Category: Metabolic Disorders

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A Single Gene Causes Mitochondria to ‘Fragment’ in Obesity

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These coloured streaks are mitochondrial networks within fat cells. Researchers from UC San Diego discovered that a high-fat diet dismantles mitochondria, resulting in weight gain. Credit: UC San Diego

While lifestyle factors like diet and exercise play a role in the development and progression of obesity, scientists have come to understand that obesity is also associated with intrinsic metabolic abnormalities. Now, researchers from University of California San Diego School of Medicine have shed new light on how obesity affects our mitochondria, the all-important energy-producing structures of our cells.

In a study published January 29, 2023 in Nature Metabolism, the researchers found that when mice were fed a high-fat diet, mitochondria within their fat cells broke apart into smaller mitochondria with reduced capacity for burning fat. Further, they discovered that this process is controlled by a single gene. By deleting this gene from the mice, they were able to protect them from excess weight gain, even when they ate the same high-fat diet as other mice.

“Caloric overload from overeating can lead to weight gain and also triggers a metabolic cascade that reduces energy burning, making obesity even worse,” said Alan Saltiel, PhD, professor in the Department of Medicine at UC San Diego School of Medicine. “The gene we identified is a critical part of that transition from healthy weight to obesity.”

Obesity occurs when the body accumulates too much fat, which is primarily stored in adipose tissue. Adipose tissue normally provides important mechanical benefits by cushioning vital organs and providing insulation. It also has important metabolic functions, such as releasing hormones and other cellular signaling molecules that instruct other tissues to burn or store energy.

In the case of caloric imbalances like obesity, the ability of fat cells to burn energy starts to fail, which is one reason why it can be difficult for people with obesity to lose weight. How these metabolic abnormalities start is among the biggest mysteries surrounding obesity.

To answer this question, the researchers fed mice a high-fat diet and measured the impact of this diet on their fat cells’ mitochondria, structures within cells that help burn fat. They discovered an unusual phenomenon. After consuming a high-fat diet, mitochondria in parts of the mice’s adipose tissue underwent fragmentation, splitting into many smaller, ineffective mitochondria that burned less fat.

In addition to discovering this metabolic effect, they also discovered that it is driven by the activity of single molecule, called RaIA. RaIA has many functions, including helping break down mitochondria when they malfunction. The new research suggests that when this molecule is overactive, it interferes with the normal functioning of mitochondria, triggering the metabolic issues associated with obesity.

“In essence, chronic activation of RaIA appears to play a critical role in suppressing energy expenditure in obese adipose tissue,” said Saltiel. “By understanding this mechanism, we’re one step closer to developing targeted therapies that could address weight gain and associated metabolic dysfunctions by increasing fat burning.”

By deleting the gene associated with RaIA, the researchers were able to protect the mice against diet-induced weight gain. Delving deeper into the biochemistry at play, the researchers found that some of the proteins affected by RaIA in mice are analogous to human proteins that are associated with obesity and insulin resistance, suggesting that similar mechanisms may be driving human obesity.

“The direct comparison between the fundamental biology we’ve discovered and real clinical outcomes underscores the relevance of the findings to humans and suggests we may be able to help treat or prevent obesity by targeting the RaIA pathway with new therapies,” said Saltiel “We’re only just beginning to understand the complex metabolism of this disease, but the future possibilities are exciting.”

Source: EurekAlert!

Categories : Diseases, Syndromes and Conditions Metabolic DisordersTags :

GLP-1 Agonists Associated with Reduced Risk of Liver Diseases

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

GLP1 agonists such as Ozempic (semaglutide) are associated with a reduced risk of developing cirrhosis and liver cancer in people with type 2 diabetes and chronic liver disease, according to a nationwide study from Karolinska Institutet published in the journal Gut.

GLP1 agonists reduce blood sugar levels and are mainly used to treat type 2 diabetes. Since the drug also reduces appetite, it is now increasingly used to treat obesity and has become a popular weight-loss drug.

Reduced risk of liver damage

Results from early clinical trials also suggest that GLP1 agonists may reduce the risk of liver damage. Therefore, researchers at Karolinska Institutet included all people in Sweden with chronic liver disease and type 2 diabetes in a register-based study. They then compared the risk of severe liver damage in those who were treated with GLP1 agonists and those who were not. The results show that those who took the drug for a long period of time had a lower risk of later developing more severe forms of liver disease such as cirrhosis and liver cancer.

