Category: Metabolic Disorders

Categories : Metabolic DisordersTags :

Enzyme’s Role in Kidney Disease Could Unlock New Therapies

On By ModernMedia
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

Categories : Cancer Metabolic DisordersTags :

Positive Safety News for Important Diabetes Drugs

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A systematic review and meta-analysis showed that GLP-1 receptor agonists weren’t associated with increased risk for incident breast cancer.

Giovana Fagundes Piccoli, MD, of the Hospital de Clínicas de Porto Alegre in Brazil presented the findings at the Endocrine Society’s virtual ENDO 2021 meeting.

Out of 48 267 patients treated with a GLP-1 receptor agonist there were 130 cases of incident breast cancer among versus 107 cases out of 40 755 controls. Control participants received either placebo or active treatment with a non-GLP-1 receptor agonist. 
There was also no difference in risk of benign breast neoplasms for patients on GLP-1 receptor agonists versus other drug types (RR 0.99).

No difference was seen among individual GLP-1 receptor agonists, including each of the four major drugs in the class — liraglutide, dulaglutide, semaglutide, and albiglutide  — with exendin-4 mimetic agents including exenatide and lixisenatide.

No difference in incident breast cancer risk was seen when comparing trials with an open-label design versus double-blinded trials.

Dr Piccoli explained that her team wanted to investigate the issue further following the 2015 SCALE Obesity and Prediabetes trial, which found more breast neoplasms in patients receiving liraglutide than with placebo (4.36 vs 1.80 per 1000 person years). In that study, most of those neoplasms developed in the first year of treatment with GLP-1 receptor agonist, and were more common in participants with greater weight loss on the agent.

“I think that the results of our meta-analysis adds more security and safety information about this treatment,” said Dr Piccoli during a press conference. “Patients, doctors, and other health professionals can be more secure of the safety of these drugs.”

For this analysis, her team searched a variety of medical journal databases for randomised trials assessing GLP-1 receptor agonists in adults with overweight, obesity, prediabetes, or type 2 diabetes that also reported breast cancer or benign breast neoplasm incidence.

Participant ages ranged from 45 to 70 years old and follow-up lasted between 24 weeks to 7.5 years.

Piccoli emphasised that these findings only apply to patients treated with a GLP-1 receptor agonist for diabetes control or weight loss in the absence of pre-existing breast cancer. She added that patients with a history of breast or any other cancer were usually excluded from the trials in this meta-analysis.

“We can say in a general population with type 2 diabetes and obesity, [GLP-1 receptor agonists] are safe,” Piccoli said. But the class’s safety in patients with a history of breast cancer is less certain, she added.

Source: MedPage Today

Presentation information: Piccoli G, et al “Do GLP-1 receptor agonists increase the risk of breast cancer? A systematic review and meta- analysis” ENDO 2021.

Categories : Cancer Metabolic DisordersTags :

‘Obesity Paradox’ in Kidney Cancer Continues to Mystify

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Obese patients with metastatic renal cell carcinoma (RCC) were more likely to survive compared to their normal weight counterparts when receiving immune checkpoint inhibitors (ICI), a study has shown.

RCC is the most deadly of the urogenital cancers, and its incidence is increasing. Males are twice as likely as females to develop it.
A team of researchers including Toni Choueiri, MD, of Dana-Farber Cancer Institute in Boston, conducted an analysis of 735 metastatic RCC patients who received PD-1/L1 immunotherapies. 

Those with a BMI of 25 or greater had significantly longer overall survival (OS), with 1-year rates of 79% versus 66% for those with a BMI below that cutoff. This relationship was observed across tumour categories.

“These findings are consistent with the obesity paradox that was previously seen during the VEGF-targeted therapy era,” the team noted.

“Several hypotheses have attempted to explain this clinical observation in RCC,” Choueiri’s team wrote. “Low fatty acid synthase gene expression, which is inversely correlated with BMI, was associated with longer OS in VEGF-treated patients. Transcriptomic analysis suggests that patients with obesity have tumors with increased angiogenesis gene signatures and peritumoral adipose tissues with increased hypoxia, inflammation, and immune cell infiltration signatures.”

In 319 patients with next-generation sequencing technology, there was no difference between groups for tumour mutation burden, at an average 6.8 mutations per megabase for the low and high BMI groups. Genomic alteration frequency analysis also picked up no differences.

Limitations of the study authors included its retrospective nature, incomplete gene-expression profiling, and between-group imbalances. Patients with higher BMI had greater odds of having better performance status and being in more favourable risk groups, had greater odds of having clear cell histology, having had prior nephrectomy, and having received a checkpoint inhibitor as first-line therapy.

