Category: Metabolic Disorders

Categories : Injury & Trauma Metabolic DisordersTags :

Time of Injury Matters: Circadian Rhythms Affect Muscle Repair

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Photo by Mat Napo on Unsplash

Circadian rhythms doesn’t just dictate when we sleep — it also determines how quickly our muscles heal. A new Northwestern Medicine study in mice, published in Science Advances, suggests that muscle injuries heal faster when they occur during the body’s natural waking hours.

The findings could have implications for shift workers and may also prove useful in understanding the effects of aging and obesity, said senior author Clara Peek, assistant professor of biochemistry and molecular genetics at Northwestern University Feinberg School of Medicine.

The study also may help explain how disruptions like jetlag and daylight saving time changes impact circadian rhythms and muscle recovery.

“In each of our cells, we have genes that form the molecular circadian clock,” Peek said. “These clock genes encode a set of transcription factors that regulate many processes throughout the body and align them with the appropriate time of day. Things like sleep/wake behaviour, metabolism, body temperature and hormones — all these are circadian.”

How the study was conducted

Previous research from the Peek laboratory found that mice regenerated muscle tissues faster when the damage occurred during their normal waking hours. When mice experienced muscle damage during their usual sleeping hours, healing was slowed.

In the current study, Peek and her collaborators sought to better understand how circadian clocks within muscle stem cells govern regeneration depending on the time of day.

For the study, Peek and her collaborators performed single-cell sequencing of injured and uninjured muscles in mice at different times of the day. They found that the time of day influenced inflammatory response levels in stem cells, which signal to neutrophils — the “first responder” innate immune cells in muscle regeneration.

“We discovered that the cells’ signalling to each other was much stronger right after injury when mice were injured during their wake period,” Peek said. “That was an exciting finding and is further evidence that the circadian regulation of muscle regeneration is dictated by this stem cell-immune cell crosstalk.”

The scientists found that the muscle stem cell clock also affected the post-injury production of NAD+, a coenzyme found in all cells that is essential to creating energy in the body and is involved in hundreds of metabolic processes.

Next, using a genetically manipulated mouse model, which boosted NAD+ production specifically in muscle stem cells, the team of scientists found that NAD+ induces inflammatory responses and neutrophil recruitment, promoting muscle regeneration.  

Why it matters

The findings may be especially relevant to understanding the circadian rhythm disruptions that occur in aging and obesity, Peek said.

“Circadian disruptions linked to aging and metabolic syndromes like obesity and diabetes are also associated with diminished muscle regeneration,” Peek said. “Now, we are able to ask: do these circadian disruptions contribute to poorer muscle regeneration capacity in these conditions? How does that interact with the immune system?”

What’s next

Moving forward, Peek and her collaborators hope to identify exactly how NAD+ induces immune responses and how these responses are altered in disease.

“A lot of circadian biology focuses on molecular clocks in individual cell types and in the absence of stress,” Peek said. “We haven’t had the technology to sufficiently look at cell-cell interactions until recently. Trying to understand how different circadian clocks interact in conditions of stress and regeneration, is really an exciting new frontier.”

Source: Northwestern University

Categories : Metabolic Disorders PaediatricsTags :

A Third of Children Worldwide Forecast to be Obese or Overweight by 2050

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AI image created with Gencraft

Obesity rates are set to skyrocket, with one in six children and adolescents worldwide forecast to be obese by 2050, according to a new study. But with significant increases predicted within the next five years, the researchers stress urgent action now could turn the tide on the public health crisis.

The research, led by Murdoch Children’s Research Institute (MCRI) and published in The Lancet, found a third of children and adolescents will be overweight (385 million) or obese (360 million) within the next 25 years. The forecast equates to 356 million children aged 5–14 years and 390 million aged 15–24 years with one in six facing obesity.

The global obesity rate for those between 5-24 years old tripled from 1990 to 2021, rising by 244 per cent to 174 million, suggesting that current approaches to curbing increases in obesity have failed a generation of young people. As of 2021, 493 million children and adolescents were overweight or obese.