According to the researchers, this suggests that GLP1 agonists could be an effective treatment to avoid severe liver disease in people with concurrent type 2 diabetes.

“Fatty liver disease is estimated to affect up to one in five people in Sweden, many of whom have type 2 diabetes, and about one in twenty develop severe liver disease,” says first author Axel Wester, assistant professor at the Department of Medicine, Huddinge, Karolinska Institutet. “Our findings are interesting because there are currently no approved drugs to reduce this risk.”

Many of the people in the study stopped taking GLP1 agonists, resulting in a lack of protective effect. However, those who continued taking their medication over a ten-year period were half as likely to develop severe liver disease.

Clinical trials needed for confirmation

“The results need to be confirmed in clinical trials, but it will take many years for these studies to be completed,” says Axel Wester. “Therefore, we use existing registry data to try to say something about the effect of the drugs before that.”

A limitation of the method is that it is not possible to control for factors for which there is no data, such as blood tests to describe the severity of liver disease in more detail. However, the researchers have recently built a new database called HERALD where they have access to blood samples from patients in Region Stockholm.

“As a next step, we will investigate the effect of GLP1 agonists in this database,” says the study’s last author Hannes Hagström, consultant in hepatology at the Karolinska University Hospital and adjunct professor at the Department of Medicine, Huddinge, Karolinska Institutet. “If we get similar results, it would further strengthen the hypothesis that GLP1 agonists can be used to reduce the risk of severe liver disease.”

The research was mainly funded by Region Stockholm (CIMED), the Swedish Research Council and the Swedish Cancer Society. Hannes Hagström’s research group has received funding from Astra Zeneca, EchoSens, Gilead, Intercept, MSD, Novo Nordisk and Pfizer, although no industry-supported funding was obtained for this specific study.

Source: Karolinska Institutet

Categories : Metabolic DisordersTags :

Few Patients Successfully Treat their Type 2 Diabetes Through Weight Loss

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People with the most weight loss in the first year were most likely to achieve sustained remission

Photo by Andres Ayrton on Pexels

A new study finds that very few patients diagnosed with type 2 diabetes are able to achieve normal blood glucose levels through weight loss alone. A team led by Andrea Luk of the Chinese University of Hong Kong, report these findings January 23rd in the open access journal PLOS Medicine.

Clinical trials suggest that people with type 2 diabetes can control their blood glucose levels without medication if they lose weight and keep it off. However, it is unknown how many patients can achieve remission through weight loss alone under real-world conditions. In the new study, researchers looked at 37 326 people in Hong Kong who were newly diagnosed with type 2 diabetes to see whether – and low long – patients could control the disease through weight loss.

The researchers discovered that only 6% of people achieved diabetes remission solely through weight loss by about eight years after diagnosis. For people who initially achieved remission, two-thirds had elevated blood glucose levels by three years after diagnosis. These rates are significantly lower than in clinical trials, where remission occurred in up to 73% of patients at one year post-diagnosis. People with the greatest weight loss in the first year were most likely to have sustained remission.

The study shows that controlling type 2 diabetes through sustained weight loss is possible in real-world settings, but that few patients will achieve normal blood glucose levels through weight management alone, especially over the long-term. One reason for the discrepancy with clinical trials is that trial participants receive intensive lifestyle interventions, including holistic support for dietary changes, physical exercise and mental health. The researchers conclude that patients should receive early weight management interventions as a way to increase the odds that they will achieve sustained remission. Furthermore, the data suggest that early weight management interventions increase the odds of sustained remission and that sustained lifestyle changes are likely to be paramount.

Luk adds, “Greater weight loss within the first year of diabetes diagnosis was associated with an increased likelihood of achieving diabetes remission. However, the incidence of diabetes remission was low with only 6% of people achieving remission over 8 years, and half of those with initial remission returned to hyperglycaemia within 3 years indicating poor sustainability of diabetes remission in real-world setting.”

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New Nanoparticle-based Oral Insulin could be Ready for Human Trials Next Year

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Photo by Nataliya Vaitkevich on Pexels

Scientists have developed a ‘smart’ insulin which can be taken orally. The insulin is encapsulated within tiny nano-carriers, 1/10 000th the width of a human hair. The results of its testing in baboons were recently published in Nature Nanotechnology.

