Tag: metabolic syndrome

Categories : Metabolic DisordersTags :

Worsening Metabolic Syndrome Exacerbates Cancer Risk

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

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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

Categories : Genetics Metabolic DisordersTags :

Abdominal Fat Accumulation may not be as Great a Diabetes Risk as Previously Thought

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Conventional wisdom holds that abdominal fat accumulation increases the risk for type 2 diabetes. But surprising new findings from the University of Virginia School of Medicine suggest that naturally occurring genetic variations in our genes can lead some people to store fat at the waist but also protect them from diabetes.

The unexpected discovery, which is published in eLife, provides a more nuanced view of the role of obesity in diabetes and related health conditions. It also could pave the way for more personalised medicine, such as prioritising weight loss for patients whose genes put them at increased risk but place less emphasis on it for patients with protective gene variants, the researchers say.

“There is a growing body of evidence for metabolically healthy obesity. In this condition, people who would normally be at risk for cardiovascular diseases and diabetes because they are obese are actually protected from adverse effects of their obesity. In our study, we found a genetic link that may explain how this occurs in certain individuals,” said researcher Mete Civelek, PhD, of UVA’s Center for Public Health Genomics. “Understanding various forms of obesity is important to tailor treatments for individuals who are at high risk for adverse effects of obesity.”

As medicine grows more sophisticated, understanding the role of naturally occurring gene variations will play an important role in ensuring patients get the best, most tailored treatments. The new work by Civelek and his team, for example, indicates that variants can simultaneously predispose some people to store fat at the abdomen, thought to put them at increased risk for metabolic syndrome, while also protecting them from type 2 diabetes. (Metabolic syndrome raises the risk for diabetes, stroke and other serious health issues.)

One of the metrics doctors use to determine if a patient has metabolic syndrome is abdominal obesity. This is often calculated by comparing the patient’s waist and hip measurements. But Civelek’s research suggest that, for at least some patients, it may not be that simple, with doctors using genetic testing to guide patients to good health.

“We found that among the hundreds of regions in our genomes which increase our propensity to accumulate excess fat in our abdomens, there are five which have an unexpected role,” said Yonathan Aberra, the lead author of the study and a PhD candidate at UVA’s Department of Biomedical Engineering, a joint program of the School of Medicine and School of Engineering. “To our surprise, these five regions decrease an individual’s risk for type 2 diabetes.”

In addition to producing surprising findings, Civelek’s research provides important new tools for his fellow researchers seeking to understand the complexities of gene variations. The sophisticated approach Civelek and his collaborators developed to identify the relevant variants and their potential effects will be useful for future research into metabolic syndrome and other conditions.

The tools could also prove invaluable in the development of new and better treatments for metabolic syndrome, the scientists say.

“We now need to expand our studies in more women and people from different genetic ancestries to identify even more genes that underlie the metabolically health obesity phenomenon,” Civelek said. “We plan to build on our findings to perform more experiments to potentially identify a therapeutic target.”

Source: University of Virginia Health System

Categories : Metabolic DisordersTags :

Metabolic Syndrome Increases Gout Risk Nearly Four-fold

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Doctor shows an X-ray of a foot
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In a population-based study published in Arthritis & Rheumatology, researchers found that men with metabolic syndrome (MetS) and those who developed MetS – especially those with the MetS components of elevated triglycerides and abdominal obesity – were at higher risk of developing gout.

Gout is one of the most common causes of chronic inflammatory arthritis, characterised by monosodium urate (MSU) monohydrate crystals deposition in the tissues. 

Dietary sources that can contribute to hyperuricemia and gout include the consumption of animal food such as seafood (eg, shrimp, lobster), organs (eg, liver and kidney), and red meat (pork, beef). Some drinks like alcohol and sweetened drinks may also contribute to this disease. Epidemiological studies reported an increased disease burden of gout, which is largely explained by lifestyle changes like increased protein consumption and a sedentary lifestyle. 

The study included nearly 1.3 million men aged 20–39 years who participated in three serial health check-ups at two-year intervals. Among these participants, 18 473 developed gout, and those with MetS at all checkups had a nearly four-fold higher risk than participants who were MetS-free. Development of MetS more than doubled the risk of incident gout. Conversely, recovery from MetS reduced incident gout risk by nearly half.

Among MetS components, changes in elevated triglycerides and abdominal obesity displayed the greatest association with altered risk of incident gout. Age was also a factor: associations among MetS changes and incident gout were more pronounced in subjects in their 20s than subjects in their 30s and in subjects who were under- or normal weight.