MCRI Dr Jessica Kerr said if immediate five-year action plans were not developed, the future was bleak for our youth. 

“Children and adolescents remain a vulnerable population within the obesity epidemic,” she said, adding that obesity drives a whole range of diseases. Prevention is key as obesity rarely resolves after adolescence.

“Despite these findings indicating monumental societal failures and a lack of coordinated global action across the entire developmental window to reduce obesity, our results provide optimism that this trajectory can be avoided if action comes before 2030.”

The analysis, released on World Obesity Day, used the 2021 Global Burden of Diseases, Injuries, and Risk Factors Study to estimate the latest overweight and obesity levels and forecasts in 204 countries and territories.

The United Arab Emirates, Cook Islands, Nauru and Tonga are forecast to have the highest prevalence while China, Egypt, India and the US will have the greatest number of children and adolescents with obesity by 2050.

In Australia, children and adolescents have experienced some of the fastest transitions to obesity in the world. Girls are already more likely to be obese than overweight. Overall, by 2050 for those aged 5-24 years, 2.2 million are forecasted to be obese and 1.6 million overweight.

Globally, there will be more boys, 5–14 years, with obesity than being overweight by 2050.

“Without urgent policy reform, the transition to obesity will be particularly rapid in north Africa, the Middle East, Latin America and in the Caribbean, where the rise is concurrent with high population numbers and limited resources,” Dr Kerr said.

“Many regions have historically had to focus on preventing undernutrition and stunting in children. To prevent a public health emergency from this newer threat, an immediate imperative should be creating national surveillance surveys of obesity in children and adolescents in every country.”

Dr Kerr said older adolescent girls, aged 15-24 years entering their reproductive years, were a priority population for intervention.

“Adolescent girls who are obese are a main focus if we are to avoid intergenerational transmission of obesity, chronic conditions and the dire financial and societal costs across future generations,” she said.

“With this age group increasingly being out of school and cared for by adult services, we need to focus interventions at the community and commercial level.”

Source: Murdoch Childrens Research Institute

Categories : Metabolic DisordersTags :

Mitochondria may Hold the Key to Curing Diabetes

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Cells with nuclei in blue, energy factories in green and the actin cytoskeleton in red. Credit: NIH

A new study has revealed that abnormalities in mitochondria, the powerhouses of the cell, can affect the development and maturation of pancreatic beta cells, eventually leading to them no longer being able to produced. This opens to the door to possibly restoring their function – and reversing the course of type 2 diabetes.

Mitochondrial defects are associated with the development of diseases such as type 2 diabetes. Several studies have shown that insulin-producing pancreatic β-cells of patients with diabetes have abnormal mitochondria and are unable to generate energy. Yet, these studies were unable to explain why the cells behaved this way.

In a study published in Science, University of Michigan researchers used mice to show that dysfunctional mitochondria trigger a response that affects the maturation and function of β-cells.

“We wanted to determine which pathways are important for maintaining proper mitochondrial function,” said first author Emily M. Walker, PhD, a research assistant professor of internal medicine.

To do so, the team damaged three components that are essential for mitochondrial function: their DNA, a pathway used to get rid of damaged mitochondria, and one that maintains a healthy pool of mitochondria in the cell.

“In all three cases, the exact same stress response was turned on, which caused β-cells to become immature, stop making enough insulin, and essentially stop being β-cells,” Walker said. 

“Our results demonstrate that the mitochondria can send signals to the nucleus and change the fate of the cell.”

The researchers also confirmed their findings in human pancreatic islet cells.

Mitochondrial dysfunction affects several types of cells

Their results prompted the team to expand their search into other cells that are affected during diabetes.  

Losing your β-cells is the most direct path to getting type 2 diabetes. Through our study we now have an explanation for what might be happening and how we can intervene and fix the root cause.”

-Scott A. Soleimanpour, M.D.

