrome may help prevent cancer.

Source: Pixabay CC0

New research indicates that individuals with persistent and worsening metabolic syndrome – which encompasses conditions such as high blood pressure, elevated blood sugar, excess abdominal fat, and abnormal cholesterol – face an elevated risk of developing various types of cancer. The findings are published by Wiley online in CANCER, a peer-reviewed journal of the American Cancer Society.

In the study, 44 115 adults in China with an average age of 49 years were categorised into 4 different trajectories based on trends from 2006 (the time of the first physical exam) to 2010: 10.56% exhibited a low-stable pattern and maintained low metabolic syndrome scores; 40.84% exhibited a moderate-low pattern and maintained moderate to low metabolic syndrome scores; 41.46% exhibited a moderate-high pattern and consistently maintained moderate to high metabolic syndrome scores; and 7.14% exhibited an elevated-increasing pattern in which initially elevated metabolic syndrome scores increased over time.

During the follow-up period of 2010–2021, with a median follow-up of 9.4 years, there were 2271 cancer diagnoses among participants. Compared with participants with a low-stable trajectory pattern, those with an elevated-increasing trajectory pattern had 1.3-, 2.1-, 3.3-, 4.5-, 2.5-, and 1.6-times higher risks of developing any cancer, breast cancer, endometrial cancer, kidney cancer, colorectal cancer, and liver cancer, respectively.

Even when the low-stable, moderate-low, and moderate-high trajectory pattern groups were combined, the elevated-increasing trajectory pattern group had higher risks of developing all cancer types.

Also, participants with persistently high metabolic syndrome scores and concurrent chronic inflammation had the highest risks of developing breast, endometrial, colon, and liver cancer, whereas the risk of kidney cancer was predominantly observed among participants with persistently high scores but without chronic inflammation.

“This research suggests that proactive and continuous management of metabolic syndrome may serve as an essential strategy in preventing cancer,” said senior author Han-Ping Shi, MD, PhD, of Capital Medical University, in Beijing. “Our study can guide future research into the biological mechanisms linking metabolic syndrome to cancer, potentially resulting in targeted treatments or preventive strategies. Formal evaluation of these interventions will be needed to determine if they are able to modulate cancer risk.” 

Source: Wiley

Waist-to-height Ratio Superior to BMI for Detecting Fat Obesity in Children and Adolescents

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A simple measure of obesity in children and adolescents that could replace body mass index (BMI) has been identified in a new study as waist circumference-to-height ratio. This measure detected excess fat mass and distinguished fat mass from muscle mass in children and adolescents more accurately than BMI. The study was conducted in collaboration between the University of Bristol in the UK, the University of Exeter in the UK, and the University of Eastern Finland, and the results were published in Pediatric Research.

The prevalence of childhood and adolescent obesity has reached an epidemic proportion and is affecting nearly 1 in 4 children in the current decade.

Unfortunately, obesity in the young population has been associated with cardiovascular, metabolic, neurological, musculoskeletal diseases and premature death in adulthood.

Accurately detecting overweight and obesity in children is critical to initiating timely interventions.

For nearly a generation, weight-to-height ratio charts and BMI for age and sex have been used to diagnose children with obesity.

However, these surrogate assessment tools are inaccurate in childhood and adolescence since they do not distinguish fat mass from muscle mass.For instance, two children with similar BMI might have different proportions of fat and muscle mass which makes obesity diagnosis difficult.

Expensive tools such as the dual-energy Xray absorptiometry (DEXA) scan accurately measures fat and muscle content of the body, but this device is not readily available in primary health care centres.

Recently, the American Academy of Pediatrics (AAP) published a clinical guideline on childhood obesity and requested urgent research on inexpensive and accurate alternative measures of obesity.

Emerging studies in adults appear to suggest that waist circumference-to-height ratio predicts premature death better than BMI and could be a potential added tool to BMI measure in improving the diagnosis of obesity.

However, there has been no former evaluation of how much waist circumference-to-height ratio measurements agree with DEXA-measured fat mass and muscle mass during growth from childhood to young adulthood.

In addition, the threshold of waist circumference-to-height ratio needed to detect excess fat in children is not clear, hence this study.

The current study is the largest and the longest follow-up DEXA-measured fat mass and muscle mass study in the world using the University of Bristol’s Children of the 90s data (also known as the Avon Longitudinal Study of Parents and Children). The study included 7,237 children (51% females) aged 9 years who were followed-up until age 24 years.

Their BMI and waist circumference-to-height ratio were measured at ages 9, 11, 15, 17, and 24 years.

When different devices measure a variable with an exact resemblance, it is described as perfect agreement of the devices with a score of 100%. For example, two DEXA scans from different manufacturers would measure fat mass with a near-perfect agreement of 99 to 100%.

Waist circumference-to-height ratio had a very high agreement of 81 — 89% with DEXA-measured total body fat mass and trunk fat mass, but a low agreement with muscle mass (24 — 39%). BMI had a moderate agreement with total fat mass and trunk fat mass (65 — 72%) and muscle mass (52 — 58%). Since BMI had a moderate agreement with DEXA-measured muscle mass, it is difficult to specify whether BMI measures excess fat or muscle mass.

The optimal waist circumference-to-height ratio cut points that predicted the 95th percentile of total fat mass in males was 0.53 and 0.54 in females.

This cut point detected 8 out of 10 males and 7 out of 10 females who truly had excess DEXA-measured fat.

The cut point also identified 93 out of 100 males and 95 out of 100 females who truly do not have excess fat.

“This study provides novel information that would be useful in updating future childhood obesity guidelines and policy statements. The average waist circumference-to-height ratio in childhood, adolescence, and young adulthood is 0.45, it does not vary with age and among individuals like BMI. Waist circumference-to-height ratio might be preferable to BMI assessment in children and adolescent clinics as an inexpensive tool for detecting excess fat. Parents should not be discouraged by the BMI or weight of their children but can inexpensively confirm whether the weight is due to increase in excess fat by examining their kid’s waist circumference-to-height ratio,” says Andrew Agbaje, an award-winning physician and pediatric clinical epidemiologist at the University of Eastern Finland.

Source: University of Eastern Finland