“This way of taking insulin is more precise because it delivers the insulin rapidly to the areas of the body that need it most. When you take insulin with a syringe, it is spread throughout the body where it can cause unwanted side effects,” explains Professor Peter McCourt at UiT Norway’s Arctic University. He is one of the researchers behind the study.

Delivered insulin to where it’s needed

It was researchers at the University of Sydney and Sydney Local Health District who, in collaboration with UiT, discovered many years ago that it was possible to deliver medicines via nano-carriers to liver. The method has then been further developed in Australia and in Europe.

Many medicines can be taken orally, but until now people have had to inject insulin into the body. McCourt explains that the problem with insulin with a nano-carrier is that it breaks down in the stomach and thus does not get to where it is needed in the body. This has been a major challenge for developing a diabetes medicine that can be taken orally.

But now the researchers have solved this challenge.

“We have created a coating to protect the insulin from being broken down by stomach acid and digestive enzymes on its way through the digestive system, keeping it safe until it reaches its destination, namely the liver,” says McCourt, who is a liver biologist.

The coating is then broken down in the liver by enzymes that are active only when the blood sugar levels are high, releasing the insulin where it can then act in the liver, muscle, and fat to remove sugar from the blood.

“This means that when blood sugar is high, there is a rapid release of insulin, and even more importantly, when blood sugar is low, no insulin is released,” says Nicholas J. Hunt at the University of Sydney who, together with Victoria Cogger, leads the project.

He explains that this is a more practical and patient-friendly method of managing diabetes because it greatly reduces the risk of a low blood sugar event occurring, namely hypoglycaemia and allows for the controlled released of insulin depending on the patient’s needs, unlike injections where all the insulin is released in one shot.

Fewer side effects

The new method works similarly to how insulin works in healthy people. The pancreas produces insulin which first passes through the liver where a large portion of it is absorbed and maintains stable blood sugar levels. In the new insulin method, the nano-carrier releases insulin in the liver, where it can be taken up or enter the blood to circulate in the body.

When insulin is injected subcutaneously, far more of it goes to the muscles and to adipose tissues that would normally happen if it was released from the pancreas, which can lead to fat accumulation. It can also lead to hypoglycaemia.

With the new method, there will be fewer such side effects, and no need for injection – or refrigeration.

Tested on baboons

The oral insulin has been tested on nematodes, on mice and rats. And lastly, the medicine has now been tested on baboons in the National Baboon Colony in Australia.

“In order to make the oral insulin palatable we incorporated it into sugar-free chocolate, this approach was well received” says Hunt.

He says that 20 baboons have taken part in this study. When they received the medicine, their blood sugar was lowered.

The baboons were normal, healthy baboons, but the oral insulin have also been tested on mice and rats that actually have diabetes. The mice and rats did not have hypoglycaemic events, gain weight or fat accumulation in the liver overcoming current challenges with injectable and other oral insulins.

What remains now is to test the new method on humans.

Ready for use in 2-3 years

“Trials on humans will start in 2025 led by the spin out company Endo Axiom Pty Ltd. Clinical trials are performed in 3 phases; in the phase I trial we will investigate the safety of the oral insulin and critically look at the incidence of hypoglycaemia in healthy and type 1 diabetic patients. Our team is very excited to see if we can reproduce the absent hypoglycaemia results seen in baboons in humans as this would be a huge step forward. The experiments follow strict quality requirements and must be carried out in collaboration with physicians to ensure that they are safe for the test subjects” says Hunt.

Source: UiT The Arctic University of Norway

Categories : Exercise Metabolic DisordersTags :

Benefits of Adolescent Fitness to Future Cardiovascular Health Possibly Overestimated

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There is a well-known relationship between good physical fitness at a young age and a lower risk of cardiovascular disease later in life. But when researchers adjusted for familial factors by means of sibling analysis, they found a weaker association, although the link between high body mass index (BMI) and cardiovascular disease remained strong. The study, which was conducted by researchers from Karolinska Institutet and other universities, is published in JAMA Network Open.