“Diabetes is a multi-system disease – you gain weight, your liver produces too much sugar and your muscles are affected. That’s why we wanted to look at other tissues as well,” said Scott A. Soleimanpour, M.D., director of the Michigan Diabetes Research Center and senior author of the study.

The team repeated their mouse experiments in liver cells and lipid cells and saw that the same stress response was turned on. Both cell types were unable to mature and function properly.

“Although we haven’t tested all possible cell types, we believe that our results could be applicable to all the different tissues that are affected by diabetes,” Soleimanpour said.

Reversing mitochondrial damage could help cure diabetes

Regardless of the cell type, the researchers found that damage to the mitochondria did not cause cell death. 

This observation brought up the possibility that if they could reverse the damage, the cells would function normally.

To do so, they used a drug called ISRIB that blocked the stress response. They found that after four weeks, the β-cells regained their ability to control glucose levels in mice.

“Losing your β-cells is the most direct path to getting type 2 diabetes. Through our study we now have an explanation for what might be happening and how we can intervene and fix the root cause,” Soleimanpour said.

The team is working on further dissecting the cellular pathways that are disrupted and hope that they will be able to replicate their results in cell samples from diabetic patients.

Source: Michigan Medicine – University of Michigan

Categories : Antibiotics Metabolic DisordersTags :

Diabetes Can Drive the Evolution of Antibiotic Resistance

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Staphylococcus aureus is a leading cause of antibiotic resistance associated infections and deaths. It is also the most prevalent bacterial infection among those with diabetes mellitus, a chronic condition that affects blood sugar control and reduces the body’s ability to fight infections.

Microbiologists at the UNC School of Medicine have just shown that people with diabetes are more likely to develop antibiotic-resistant strains of Staph, too. Their results, which were published in Science Advances, show how the diabetic microbial environment produces resistant mutations, while hinting at ways antibiotic resistance can be combatted in this patient population.

“We found that antibiotic resistance emerges much more rapidly in diabetic models than in non-diabetic models of disease,” said Brian Conlon, PhD, associate professor of immunology. “This interplay between bacteria and diabetes could be a major driver of the rapid evolution and spread of antibiotic resistance that we are seeing.”

 Staph feeds off the high levels of blood glucose in diabetes, allowing it to reproduce more rapidly. The bacterium can also grow without consequence, as diabetes also impairs the immune system’s ability to destroy cells and control infection.

As the numbers of bacteria increase in a diabetic infection, so does the likelihood of resistance. Random mutations appear and some build up resistance to external stressors, like antibiotics. Once a resistant mutant is present in a diabetic infection, it rapidly takes over the population, using the excess glucose to drive its rapid growth.

“Staphylococcus aureus is uniquely suited to take advantage of this diabetic environment,” said Lance Thurlow, PhD, assistant professor of microbiology and immunology. “Once that resistant mutation happens, you have excess glucose and you don’t have the immune system to clear the mutant and it takes over the entire bacterial population in a matter of days.”

Conlon, an expert on antibiotic treatment failure, and Thurlow, an expert on Staph pathogenesis in diabetes, have long been interested in comparing the effectiveness of antibiotics in a model with and without diabetes. Using their connections within the Department of Microbiology and Immunology, the researchers brought their labs together to perform a study with antibiotics in a diabetic mouse model of S. aureus infection.

First, the team prepared a mouse model with bacterial infection in the skin and soft tissue. The mouse models were divided into two groups: one half was given a compound that selectively kills cells in the pancreas, rendering them diabetic, and the other half was not given the compound. Researchers then infected both diabetic and non-diabetic models with S. aureus and treated them with rifampicin, an antibiotic where resistance evolves at a high rate.

After five days of infection, it was time to observe the results.

Conlon and Thurlow were quick to notice that the rifampicin had practically no effect in diabetic models. So, they took some samples to investigate. Researchers were shocked to find that the bacteria had evolved to become resistant to rifampicin, with the infection harboring over a hundred million rifampicin resistant bacteria. There were no rifampicin resistant bacteria in the non-diabetic models.