“This is the first large-scale study to explore the association between dynamic changes in MetS and risk of gout,” said co–corresponding author Jaejoon Lee, MD, PhD of the Sungkyunkwan University School of Medicine, in South Korea. “Prevention and recovery from MetS can significantly lower the risk of gout in young adults.”

Source: Wiley

Categories : Cardiovascular DiseaseTags :

Heart Attack Survivors can Extend Healthy Lifespan

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If patients follow lifestyle advice and medications after a heart attack, it could add seven healthy years of life, according to a new study.

“Most heart attack patients remain at high risk of a second attack one year later,” explained study author Dr Tinka Van Trier of Amsterdam University Medical Centre. “Our study suggests that improving both lifestyles and medication use could lower this risk, with a gain in many years of life without a cardiovascular event.”

A previous study showed that 80–90% of the risk of a heart attack can be modified by managing factors such as smoking, unhealthy diet, abdominal obesity, inadequate physical activity, hypertension, diabetes and raised blood lipid levels. Two main strategies are used: lifestyle change and medication.

However, risk factors are rarely reduced sufficiently after a heart attack, even in programmes aiming to help patients improve their lifestyles and optimise their medication. Therefore, residual risk is high to very high in a large number of patients. Dr Van Trier said: “This study was conducted to quantify this residual risk and estimate the extent to which it could be lowered with optimal management.”

The study pooled data from 3230 patients, average age 61 and 24% women, that had a heart attack or received a stent or bypass surgery. At an average of one year after the cardiac event, 30% continued smoking, 79% were overweight, and 45% reported insufficient physical activity. Only 2% of attained treatment targets for blood pressure, LDL cholesterol, and glucose levels with 40% having hypertension and 65% having high LDL cholesterol. Preventative medication use was common: 87% used antithrombotic medications, 85% took lipid lowering drugs and 86% were on blood pressure lowering drugs.

The researchers calculated the lifetime risk of a heart attack, stroke, or death from cardiovascular disease and estimated changes in healthy years when lifestyle or medication was changed or optimised. 

The estimated average residual lifetime risk for cardiovascular disease mortality was 54%. If all targets in the model were met, this risk would drop to 21%.

Dr Van Trier said: “The findings show that despite current efforts to reduce the likelihood of new events after a heart attack, there is considerable room for improvement. Our analysis suggests that the risk of another cardiovascular event could, on average, be halved if therapies were applied or intensified. For individual patients, this would translate into gaining an average of 7.5 event-free years.”

Source: European Society of Cardiology

Categories : Cardiovascular Disease Metabolic DisordersTags :

Are Lower Haemoglobin Levels Protective?

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A new study challenges the view that high haemoglobin levels are always desirable for health. 

A study based on two large human cohorts as well as experimental work supported the idea that lower haemoglobin levels may protect against both obesity and metabolic syndrome. The phenomenon may be related to the body’s adaptive response to low-oxygen conditions, which is exploited by endurance athletes in high-altitude training.

Haemoglobin levels vary from one individual to another, with normal levels in Finnish population ranging from 117 to 155 grams per litre in females and 134 to 167 grams per litre in males.

A recent study showed that individual differences in haemoglobin levels are strongly associated with metabolic health in adulthood. The haemoglobin levels were associated with body mass index, glucose metabolism, blood lipids and blood pressure. Subjects with lower haemoglobin levels were healthier in terms of metabolic measures. The study examined haemoglobin values within the normal range.  

“We found a clear association between hemoglobin levels and key cardiovascular traits, and the associations became more pronounced as the subjects aged,” said principal investigators Professor Juha Auvinen, doctoral student Joona Tapio and postdoctoral researcher Ville Karhunen.  

The effect of lower haemoglobin observed in the study is related to a mild oxygen deficiency in the body and the corresponding hypoxia inducible factors (HIF) response which is activated as a result. The research team of Professor Peppi Karppinen is internationally known for its studies on this phenomenon. The finding reinforces the understanding of the central role that the HIF response has in regulating the body’s energy metabolism.

“Haemoglobin levels are a good measure of the body’s ability to carry oxygen. A mild lack of oxygen activates the HIF response, which makes the body’s energy metabolism less economical and thus may protect against obesity and unfavourable metabolism,” explained study leader Prof Karppinen.