“This does not mean that fitness is irrelevant,” cautions the study’s last author Viktor Ahlqvist, doctoral student at the Department of Global Public Health, Karolinska Institutet. “We could still see an association, although it was weaker after taking into account factors shared by full siblings. We also think that adolescence is an important time in life for establishing good habits such as exercising and having a healthy diet.”

Many observational studies have previously demonstrated links between various risk factors at a young age and cardiovascular disease in adulthood. However, whether the associations are causal is challenging to prove because of the potential influence of unaccounted genetic and environmental factors. A collaborative team including researchers from Karolinska Institutet in Sweden has therefore tried to examine if a large proportion of cardiovascular diseases in adulthood could indeed be prevented with a lower BMI, lower blood pressure, improved physical fitness or improved muscle strength in adolescence.

Data from the Military Conscription Register

Sourcing data from the Swedish Military Conscription Register and other Swedish registries, the researchers identified over a million 18-year-old males and followed them for 60 years. Almost half of them were full brothers.

“The strength of our study, which makes it more reliable than many other conventional observational studies, is that we have used sibling analyses,” says the study’s first author Marcel Ballin, researcher at Uppsala University and analyst at Region Stockholm’s Centre for Epidemiology and Community Medicine. “By doing so we could examine how the relationship changes when controlling for all shared sibling factors. This includes environmental factors such as childhood environment and half of the genetics.”

The results show that a high BMI in late adolescence was strongly associated with future cardiovascular disease, even after the researchers had controlled for shared familial factors. However, the association between physical fitness and cardiovascular disease was considerably weaker in the sibling analysis, suggesting that many previous observational studies might have overestimated the relevance of adolescent fitness to cardiovascular health later in life.

High BMI the strongest risk factor

“Our conclusion is that of the risk factors studied, high BMI is the strongest individual risk factor for cardiovascular disease, and that efforts to tackle the obesity epidemic should continue to be given high priority,” says co-author Daniel Berglind, docent at the Department of Global Public Health, Karolinska Institutet. “A good level of fitness and muscle strength in adolescence doesn’t seem as crucial, but physical activity still remains important for public health, as it can bring other health benefits.”

The study examined the association between risk factors at a young age and future cardiovascular disease; other disease outcomes were not investigated. The researchers had no data on whether the participants’ risk factors varied later in life, and they only studied men, which makes it difficult to extend their findings to women. The Military Conscription Register also lacks details on certain risk factors for future cardiovascular disease, such as diet, alcohol consumption, smoking, blood lipids and blood glucose.

The researchers received no specific grant for this study. Co-author Martin Neovius is on the advisory panels for Ethicon, Johnson & Johnson and Itrim and has been a consultant for the Swedish armed forces outside the scope of this study. No other conflicts of interest have been reported.

Source: Karolinska Institutet

Categories : Metabolic DisordersTags :

In Type 2 Diabetics, Toxic Lipids and a Beneficial One Surge at Certain Times

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Credit: Cell Reports Medicine (2023).

While sugar is most frequently blamed in the development of type 2 diabetes, a better understanding of the role of fats is also essential. By analysing the blood profiles of dozens of people suffering from diabetes or pre-diabetes, or who have had their pancreas partially removed, researchers at the University of Geneva (UNIGE) and Geneva University Hospitals (HUG) have made two major discoveries.

Firstly, the lipid composition of blood and adipose tissues fluctuates during the day, and is altered in a day-time dependent manner in diabetics, who have higher levels of toxic lipids. In addition, one type of lipid, lysoPI, is capable of boosting insulin secretion when the beta cells that normally produce it fail. These results, published in the journals Cell Reports Medicine and Diabetes, may have important implications for the treatment of diabetic patients.

The role of lipids in the physiological and pathological processes of human metabolism is gradually becoming clearer, particularly in type 2 diabetes, one of the most widespread serious metabolic disorders. Thanks to cutting-edge tools, in particular mass spectrometry, researchers are now able to simultaneously measure the levels of several hundred different types of lipids, each with its own specific characteristics and beneficial or harmful effects on our metabolism.

‘‘Identifying which lipids are most present in type 2 diabetics could provide a basis for a wide range of interventions: early detection, prevention, potential therapeutic targets or personalised recommendations – the possibilities are immense,’’ says Charna Dibner, a professor in the Department of Surgery and a specialist in circadian rhythms in metabolic disorders, . ‘‘This is why we carried out a detailed analysis of the blood profiles of patients recruited in four European countries and confirmed some of our results on a mouse model of the disease.’’