Their new findings have left Conlon and Thurlow with many questions; however, they are certain that the evolution of antibiotic resistance in people with diabetes could spell trouble for the population at large.

And, even more surprisingly, the mutation had taken over the entire infection in just four days. They next inoculated diabetic and non-diabetic models with Staphylococcus aureus as before, but this time supplemented with a known number of rifampicin resistant bacteria. Again, these bacteria rapidly took over the diabetic infection, but remained as only a sub-population in non-diabetic models after 4 days rifampicin treatment.

Their new findings have left Conlon and Thurlow with many questions; however, they are certain that the evolution of antibiotic resistance in people with diabetes could spell trouble for the population at large. Antibiotic-resistant strains of bacteria spread from person to person in the same ways as other bacteria and viruses do – in the air, on doorknobs, and the food that we eat – which makes preventing these types of infections a major priority.

So, what can be done to prevent it? Well, the Conlon and Thurlow labs showed that reducing blood sugar levels in diabetic models (through administration of insulin) deprived bacteria of their fuel, keeping their numbers at bay, and reducing the chances of antibiotic-resistant mutations from occurring. Their findings suggest that controlling blood sugar through insulin use could be key in preventing antibiotic resistance.

“Resistance and its spread are not only associated with the prescription of drugs, but also the health status of those that are taking antibiotics,” said Conlon. “Controlling blood glucose then becomes really important. When we gave our mice insulin, we were able to bring their blood sugar back to normal and we didn’t get this rapid proliferation of resistant bacteria.”

Now, Conlon and Thurlow are expanding their efforts to study the evolution of resistance in humans (with and without diabetes) and other antibiotic-resistant bacteria of interest, including Enterococcus faecalis, Pseudomonas aeruginosa, and Streptococcus pyogenes. Recognizing how large a role the host plays a role in the evolution of antibiotic resistance, the researchers plan to perform similar studies in patients undergoing chemotherapy and recent transplant recipients to see if those populations are also prone to antibiotic resistant infections.

Source: University of North Carolina Health Care

Categories : Metabolic DisordersTags :

Skeletal Muscle Health Amid Growing use of Weight Loss Medications

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A recent commentary published in The Lancet highlights the critical importance of skeletal muscle mass in the context of medically induced weight loss, particularly with the widespread use of GLP-1 receptor agonists. These medications, celebrated for their effectiveness in treating obesity, have raised concerns regarding the potential for substantial muscle loss as part of the weight loss process. 

Dr Steven Heymsfield, professor of metabolism and body composition, and Dr M. Cristina Gonzalez, adjunct professor in metabolism-body composition, both of Pennington Biomedical Research Center joined colleagues Dr Carla Prado of the University of Alberta, and Dr Stuart Phillips of McMaster University on authoring the commentary, titled “Muscle Matters: The Effects of Medically Induced Weight Loss on Skeletal Muscle.”  

The authors emphasise that muscle loss, as measured by decreases in fat-free mass, can account for 25 to 39% of total weight lost over a period of 36 to 72 weeks. This rate of muscle decline is significantly higher than what is typically observed with non-pharmacological caloric restriction or normal aging and could lead to unintended negative health consequences. 

Despite the promising metabolic benefits associated with GLP-1 receptor agonists, including improvements in fat-to-fat-free tissue ratios, the potential adverse effects of muscle loss are gaining attention. Skeletal muscle plays critical roles not only in physical strength and function but also in metabolic health and immune system regulation.  

A decline in muscle mass has been linked to decreased immunity, increased risk of infections, poor glucose regulation, and other health risks. The authors suggest that muscle loss due to weight reduction may exacerbate conditions like sarcopenic obesity, which is prevalent among individuals with obesity and contributes to poorer health outcomes, including cardiovascular disease and higher mortality rates. 

While the short-term effects of muscle loss on physical strength and function remain unclear, the commentary calls for future research to explore how reductions in muscle mass might improve muscle composition and quality. The authors stress the need for a multimodal approach to weight loss treatment, combining GLP-1 receptor agonists with exercise and nutritional interventions to preserve muscle mass. 