Prof Karppinen’s team has already shown in previous research that activation of the hypoxia response protects mice from obesity, metabolic syndrome, fatty liver and atherosclerosis. This is the first study to show the link between oxygen deficiency and a wide range of metabolic health markers in humans as well.

“Although this study uses multiple methods to establish links between lower body oxygen levels and metabolic health, it is very challenging to establish causality for the observed associations in human data. However, combining evidence from different components of the study, the results support that hypoxia response may also play an important role in peoples’ metabolic health,”explained co-leader of the study Professor Marjo-Riitta Järvelin.

“We also already know that in people living high above sea level, low oxygen levels in the habitat cause long-term activation of the HIF response. These people are slimmer, and they have better sugar tolerance and a lower risk of cardiovascular death,” said Prof Karppinen.

The study was based on a large cohort of people born in Northern Finland in 1966, which followed the health of 12 000 people since birth. The results were also replicated in The Cardiovascular Risk in Young Finns Study cohort material, which covers more than 1800 individuals. 

“Although this study uses multiple methods to establish links between lower body oxygen levels and metabolic health, it is very challenging to establish causality for the observed associations in human data. However, combining evidence from different components of the study, the results support that hypoxia response may also play an important role in peoples’ metabolic health”, explained study co-leader Professor Marjo-Riitta Järvelin.

Professor Peppi Karppinen said, “We also already know that in people living high above sea level, low oxygen levels in the habitat cause long-term activation of the HIF response. These people are slimmer, and they have better sugar tolerance and a lower risk of cardiovascular death.”

A question for future research is how to reduce the body’s oxidation levels if needed. This would be to achieve a permanent low-level activation of the HIF response and thus obesity protection. According to Prof Karppinen, the HIF enzymes that prompt a hypoxic response could potentially be used as targets of obesity and metabolism drugs in humans. Currently they are being used in Asia to treat renal anaemia.

Source: University of Oulu

Journal information: Auvinen, J., et al. (2021) Systematic evaluation of the association between hemoglobin levels and metabolic profile implicates beneficial effects of hypoxia. Science Advances. doi.org/10.1126/sciadv.abi4822.

Categories : Metabolic DisordersTags :

A New Bacterium Might Help Treat Type 2 Diabetes and Obesity

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E. Coli bacteria. Image by CDC
E. Coli bacteria. Image by CDC

A newly discovered bacterium has been shown to have a possible link to type 2 diabetes and obesity, and may yield pathways to possible treatments.

It began when Patrice Cani, FNRS researcher at University of Louvain (UCLouvain), and his team repeatedly observed that a certain bacterium, Subdoligranulum, is usually lacking in obese and diabetic people, while it is systematically present in healthy people. Based on this, they decided to examine this family of bacteria.

Currently only one cultivated strain of this family is available in the world (the only known member of a large family) and was not the strain that was seen to be decreased in obese and diabetic people. This is not unusual: nearly 70% of bacteria in the intestine have not yet been identified — this is called the dark matter of the intestine.

In 2015, the team then set out to isolate the bacterium themselves in order to learn about its action on the human body, knowing that it is only present in healthy people. To find a second member of the family, the scientists spent two years searching, isolating and cultivating nearly 600 intestinal bacteria. 

All of this was in vain. Instead, the UCLouvain team uncovered a bacterium of a new, previously unknown kind. They named it Dysosmobacter welbionis: Dysosmo (“which smells bad”, in Greek), bacter (bacterium) is the bacterium which stinks, “Because, when you grow it, it has a slight odour,” they explained. Welbionis for WELBIO, the organisation in the Walloon region which funded this research.

The bacterium is peculiar for a number of reasons, including the fact that it produces butyrate. Though many other bacteria produce this colon cancer-promoting molecule, for example by strengthening the intestinal barrier and boost immunity. But the team also discovered that Dysosmobacter welbionis was less present in people with type 2 diabetes.

By analysing the microbiota from 12 000 faecal samples gathered from around the world, the UCLouvain scientists observed that the bacteria is present in 70% of the population. As to why such a widely prevalent bacteria was never discovered before, the answer likely lies in the improved cultivation techniques developed by the UCLouvain team.

The UCLouvain team including doctoral student Emilie Moens de Hase and post-doctoral fellow Tiphaine Le Roy then tested the action of Dysosmobacter welbionis in mice. The Results? The bacteria increased the number of mitochondria (a kind of power plants within cells that burns fat), thereby lowering sugar levels and weight, in addition to having strong anti-inflammatory effects. All these effects are very promising for type 2 diabetic and obese subjects and resemble those of Akkermansia, a beneficial bacterium that is at the heart of the research in Patrice Cani’s lab.