Dibner led the studies along with Pierre Maechler, a professor in the Department of Cell Physiology and Metabolism, at the UNIGE Faculty of Medicine, and members of the Diabetes Faculty Centre.

Chronobiology to better identify diabetes

The team carried out a ‘‘lipidomic’’ analysis of two groups of patients in order to establish the profile, over a 24-hour cycle, of multiple lipids present in the blood and adipose tissues. ‘‘The differences between the lipid profiles of type 2 diabetics and people without diabetes are particularly pronounced in the early morning, when there is an increase in certain toxic lipids,’’ explains Dibner. ‘‘Why? We don’t know yet. But this could be a marker of the severity of diabetes and paves the way for personalised care according to each patient’s specific chronotype.”

And implications go beyond diabetes: if samples are taken at very different times of the day, the results can be distorted and give contradictory results. ‘‘It’s the same thing in the clinic: an examination carried out in the morning or evening, or a treatment taken at different times, can have an impact on diagnosis and even on the effectiveness of treatments.’’

A crutch for beta cells

Charna Dibner and Pierre Maechler extended their lipidomic analyses to include not only people with type 2 diabetes but also a mouse model of pre-diabetes and patients who had lost around half their insulin-producing beta cells after a surgery. ‘‘We discovered that a type of lipid, lysoPIs, increases when there is a sharp decrease in functional β cells, even before the onset of clinical symptoms of diabetes.’’

The scientists then administered lysoPI to diabetic mice and observed an increase in insulin production. ‘‘The same phenomenon occurred in vitro, on pancreatic cells from diabetic patients,’’ adds Pierre Maechler. ‘‘The lysoPIs therefore have the capacity to reinforce insulin secretion by acting as a crutch when the number of beta cells decreases or when these cells malfunction. Yet, certain foods, such as legumes, naturally contain lysoPI precursors.’’

By bringing to light the unsuspected role of lysoPIs, researchers will be able to explore new avenues opened by their discoveries. The development of dietary supplements or even molecules specific to lysoPI receptors could be an interesting strategy for controlling diabetes, as could taking better account of the chronobiological profiles of patients. Diabetes is a complex disease that calls for much more personalised management than is currently the case.

Source: University of Geneva

Categories : Metabolic DisordersTags :

GLP-1 Agonist Users Report Reduced Alcohol Cravings

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In social media posts on the community network Reddit, users reported reduced cravings for alcohol when taking drugs intended to treat Type 2 diabetes and obesity. Across a number of threads – with titles such as “Did scientists accidentally invent an anti-addiction drug?” and “I don’t know if this is a side effect but … Mounjaro makes me drink less!!!!!” – users reported a changing relationship with beer, wine, and liquor.

An analysis of those posts, together with a remote study of individuals with obesity who reported using semaglutide and tirzepatide, found that the drugs decreased cravings and reduced alcohol consumption, according to a study by Virginia Tech researchers published in Scientific Reports.

“These findings add to a growing literature that these medications may curb dangerous drinking habits,” said Warren Bickel, Virginia Tech Carilion Behavioral Health Research Professor at the Fralin Biomedical Research Institute at VTC and corresponding author.

Combing Reddit for users’ experiences

Scientists with the Fralin Biomedical Research Institute’s Addiction Recovery Research Center combined two different studies to build on existing research, including studies that showed the drugs were effective in reducing alcohol consumption in animal models.

The first was an analysis of more than 68 000 Reddit posts from 2009-23 that included terms linked to GLP-1 approved medications.

Semaglutide is a GLP-1 agonist, a class of drugs that reduce blood sugar and energy intake by mimicking the actions of hormones released after eating.

Among the keywords included in the search were Mounjaro, Wegovy, Ozempic, and Trulicity.

After cleaning the resulting data – such as eliminating comments with fewer than 100 characters – the set was narrowed to 33 609 posts from 14 595 unique users.

The study was unique in using Reddit to analyse the reported experience of thousands of users.

On examining alcohol-related discussions, researchers found that 962 individuals made 1580 alcohol-related posts.

Of those, 71.7% addressed reduced cravings, reduced usage, and other negative effects due to drinking.