“We have to be mindful of the side effects that we are seeing with the new weight loss medications, such as a person eating less while on the medications and not getting the appropriate amount of dietary vitamins and minerals,” Dr Heymsfield said. “Also, when a person loses weight, they are not only losing fat, they also lose muscle. We are looking at how that muscle loss can be better managed with consumption of an adequate amount of protein along with an optimum amount of exercise.” 

This evolving conversation underscores the importance of ensuring that weight loss interventions promote overall health, including muscle preservation, as part of a comprehensive strategy for treating obesity. 

For more information, please refer to the full commentary in The Lancet at https://www.thelancet.com/journals/landia/article/PIIS2213-8587(24)00272-9/fulltext.  

Source: Pennington Biomedical Research Center

Categories : Metabolic DisordersTags :

Drug may Counteract the Muscle Loss and Osteoporosis after Rapid Weight Loss

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Weight loss medication has taken the world by storm and helped many overweight people. But for some, significant weight loss also comes with a loss of muscle mass and can lead to an increased risk of osteoporosis.

New research now suggests that the monoclonal antibody drug bimagrumab may be able to alleviate some of this risk, says PhD student Frederik Duch Bromer and postdoc Andreas Lodberg from the Department of Biomedicine at Aarhus University, who are behind the study published in the Journal of Cachexia, Sarcopenia and Muscle.

“We are the first to study how certain drugs affect bones, and the results show that bimagrumab can increase the amount of bone tissue while building muscle mass, and this could be very important for the many people currently taking weight loss medication.”

Bimagrumab was originally developed to treat muscle loss and dysfunction, but since then, it has beome apparent that it also has a fat “burning” component to it. So, if approved, it could be part of a second-generation weight loss drug on the market.

Therefore, it’s relevant to research how this particular patient group reacts to the drug,” says Andreas Lodberg.

“An estimated two billion people will be categorised as overweight by 2035, so it’s also important that we research the drugs that come on the market for this particular patient group in order to better understand their long-term impact on the body.”

Osteoporosis can prove costly for patients and society

Patients on weight loss medication often have a history of weight fluctuation, which can contribute to the development of osteoporosis. Brittle bones increase the risk of serious fractures, and this is costly for both patients and society.

Therefore, the research results could be good news for patients on weight loss medication. And according to Frederik Duch Bromer, the study shows that bimagrumab not only counteracts the breakdown of bone and muscle tissue, it actually promotes the build-up of both.

“Bimagrumab slightly increases the calcium content in bones and promotes the formation of new bone in what we call the shell (cortex) of the long bones. We also saw a significant build-up of bone tissue in the area around the femoral head, which is typically where many older people incur fractures.”

According to Frederik Duch Bromer, the results also showed that bimagrumab has no effect on the blood. Similar drugs have previously been shown to increase red blood cell production, increasing the risk of blood clots.

The study is based on mice with both osteoporosis and reduced muscle mass, and the drug is now being tested in several phase 2 clinical trials. Andreas Lodberg emphasises that more research is needed.

“Our study shows that bimagrumab has a positive effect in many areas, but we also have indications that the drug may have other side effects, and we’ll now investigate this further to get a clearer picture of the implications of using the drug for patients.”

Andreas Lodberg and Frederik Duch Bromer hope to be able to continue with further research to investigate both the positive results and possible side effects.

Source: Aarhus University

Categories : Cardiovascular Disease Metabolic DisordersTags :

Research Reveals New Insights into how LDL Cholesterol Works in the Body

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Image by Scientific Animations, CC4.0

National Institute of Health (NIH) scientists have made a significant breakthrough in understanding how “bad” cholesterol, known as low-density lipoprotein-cholesterol or LDL-C, builds up in the body. The researchers were able to show for the first time how the main structural protein of LDL binds to its receptor – a process that starts the clearing of LDL from the blood – and what happens when that process gets impaired.

The findings, published in Nature, further the understanding of how LDL contributes to heart disease, the world’s leading cause of death, and could open the door to personalising LDL-lowering treatments like statins to make them even more effective.