Source: MedPage Today

Journal information: AKA Lalani, et al “Assessment of immune checkpoint inhibitors and genomic alterations by body mass index in advanced renal cell carcinoma” JAMA Oncol 2021; DOI: 10.1001/jamaoncol.2021.0019.

Categories : Metabolic Disorders PaediatricsTags :

Regular Sleep Patterns in Toddlers Important for BMI

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Although getting regular sleep patterns in toddlers has long been a priority for parents, researchers have shown it is important for toddlers’ BMI.

The researchers, led by Lauren Covington, an assistant professor in the University of Delaware School of Nursing, investigated the link between poverty, regular sleep patterns and BMI in toddlers. According to The National Sleep Foundation, toddlers 1- to 3-years-old should have 12 to 14 hours of sleep in a 24-hour period.

“We’ve known for a while that physical activity and diet quality are very strong predictors of weight and BMI,” said Prof Covington, the lead author of the article. “I think it’s really highlighting that sleep may be playing a bigger role here than it’s been given credit for.”

The researchers aimed to investigate the relationship between poverty and BMI in toddlers, and wanted to see whether sleep behaviour, activity or food intake could provide the explanation.

Using data from families in an obesity prevention trial, 70% of whom were below the poverty line, and all eligible for nutritional supplementation grants, Toddlers were given accelerometers to wear to measure physical activity and parents filled out food diaries.

The researchers found that children from households with greater poverty were more likely to have greater inconsistent bedtimes, and those with more inconsistent bedtimes had higher BMI percentages.

Prof Covington said this is likely to be a bidirectional relationship. “There’s a lot of teasing out the relationships of the mechanisms that are at play here, which is really difficult to do because I think they’re all influencing each other,” she said.

Having consistent bedtimes where children go to bed within one hour of the normal time is a recommended guideline, but for families in poverty this may be impossible for a variety of reasons. Single parent households and juggling multiple jobs are part of the challenges they face.

“Implementing a consistent bedtime could be one behavioural change that a family could potentially do,” said Prof Covington. “It’s more attainable than maybe getting healthy food at the grocery store or playing outside on the playground, especially now with the cold weather. Just having a consistent bedtime can help provide some sense of structure, but then maybe have better implications for health and BMI as well.”

Source: Medical Xpress

Journal information: Lauren Covington et al. Longitudinal Associations Among Diet Quality, Physical Activity and Sleep Onset Consistency With Body Mass Index z-Score Among Toddlers in Low-income Families, Annals of Behavioral Medicine (2020). DOI: 10.1093/abm/kaaa100

Categories : Mental Health Metabolic DisordersTags :

Why Antipsychotic Drugs Cause Weight Gain

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A University of Pittsburgh study has discovered that the reason antipsychotic medications have weight gain as side effects is because the pancreas also produces and responds to dopamine.

Dopamine is a neurotransmitter involved in mood regulation, pleasure and reward signalling. Many psychological disorders are thought to involve dopamine imbalances and are treated by medications designed to this end.
“There are dopamine theories of schizophrenia, drug addiction, depression and neurodegenerative disorders, and we are presenting a dopamine theory of metabolism,” said lead author Despoina Aslanoglou, PhD, at the University of Pittsburgh. “We’re seeing now that it is not only interesting to study dopamine in the brain, but it is equally interesting and important to study it in the periphery.”

Senior author Zachary Freyberg, MD, PhD, assistant professor of psychiatry and cell biology at Pitt, observed that the dopamine theory is not as simple or as well understood as we would like to think.

“We still don’t really understand how dopamine signals biologically,” said Dr Freyberg. “Even decades after dopamine receptors have been discovered and cloned, we still deploy this ‘magical thinking’ approach: something happens that’s good enough. We use drugs that work on dopamine receptors, but how they intersect with this ‘magical system’ is even less understood.”

The researchers found that dopamine is not only produced in the brain but also in the alpha and beta cells of the pancreas, which secrete glucagon and insulin, respectively.

Alpha cells can produce their own dopamine with no precursors in response to glucose levels, while beta cells require an L-DOPA precursor. It may be possible that alpha cells secrete dopamine for their own receptors, while also supplying it to beta cells to suppress the release of insulin.

Surprisingly, the researchers also discovered that pancreatic dopamine can affect other receptors, such as noradrenaline and adrenaline.
At low concentrations, dopamine binds to D2-like dopamine receptors, blocking the release of glucagon or insulin. At high concentrations, dopamine binds to beta-adrenergic receptors, becoming stimulatory and pushing up glucagon levels while inhibiting insulin levels by blocking alpha-adrenergic receptors.

The study revealed how blocking inhibitory dopamine receptors causes an unchecked release of insulin and glucagon, leading to metabolic disorders and eventually, obesity and diabetes. This finding will help to formulate better drugs that target the dopamine system, reducing the effect on the pancreas.

Source: News-Medical.Net