In a second study, 153 participants who self-reported having obesity were recruited from various social media platforms.

Roughly a third of these participants represented the control group, a third were taking either a semaglutide injection or tablet, and a third were using tirzepatide.

Participants on semaglutide or tirzepatide reported drinking significantly fewer drinks, on average, than those in the control group who were not on any medication for diabetes or weight loss.

In addition, researchers found that both the average number of drinks and the odds of binge drinking were found to be significantly lower.

Results also found that the stimulative and sedative effects of alcohol intoxication are reduced when taking these medications.

“Participants reported drinking less, experienced fewer effects of alcohol when they did drink it, and decreased odds of binge drinking,” said Alexandra DiFeliceantonio, assistant professor at Fralin Biomedical Research Institute and one of the study’s co-authors.

Researchers believe theirs is the first published report following tirezepatide, sold under the brand name Mounjaro, which was approved in 2022 and is used for treatment of Type 2 diabetes and weight loss.

Why this matters

Case studies and reports in the popular press hint at the drugs’ unexpected side effect of reducing addictive behaviors, including the desire to consume alcohol.

The US Food and Drug Administration has approved only three medications to treat alcohol use disorder: disulfiram, naltrexone, and acamprosate.

They have shown only modest success, have poor compliance, and are underprescribed.

The authors suggest further randomized controlled trials to explore the therapeutic potential of GLP-1 agonists and GIP/GLP-1 combination drugs to treat alcohol use disorder, which affects 5.9% of individuals in the United States ages 12 and older.

In addition, the participants identified as mostly white and female, and further studies in more diverse populations are needed to examine sex and race differences.

“Although evidence supporting the use of these medications for alcohol use disorder is growing, the field still needs to learn considerably more about them, particularly in identifying the underlying mechanisms. We plan to contribute to that effort,” Bickel said.

The drugs are a promising development in the study of alcohol use disorder. Data from the National Survey on Drug Use and Health indicate 15.7 million people in the United States meet the criteria for the chronic, relapsing brain disorder that is a significant contributor to global mortality yet remains one of the most undertreated conditions, Bickel said.

Source: Virginia Tech

Categories : Metabolic DisordersTags :

Liraglutide Results in Increased Insulin Sensitivity Independent of Weight Loss

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A new Vanderbilt University study published in the journal Diabetes demonstrates that a glucagon-like peptide-1 receptor (GLP-1R) agonist, a member of a class of medication used to treat Type 2 diabetes and obesity, can lead to a rapid improvement in insulin sensitivity.

Insulin sensitivity is how responsive cells are to insulin; reduced insulin sensitivity or insulin resistance is a feature of Type 2 diabetes, so improving it can reduce the risk of developing the disease or improve its treatment.

GLP-1R agonists are medications that influence metabolism, such as decreasing blood sugar levels by promoting insulin secretion. Dipeptidyl peptidase 4 (DPP-4) inhibitors block the degradation of the body’s own endogenous GLP-1, as well as other peptide hormones such as glucose-dependent insulinotropic peptide (GIP).

“We know that GLP-1R agonists promote weight loss, but we were surprised to find that the GLP-1R agonist liraglutide also has rapid effects on insulin sensitivity, independent from weight loss,” said Mona Mashayekhi MD, PhD, assistant professor of Medicine in the Division of Diabetes, Endocrinology and Metabolism.

“This effect requires activation of the GLP-1 receptor, but increasing the body’s own endogenous GLP-1 through the use of the DPP4 inhibitor sitagliptin does not achieve similar effects.”

“Our research suggests that liraglutide, and presumably other GLP-1R agonists, are having important metabolic effects in a way that’s different from increasing endogenous GLP-1 levels, even though they’re using the same receptor. Future research will focus on potential mechanisms of how GLP-1R agonists are improving insulin sensitivity independent of weight loss.”

Eighty-eight individuals with obesity and pre-diabetes were randomized for 14 weeks to receive the GLP-1R agonist liraglutide, the dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin, or weight loss without drug using a low-calorie diet.

To further investigate the GLP-1R-dependent effects of the treatments, the GLP-1R antagonist exendin and a placebo were given in a two-by-two crossover study during mixed meal tests.

Crossover studies allow the response of a subject to treatment A to be compared with the same subject’s response to treatment B.