“LDL is one of the main drivers of cardiovascular disease which kills one person every 33 seconds, so if you want to understand your enemy, you want to know what it looks like,” said Alan Remaley, MD, PhD, co-senior author on the study who runs the Lipoprotein Metabolism Laboratory at NIH’s National Heart, Lung, and Blood Institute.

Until now scientists have been unable to visualise the structure of LDL, specifically what happens when it links up with its receptor, a protein known as LDLR. Typically, when LDL binds to LDLR, the process of clearing LDL from the blood begins. But genetic mutations can prevent that work, causing LDL to build up in the blood and get deposited into the arteries as plaque, which can lead to atherosclerosis, a precursor for heart disease.

In the new study, the researchers were able to use high-end technology to get a view of what’s happening at a critical stage of that process and see LDL in a new light.

“LDL is enormous and varies in size, making it very complex,” explained Joseph Marcotrigiano, PhD, chief of the Structural Virology Section in the Laboratory of Infectious Diseases at NIH’s National Institute of Allergy and Infectious Diseases and co-senior author on the study. “No one’s ever gotten to the resolution we have. We could see so much detail and start to tease apart how it works in the body.”

Using cryo-electron microscopy, the researchers were able to see the entirety of the structural protein of LDL when it bound to LDLR. Then, with AI-driven protein prediction software, they were able to model the structure and locate the known genetic mutations that result in increased LDL.

The researchers found that many of the mutations that mapped to the location where LDL and LDLR connected, were associated with familial hypercholesterolaemia (FH). FH is marked by defects in how the body uptakes LDL into its cells, and people with it have extremely high levels of LDL and can have heart attacks at a very young age. They found that FH-associated variants tended to cluster in particular regions on LDL.

The study findings could open new avenues to develop targeted therapies aimed at correcting these kinds of dysfunctional interactions caused by mutations. But, as importantly, the researchers said, they could also help people who do not have genetic mutations, but who have high cholesterol and are on statins, which lower LDL by increasing LDLR in cells. By knowing precisely where and how LDLR binds to LDL, the researchers say they may now be able to target those connection points to design new drugs for lowering LDL from the blood.

Source: NIH/National Heart, Lung and Blood Institute

Categories : Metabolic DisordersTags :

Why do Some People with Obesity Remain Healthy?

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Source: Pixabay CC0

Although obese individuals are at greater risk of diabetes, high blood pressure or high cholesterol, not all obese people develop metabolic diseases of this kind. With around a quarter of all obese individuals are healthy, scientists are trying to work out why some obese people become unhealthy while others do not.

Now, a comprehensive study by researchers from Zurich and Leipzig has provided a vital basis for this work. Specifically, the researchers have produced a detailed atlas with data from healthy and unhealthy overweight people, on their fat (adipose) tissue, and on the gene activity in this tissue’s cells. “Our results can be used to look for cellular markers that provide information on the risk of developing metabolic diseases,” explains Adhideb Ghosh, a researcher in ETH Professor Christian Wolfrum’s group and one of the two lead authors of the study. “The data is also of great interest for basic research. It could help us develop new therapies for metabolic diseases.”

The study appears in Cell Metabolism.

Investigating a large biobank

For this study, Ghosh and his colleagues used the Leipzig Obesity Biobank, an extensive collection of biopsies taken from obese individuals. Compiled by scientists from the University of Leipzig, these samples originate from obese patients who underwent elective surgery and consented to the collection of adipose tissue samples for research purposes. The collection also includes extensive medical information on the patients’ health.

Since the tissue samples were all taken from obese individuals with or without metabolic diseases, they allow comparison between individuals with healthy and unhealthy obesity. In samples from 70 volunteers, the researchers at ETH Zurich examined which genes were active, and to what extent, on a cell-by-cell basis for two types of adipose tissue: subcutaneous and visceral.

Scientists and medical experts assume that visceral fat, which lies deep in the abdominal cavity and surrounds the internal organs, is primarily responsible for metabolic diseases. By contrast, experts generally believe that fat located directly beneath the skin is less problematic.