They also observed that the bacteria’s effects are not limited to the gut: Scientists have found that certain molecules produced by Dysosmobacter migrate around the body and have distant actions as well. This could explain the effects the bacteria have on the fat tissues, and also opens the doors for a possible impact on other diseases such as cancer. This is currently being investigated by the team.

The next step is to test the action of Dysosmobacter welbionis coupled with that of Akkermansia, in order to see if their association has cumulative effect on health, while always keeping in mind the fight against type 2 diabetes, inflammatory diseases, obesity and cancer. “That’s the fun of research: you dig for dinosaur bones and you end up finding a treasure,” Patrice Cani enthused.

Source: Université catholique de Louvain

Journal reference: Roy, T. L., et al. (2021) Dysosmobacter welbionis is a newly isolated human commensal bacterium preventing diet-induced obesity and metabolic disorders in mice. Gut. doi.org/10.1136/GUTJNL-2020-323778.

Categories : Metabolic Disorders New Compounds and TreatmentsTags :

‘Game-changing’ Weight Loss Drug Semaglutide Approved by FDA

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The US Food and Drug Administration approved a ‘game changing’ weight loss drug called Wegovy (semaglutide) for chronic weight management in adults with obesity or overweight.

This injection is the first drug for chronic weight management in adults with general obesity or overweight to be approved since 2014. The drug is indicated for chronic weight management in patients with a body mass index (BMI) of 27 kg/m2 or greater who have at least one weight-related ailment or in patients with a BMI of 30 kg/m2 or greater, and is to be used in conjunction with diet and exercise.

“Today’s approval offers adults with obesity or overweight a beneficial new treatment option to incorporate into a weight management program,” said John Sharretts, MD, deputy director of the Division of Diabetes, Lipid Disorders, and Obesity in the FDA’s Center for Drug Evaluation and Research. “FDA remains committed to facilitating the development and approval of additional safe and effective therapies for adults with obesity or overweight.”

Approximately 70% of American adults have obesity or overweight, and >67% of sub-Saharan Africans. This is a serious health issue linked to leading causes of death such as heart disease, stroke and diabetes, and also to increased risk of certain types of cancer. Losing 5% to 10% of body weight through diet and exercise has been associated with a reduced risk of cardiovascular disease in adult patients with obesity or overweight.

Wegovy works by mimicking a hormone called glucagon-like peptide-1 (GLP-1) that targets areas of the brain regulating appetite and food intake. The medication dose must be increased gradually over 16 to 20 weeks to 2.4 mg once per week to reduce gastrointestinal side effects.

The drug’s safety and efficacy were studied in four 68-week trials. Over 2600 patients received Wegovy for up to 68 weeks in these four studies and more than 1500 patients received placebo.

The largest placebo-controlled trial enrolled diabetes free adults with an average age of 46 years, and 74% of whom were female. The average body weight was 105 kg and average BMI was 38 kg/m2. Individuals receiving Wegovy lost an average of 12.4% of their initial body weight compared to individuals who received placebo. Another trial enrolled adults with type 2 diabetes. The average age was 55 years and 51% were female, with an average body weight of 100 kg and average BMI of 36 kg/m2. In this trial, individuals receiving Wegovy lost 6.2% of their initial body weight compared to the placebo group.

“The approval of Wegovy in the US brings great promise to people with obesity. Despite the best efforts to lose weight, many people with obesity struggle to achieve and maintain weight loss due to physiological responses that favour weight regain,” said Martin Holst Lange, executive vice president, Development at Novo Nordisk. “The unprecedented weight loss for an anti-obesity medication marks a new era in the treatment of obesity, and we now look forward to making Wegovy available to people living with obesity in the US”.

Unfortunately, the drug may be out of the reach of many people in need of it, with indications being that the medication may be charged at around US$1,300 a month.

Source: Food and Drug Administration

Categories : Metabolic DisordersTags :

Familial High Cholesterol Often Eludes Genetic Testing

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Most familial hypercholesterolemia (FH) cases would go undetected if people were to rely on array-based genetic tests alone, a new study suggests.

FH predisposes people to elevated levels of LDL cholesterol, which can lead to premature coronary artery disease and early death.  

For example, the 23andMe test, which has a limited screen for only 24 known FH variants, would have missed over 60% of individuals with the autosomal dominant disorder. This figure was even worse for non-European ancestry individuals.