Liraglutide was shown to rapidly improve insulin sensitivity as well as decrease blood glucose within two weeks of beginning treatment and before any weight loss.

“GLP-1R agonists are an exciting class of medications, given their strong glucose-lowering effects combined with tremendous weight-loss benefits, and they have transformed how we manage diabetes and obesity in the clinic,” Mashayekhi said.

“Since the number of medications in this class is rapidly expanding, a deeper understanding of the mechanisms of benefit is crucial so we can design the right drugs for the desired effects in the right patients.”

The investigators’ prior research demonstrated that liraglutide, but not sitagliptin or diet, improves measures of heart disease and inflammation.

This matches the clinical findings of reduced cardiovascular disease with GLP-1R agonist treatment.

Future studies will continue to explore both receptor- and weight loss-dependent effects of GLP-1R agonists in humans.

Source: Vanderbilt University Medical Center

Categories : Mental Health Metabolic DisordersTags :

Feeling Depressed Linked to Short-term Increase in Bodyweight

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Increases in symptoms of depression are associated with a subsequent increase in bodyweight when measured one month later, new research from the University of Cambridge has found.

The study, published in PLOS ONE, found that the increase was only seen among people with overweight or obesity, but found no link between generally having greater symptoms of depression and higher bodyweight.

Research has suggested a connection between weight and mental health – with each potentially influencing the other – but the relationship is complex and remains poorly understood, particularly in relation to how changes in an individual’s mental health influence their bodyweight over time.

To help answer this question, researchers at Cambridge’s Medical Research Council (MRC) Epidemiology Unit examined data from over 2,000 adults living in Cambridgeshire, UK, who had been recruited to the Fenland COVID-19 Study.

Participants completed digital questionnaires on mental wellbeing and bodyweight every month for up to nine months during the COVID-19 pandemic (August 2020 – April 2021) using a mobile app developed by Huma Therapeutics Limited.

Questions assessed an individual’s symptoms of depression, anxiety and perceived stress.

A higher score indicated greater severity, with the maximum possible scores being 24 for depression, 21 for anxiety and 40 for stress.

The team then used statistical modelling to explore whether having poorer mental wellbeing than usual was related to changes in bodyweight one month later.

The researchers found that for every increment increase in an individual’s usual score for depressive symptoms, their subsequent weight one month later increased by 45g.

This may seem small but would mean, for example, that in an individual whose depressive symptoms score rose from five to 10 (equal to an increase from ‘mild’ to ‘moderate’ depressive symptoms) it would relate to an average weight gain of 225g (0.225kg).

This effect was only observed in those individuals with overweight (defined as BMI 25-29.9kg/m2) or with obesity (BMI of over 30kg/m2). Individuals with overweight had on average an increase of 52g for each increment point increase from their usual depressive symptoms score and for those with obesity the comparable weight gain was 71g.

The effect was not seen in those individuals with a healthy weight.

First author Dr Julia Mueller from the MRC Epidemiology Unit said: “Overall, this suggests that individuals with overweight or obesity are more vulnerable to weight gain in response to feeling more depressed. Although the weight gain was relatively small, even small weight changes occurring over short periods of time can lead to larger weight changes in the long-term, particularly among those with overweight and obesity.

“People with a high BMI are already at greater risk from other health conditions, so this could potentially lead to a further deterioration in their health. Monitoring and addressing depressive symptoms in individuals with overweight or obesity could help prevent further weight gain and be beneficial to both their mental and physical health.”

The researchers found no evidence that perceived stress or anxiety were related to changes in weight.

Senior author Dr Kirsten Rennie from the MRC Epidemiology Unit said: “Apps on our phones make it possible for people to answer short questions at home more frequently and over extended periods of time, which provides much more information about their wellbeing. This technology could help us understand how changes in mental health influence behaviour among people with overweight or obesity and offer ways to develop timely interventions when needed.”

Although previous studies have suggested that poor mental health is both a cause and consequence of obesity, the research team found no evidence that weight predicted subsequent symptoms of depression.

The research was supported by the Medical Research Council.

The original text of this story is licensed under Creative Commons CC BY-SA 4.0.

Source: University of Cambridge.  Note: Content may be edited for style and length.