For the study, it was vital that the adipose tissue cells were not all simply lumped together, as this tissue comprises not only fat cells (adipocytes) but also cells of other types. “In fact, the adipocytes are in the minority,” explains lead author Isabel Reinisch, a postdoc in Wolfrum’s group. A large part of adipose tissue is made up of immune cells, cells that form blood vessels, and immature precursor cells of adipocytes. Another cell type, known as mesothelial cells, are found only in visceral adipose tissue and mark its outer boundary.

Abdominal fat remodelled – and gender differences

As the researchers were able to show, there are significant functional changes in cells in the visceral adipose tissue of people with metabolic diseases. This remodelling affects almost every cell type in this form of tissue. For example, the genetic analyses showed that the adipocytes of unhealthy individuals could no longer burn fats as effectively and instead produced greater quantities of immunologic messenger molecules. “These substances trigger an immune response in the visceral fat of obese people,” explains Reinisch. “It’s conceivable that this response promotes the development of metabolic diseases.”

The researchers also found very clear differences in the number and function of mesothelial cells: in healthy obese individuals, there is a far greater proportion of mesothelial cells in the visceral fat and these cells exhibit greater functional flexibility. Specifically, the cells can switch into a sort of stem cell mode and therefore convert into different cell types, such as adipocytes, in healthy individuals. “The ability of fully differentiated cells to convert into stem cells is otherwise primarily associated with cancer,” says Reinisch. She was surprised, therefore, to find this ability in adipose tissue as well. “We suspect that the flexible cells at the edge of the adipose tissue in healthy obese individuals facilitate smooth tissue expansion.”

Finally, the researchers also found differences between men and women: a certain type of progenitor cell is present only in the visceral fat of women. “This could explain differences in the development of metabolic diseases between men and women,” says Reinisch.

Finding new biomarkers

The new atlas of gene activity in overweight people describes the composition of cell types in adipose tissue and their function. “However, we cannot say whether the differences are the reason why someone is metabolically healthy or whether, conversely, metabolic diseases cause these differences,” says Ghosh. Instead, the scientists view their work as providing the basis for further research. They have published all the data in a publicly accessible web app so that it is available for other researchers to work with.

In particular, this atlas now makes it possible to find new markers that provide information on the risk of developing a metabolic disease. At present, the ETH researchers are also looking for these kinds of markers, which could help to improve the treatment of such diseases. For example, there is a new class of drugs that suppress the appetite and promote insulin release in the pancreas – but these medications are in short supply. “Biomarkers that can be derived from our data could help to identify those patients who are most in need of this treatment,” says Reinisch.

Source: ETH Zurich

Categories : Metabolic DisordersTags :

Study Identifies Risk Factors in Heavy Drinkers for Advanced Liver Disease

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A new study finds that heavy drinkers with either diabetes, high blood pressure or a high waist circumference are as much as twice as likely to develop advanced liver disease.

The answer may lie in three common underlying medical conditions, according to a new study published in Clinical Gastroenterology and Hepatology from Keck Medicine of USC. The research found that heavy drinkers with either diabetes, high blood pressure or a high waist circumference are as much as 2.4 times more likely to develop advanced liver disease.  

“The results identify a very high-risk segment of the population prone to liver disease and suggest that preexisting health issues may have a large impact on how alcohol affects the liver,” said Brian P. Lee, MD, MAS, a hepatologist and liver transplant specialist with Keck Medicine and principal investigator of the study. 

Diabetes, high blood pressure and a high waist circumference (89cm for women; 101cm for men), which is associated with obesity, belong to a cluster of five health conditions that influence an individual’s risk for heart attack and stroke known as cardiometabolic risk factors.  

Cardiometabolic risk factors have been linked to the buildup of fat in the liver (also known as metabolic dysfunction-associated steatotic liver disease), which can lead to fibrosis, or scarring of the liver. These risk factors affect more than one in three Americans, and cardiometabolic health has been worsening among the population, especially among those under 35, according to Lee.  