“Limited-variant screens may falsely reassure the majority of individuals at risk for FH that they do not carry a disease-causing variant, especially individuals of self-reported Black/African American and Hispanic ancestry,” according to Amy Sturm, of the Geisinger Genomic Medicine Institute in Danville, Pennsylvania, and colleagues.

In their study, limited-variant screening would miss nearly 94% and 85% of Black and Hispanic individuals with confirmed FH pathogenic variants. However this would be true for only a third of Ashkenazi Jewish people.

“The reduced yield of limited-variant screening could result in a major health care disparity for groups already affected by social and medical disenfranchisement that beget serious health disparities including a significantly higher rate of cardiovascular death among Black/African American individuals,” the investigators said.

“When FH is strongly clinical suspected, even if array-based FH reporting has negative results, a clinical genetic test should still be considered,” according to an accompanying note by JAMA Cardiology editors Pradeep Natarajan, MD, MMSc, of Massachusetts General Hospital and Harvard Medical School in Boston, and Elizabeth McNally, MD, PhD, of Northwestern University Feinberg School of Medicine in Chicago.

“Genetic databases overrepresent European ancestry populations and therefore make interpretation of genetic variation more accurate in these cohorts. However, even 64% of the FH mutations in European American individuals would have been missed by the 24-variant [test],” noted Drs Natarajan and McNally.

“Unfortunately, genetic testing for FH is underused, with 90% of affected individuals worldwide remaining undiagnosed and only 3.9% of patients with FH in the U.S. having a record of genetic testing,” noted Dr Sturm and colleagues.

“Recent expert statements recommend that patients suspected of having FH be offered genetic testing and that first-degree relatives of genetically positive individuals be screened for FH by lipid profile or genetic testing,” according to them.

Comprehensive genetic testing with next-generation sequencing (NGS) detects over 2000 potentially pathogenic variants within full genomes. Assay-based screens such as 23andMe only test for a small subset of known variants, and not the number present.

Both types of genetic tests for FH are available either in clinical settings or as a direct service to consumers.

“Whether testing is obtained directly by a consumer or through a clinical setting, those tested should consult with a genetic counselor or other qualified health care professional to fully understand the benefits and limitations of the different types of genetic testing for FH,” Sturm’s group urged.

For the study, the authors took deidentified NGS results, sourced from a single clinical laboratory, for gene panels of individuals receiving comprehensive genetic testing either for an FH indication (4563 participants) or as proactive health screening (6482 participants).

The researchers had tested both cohorts for more than 2000 possible variants in four FH-associated genes: LDLR, APOB, PCSK9, and LDLRAP1.

With the limited screening tests, only 8.4% of people with FH indication had a positive detection, compared to 27.0% for comprehensive NGS genotyping. In the proactive cohort of people with no clinical suspicion of FH, clinically significant FH variant prevalence was about one in 191 according to the comprehensive test.

A limitation was the researchers’ inability to confirm genetic testing results with medical and family histories.

Source: MedPage Today

Journal information: Sturm AC, et al “Limited-variant screening vs comprehensive genetic testing for familial hypercholesterolemia diagnosis” JAMA Cardiol 2021; DOI: 10.1001/jamacardio.2021.1301.

Categories : Diet and Nutrition Metabolic DisordersTags :

Milk Consumption Does Not Raise Cholesterol Levels

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Regular consumption of milk is not associated with increased levels of cholesterol, according to new research.

A study published in the International Journal of Obesity analysed three large population studies and found that people who regularly drank high amounts of milk had lower levels of both ‘good’ and ‘bad’ cholesterol, although their BMI levels were higher than non-milk drinkers. Analysis of other large studies also suggests that regular milk drinkers had a 14% lower risk of coronary heart disease.

The team of researchers took a genetic approach to milk consumption by looking at a variation in the lactase gene associated with digestion of lactose. The study found that this gene variation for digesting lactose was a good identifier for people who consumed higher levels of milk.

“We found that among participants with a genetic variation that we associated with higher milk intake, they had higher BMI, body fat, but importantly had lower levels of good and bad cholesterol,” said Vimal Karani, Professor of Nutrigenetics and Nutrigenomics at the University of Reading said. “We also found that those with the genetic variation had a significantly lower risk of coronary heart disease. All of this suggests that reducing the intake of milk might not be necessary for preventing cardiovascular diseases.”