Journal Reference:

  1. Julia Mueller, Amy L. Ahern, Rebecca A. Jones, Stephen J. Sharp, Alan Davies, Arabella Zuckerman, Benjamin I. Perry, Golam M. Khandaker, Emanuella De Lucia Rolfe, Nick J. Wareham, Kirsten L. Rennie. The relationship of within-individual and between-individual variation in mental health with bodyweight: An exploratory longitudinal study. PLOS ONE, 2024; 19 (1): e0295117 DOI: 10.1371/journal.pone.0295117
Categories : Metabolic Disorders Respiratory DiseasesTags :

Why People with Diabetes are More Vulnerable to Respiratory Infection

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It has long been known that people with diabetes are at a substantially increased risk of developing severe lung disease if they become infected with viruses such as influenza, as well as other pathogens. When the COVID-19 pandemic started in early 2020, it became even more important to understand this mysterious phenomenon. It became clear that people with diabetes were at a significantly higher risk of coming down with severe, even fatal, lung disease after developing severe COVID, but no one understood why. In fact, some 35% of the pandemic’s COVID mortalities had diabetes.

Now, research conducted at the Weizmann Institute of Science and published in Nature has revealed how, in diabetics, high levels of blood sugar disrupt the function of key cell subsets in the lungs that regulate the immune response. It also identifies a potential strategy for reversing this susceptibility and saving lives.

Prof. Eran Elinav‘s team in his lab at Weizmann, headed by Drs. Samuel Nobs, Aleksandra Kolodziejczyk and Suhaib K. Abdeen, subjected multiple mouse models of types 1 and 2 diabetes to a variety of viral lung infections. Just as in diabetic humans, in all these models the diabetic mice developed a severe, fatal lung infection following exposure to lung pathogens such as influenza. The immune reaction, which in nondiabetics eliminates the infection and drives tissue healing, was severely impaired in the diabetic mice, leading to uncontrolled infection, lung damage and eventual death.

Next, to decode the basis of this heightened risk, the team performed an evaluation of gene expression on the level of individual cells, in more than 150 000 single lung cells of infected diabetic and nondiabetic mice. The researchers also performed an extensive array of experiments involving immune and metabolic mechanisms, as well as an in-depth assessment of immune cell gene expression in infected diabetic mice. In the diabetic mice they identified a dysfunction of certain lung dendritic cells, the immune cells that orchestrate a targeted immune response against pathogenic infection. “High blood sugar levels severely disrupt certain subsets of dendritic cells in the lung, preventing these gatekeepers from sending the molecular messages that activate the critically important immune response,” says Nobs, postdoctoral fellow and study first author. “As a result, the infection rages on, uncontrolled.”

Next, they explored ways to prevent the harmful effects of hyperglycaemia in lung dendritic cells, as a means of lowering the infection’s risk in diabetic animals. Indeed, tight control of glycaemic levels by insulin supplementation prompted the dendritic cells to regain their capacity to generate a protective immune response that could prevent the cascade of events leading to a severe, life-threatening viral lung infection. Alternatively, administration of small molecules reversing the sugar-induced regulatory impairment corrected the dendritic cells’ dysfunction and enabled them to generate a protective immune response despite the presence of hyperglycaemia.

“Correcting blood sugar levels, or using drugs to reverse the gene regulatory impairment induced by high sugar, enabled our team to get the dendritic cells’ function back to normal,” says Abdeen, a senior intern who co-supervised the study. “This was very exciting because it means that it might be possible to block diabetes-induced susceptibility to viral lung infections and their devastating consequences.”

Lung tissue of a diabetic mouse (right) contains fewer immune cells (small purple dots) than that of a non-diabetic animal (left)

With over 500 million people around the world affected by diabetes, and with diabetes incidence expected to rise over the next decades, the new research has significant, promising clinical implications.

“Our findings provide, for the first time, an explanation as to why diabetics are more susceptible to respiratory infection,” Elinav says. “Controlling sugar levels may make it possible to reduce this pronounced diabetes-associated risk. In diabetic patients whose sugar levels are not easily normalized, small molecule drugs may correct the gene alterations caused by high sugar levels, potentially alleviating or even preventing severe lung infection. Local administration of such treatments by inhalation may minimize adverse effects while enhancing effectiveness, and merits future human clinical testing.”

Source: Weizmann Institute of Science