Alcohol also causes fat buildup in the liver, and alcohol consumption has been on the rise since the COVID-19 pandemic, said Lee. Due to the prevalence of both cardiometabolic risk factors and drinking in the United States, Lee and his fellow researchers undertook the study to investigate which cardiometabolic risk factors predisposed the liver to damage from alcohol. 

They analysed data from the National Health and Nutrition Examination Survey, a large national survey of more than 40 000 participants, looking at the intersection of heavy drinking, individual cardiometabolic risk factors and the incidences of significant liver fibrosis. Significant liver fibrosis refers to liver scarring that can lead to liver failure.  

For the study, heavy drinking was characterised as 1.5 drinks a day for women (20 grams) and two drinks a day for men (30 grams). 

Researchers discovered that heavy drinkers with either diabetes or a high waist circumference were 2.4 times more likely to develop advanced liver disease and those with high blood pressure 1.8 times more likely. They found that the other two cardiometabolic risk factors – high triglycerides and low HDL (high-density lipoprotein) had less significant correlations to liver disease.  

While the study did not analyse why these three cardiometabolic risk factors are more dangerous for the liver, Lee speculates that these conditions share a common pathway to fat buildup in the liver that when combined with extra fat deposits in the liver from excessive alcohol, can cause significant damage.  

Lee stresses that the study does not imply it is safe for those without these three cardiometabolic risks to consume large amounts of alcohol. “We know that alcohol is toxic to the liver and all heavy drinkers are at risk for advanced liver disease,” he said.  

Lee hopes that the study results will encourage people to consider their individual health and risk profile when making decisions about alcohol consumption. He would also like to see practitioners offer more personalized health screenings and interventions for those who drink with cardiometabolic risk factors so that liver damage among this high-risk group can be caught early and treated.  

Source: University of Southern California – Health Sciences

Categories : Mental Health Metabolic DisordersTags :

What’s the Mechanism behind Behavioural Side Effects of GLP1RAs?

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Glucagon-like peptide 1 receptor agonists (GLP1RA) – medications for type 2 diabetes and obesity that have recently been making headlines due to a rise in popularity as weight loss agents – have been linked with behavioural side effects. A large population-based analysis in Diabetes, Obesity and Metabolism assessed whether certain genetic variants might help explain these effects.

GLP1RA mimic the GLP-1 hormone in the body that helps control insulin and blood glucose levels and promotes feelings of satiety. GLP-1 binds to GLP1R on cells in the brain and pancreas.

Observational and epidemiological studies have shown that there may be neutral or protective effects of GLP1RAs on mental health symptoms. However, a study based on individuals taking GLP1RA suggests there is increased prescription of anti-depressants when used for treatment of diabetes. Early evidence in animal models suggest GLP1RA may decrease depressive and anxious symptoms, potentially presenting new treatment pathways; however, comparing these studies to human clinical evidence will not be possible for some time.

For the analysis, investigators examined common genetic variants in the GLP1R gene in 408 774 white British, 50 314 white European, 7 667 South Asian, 10 437 multiple ancestry, and 7641 African-Caribbean individuals.

Variants in the GLP1R gene had consistent associations with cardiometabolic traits (body mass index, blood pressure, and type 2 diabetes) across ancestries. GLP1R variants were also linked with risk-taking behavior, mood instability, chronic pain, and anxiety in most ancestries, but the results were less consistent. The genetic variants influencing cardiometabolic traits were separate from those influencing behavioral changes and separate from those influencing expression levels of the GLP1R gene.

The findings suggest that any observed behavioral changes with GLP1RA are likely not acting directly through GLP1R.

“Whilst it is not possible to directly compare genetic findings to the effects of a drug, our results suggest that behavioural changes are unlikely to be a direct result of the GLPRAs. Exactly how these indirect effects are occurring is currently unclear,” said corresponding author Rona J. Strawbridge, PhD, of the University of Glasgow, in the UK.

Source: Wiley