Contradictory research on the effect of high dairy intake and obesity and metabolic disorders was the motivation for the study. To exclude the effects of differences in sampling size, ethnicity and other factors, the team conducted a meta-analysis of data in up to 1.9 million people, including the UK Biobank and used the genetic approach to avoid confounding.

Even though the UK Biobank data showed that those with the lactase gene had an 11% reduced risk of type 2 diabetes, the study did not find a link between higher milk intake and increased likelihood of diabetes or related traits, such as glucose and inflammatory biomarkers.

“The study certainly shows that milk consumption is not a significant issue for cardiovascular disease risk even though there was a small rise in BMI and body fat among milk drinkers. What we do note in the study is that it remains unclear whether it is the fat content in dairy products that is contributing to the lower cholesterol levels or it is due to an unknown ‘milk factor’,” said Professor Karani.

Source: EurekaAlert

Journal information: Karani Santhanakrishnan Vimaleswaran et al, Evidence for a causal association between milk intake and cardiometabolic disease outcomes using a two-sample Mendelian Randomization analysis in up to 1,904,220 individuals, International Journal of Obesity (2021). DOI: 10.1038/s41366-021-00841-2

Categories : Metabolic DisordersTags :

Enzyme’s Role in Kidney Disease Could Unlock New Therapies

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Anatomic model of a kidney. Photo by Robina Weermeijer on Unsplash

University of South Australia (UniSA) researchers have discovered that a certain enzyme may help to curb chronic kidney disease, which affects nearly 10% of the world’s population.

This enzyme, known as NEDD4-2, is critical for kidney health, said UniSA Centre for Cancer Biology scientist Dr Jantina Manning.

Chronic kidney disease (CKD) is defined as the presence of kidney damage or reduced filtration rate, persisting for three months or more. It is a state of progressive loss of kidney function ultimately resulting in the need for dialysis or transplantation. 

Dr Manning and her colleagues, including Professor Sharad Kumar, Chair of the UniSA Centre for Cancer Biology, have shown in an animal study that there is a link between a high salt diet, low levels of NEDD4-2 and advanced kidney disease.

While a high salt diet can worsen some forms of kidney disease, it was not previously known that NEDD4-2 is involved in promoting this salt-induced kidney damage.

“We now know that both a high sodium diet and low NEDD4-2 levels promote renal disease progression, even in the absence of high blood pressure, which normally goes hand in hand with increased sodium,” says Dr. Manning.

The NEDD4-2 enzyme regulates the pathway required for sodium reabsorption in the kidneys to ensure correct levels of salt are maintained. If this enzyme is reduced or inhibited, increased salt absorption can result in kidney damage.

Even if people are on a low salt diet, they can get kidney damage if their levels of NEDD4-2 are low due to genetic causes.

Prof Kumar said the goal is to eventually to develop a drug that can raise NEDD4-2 levels in people who have CKD.

“We are now testing different strategies to make sure this protein is maintained at a normal level all the time for overall kidney health,” Prof Kumar said. “In diabetic nephropathy—a common cause of kidney disease—levels of NEDD4-2 are severely reduced. This is the case even when salt is not a factor.”

The study also revealed one other unexpected finding: that kidney disease induced by high salt diets is not always the result of high blood pressure.

“In a lot of cases, kidney disease is exacerbated by hypertension, so we wanted to investigate that link in our study. In fact, we found the complete opposite—that a high salt diet caused excessive water loss and low blood pressure. This is significant because it means that kidney disease can also happen in people who don’t have high blood pressure,” Dr Manning said.

A Lancet paper from 2020 estimated that about 700 million people—about 10% of the world’s population—suffer from chronic kidney disease, and has seen a 29% increase in the past 30 years. This massive surge in CKD is mainly due to the global obesity epidemic. Overweight and obesity lead to diabetes, one of the leading causes of CKD, along with high blood pressure. Between 1980 and 2014 there was a 300% increase in diabetes, according to World Health Organization statistics. This makes it one of the top 10 causes of death worldwide.

“Obesity and lifestyle are two main factors driving chronic kidney disease but there are other things at play as well,” said Dr Manning. “Acute kidney injuries, drugs taken for other conditions, high blood pressure and a genetic predisposition can also cause it.”

Source: Medical Xpress

Journal information: Jantina A. Manning et al. The ubiquitin ligase NEDD4-2/NEDD4L regulates both sodium homeostasis and fibrotic signaling to prevent end-stage renal disease, Cell Death & Disease (2021). DOI: 10.1038/s41419-021-03688-7