Tag Archives: #metformin

Metformin Improves Mitochondrial Function in Patients With Type-2 Diabetes (Medicine)

A research team from the Department of Physiology of the University of Valencia, the FISABIO foundation and University Hospital Dr. Peset have proven that the mitochondrial dysfunction that occurs in type-2 diabetes can be countered with metformin. The study is published in Antioxidants & Redox Signaling.

Mitochondria are organelles involved in different cell processes, such as the degradation of lipids of metabolizing carbohydrates. Furthermore, they are responsible for meeting tissues’ energetic demands through cellular respiration. When mitochondria fail to perform these tasks correctly, there is mitochondrial dysfunction.

Mitochondrial dysfunction contributes to type-2 diabetes, a chronic inflammatory disease characterized by hyperglycaemia and hyperinsulinaemia. One substance used to treat it is metformin, an anti-diabetic drug that can regulate the amount of blood glucose.

“In this study we have shown that type-2 diabetes is linked to mitochondrial dysfunction, and that metformin can modulate said effect,” explains Víctor M. Víctor, researcher at the UV and FISABIO and one of the article’s authors.

To perform the study, which is on the front page of this pioneering publication in its field, researchers analyzed the anthropometric (body size, weight, stature) and biochemical markers from 135 healthy individuals and 120 patients with type-2 diabetes recruited at the Endocrinology Department of University Hospital Dr. Peset, in Valencia. Of these, 81 patients were being treated with metformin and 39 were not.

The study shows the improvement of mitochondrial function in patients with type-2 diabetes being treated with metformin. Furthermore, also in these patients, researchers observed a decrease in the interactions between leukocytes and endothelial cells, which entails a decrease in the inflammatory process associated with type-2 diabetes.

In this sense, aside from type-2 diabetes, other diseases could derive from mitochondrial dysfunction. Several studies say that arteriosclerosis, a condition that entails the narrowing of arteries, could also be linked to the bad functioning of mitochondria. Therefore, according to this study, metformin could also be an effective treatment against developing arteriosclerosis and, as a result, cardiovascular diseases.

Aranzazu Martínez de Marañón, FISABIO researcher and first signee of the article, says, “The message we want to spread with this article is that metformin, while far from being an exclusive treatment to regulate blood glucose levels, has several benefits on a cellular level. Specifically, it improves the state of mitochondria and the function of immune cells. This decreases the initial stages of the atherosclerotic process, a common complication in patients with type-2 diabetes.”

“Our findings have significant clinical implications, as they back the idea that metformin plays a key role in modulating the inflammation that takes place in patients with type-2 diabetes. Meanwhile, the study highlights the beneficial effects of this drug, which prevents mitochondrial dysfunction and deregulation,” says researcher Víctor M. Víctor.

Featured Image Credit: Sonis Photography / Shutterstock


Reference: Aranzazu M. de Marañón et al, Does Metformin Modulate Mitochondrial Dynamics and Function in Type 2 Diabetic Patients?, Antioxidants & Redox Signaling (2021). DOI: 10.1089/ars.2021.0019


Provided by Asociacion RUVID

New Benefits from Anti-Diabetic Drug Metformin (Medicine)

Metformin inhibits disease progression in non-diabetic chronic kidney disease (ND-CKD)

Researchers from Kumamoto University (Japan) have found that the anti-diabetic drug metformin significantly prolongs the survival of mice in a model that simulates the pathology of non-diabetic chronic kidney disease (ND-CKD) by ameliorating pathological conditions like reduced kidney function, glomerular damage, inflammation and fibrosis. Metformin’s mechanism is different from existing therapeutics which only treat symptoms, such as the blood pressure drug losartan, so the researchers believe that a combination of these medications at low dose will be highly beneficial.

CKD (chronic kidney disease) is a general term for kidney damage that results from persistent decline in kidney function due to proteinuria, kidney inflammation, or fibrosis. As CKD progresses, patients are forced to undergo dialysis, and diabetes is one of its biggest risk factors. CKD can also occur in association with lifestyle-related conditions such as hypertension, insufficient exercise, smoking, hyperuricemia, and mutations in kidney-related genes. This type of CKD is classified as non-diabetic chronic kidney disease (ND-CKD) and has limited treatment options.

Alport syndrome is an inherited kidney disease that falls under the ND-CKD umbrella. In Alport syndrome, abnormalities in type 4 collagen, a constituent of the membrane responsible for urine filtration in the kidney, cause abnormal glomerular filtration which results in chronic loss of kidney function. It is a serious disease that eventually progresses to end-stage renal failure, requiring dialysis or kidney transplant. As with diabetic kidney disease and ND-CKD, Alport syndrome is currently treated by maintaining kidney function using blood pressure-lowering drugs but patients eventually transition to end-stage renal failure. Therefore, a new therapeutic agent that is effective and safe enough to be administered to patients for a long period of time is needed.

Metformin, unlike losartan, also targets amelioration of metabolic abnormalities. © Professor Hirofumi Kai

Metformin is used as a treatment for type 2 diabetes because it improves insulin sensitivity. It is an inexpensive and safe drug that has been used by diabetics for many years. Interestingly, because of its mechanism of action, metformin was also known to be protective against many diseases involving inflammation and fibrosis, and was known to improve the renal pathology of diabetic kidney disease. However, it was unclear whether metformin also had a protective effect on ND-CKD, which is not caused by diabetes.

Researchers selected an Alport syndrome mouse model for their ND-CKD experiments and worked to identify novel therapeutic targets based on pathogenic mechanisms. They focused on drugs traditionally used for CKD patients, metformin and losartan—which works by lowering blood pressure and inhibiting proteinuria caused by increased glomerular filtration.

Administration of metformin or losartan to ND-CKD model mice significantly suppressed proteinuria and serum creatinine, which are indicators of CKD. Inflammation and fibrosis, which also reduce kidney function, significantly improved. Furthermore, metformin was found to have a nephroprotective effect similar to losartan.

Left: Administration of metformin or losartan to model mice significantly prolonged survival.
Right: Combined administration of low dose metformin and losartan significantly prolonged the survival of mice at doses where metformin alone does not show any effect. © Professor Hirofumi Kai

The results of a detailed gene expression analysis found that the renal pathology of the ND-CKD mouse model was caused by abnormal expression of genes related to glomerular epithelial cell podocytes (cells responsible for kidney filtering) and genes involved in intracellular metabolism. Interestingly, the improvement caused by losartan was limited to genes involved in podocyte abnormalities. Metformin, on the other hand, improved the expression of genes related to podocyte abnormalities and those related to intracellular metabolism. In other words, metformin clearly has a different target of action (also improved targeting of metabolic abnormalities) from that of losartan.

Finally, they found that administration of low-dose metformin and losartan to model mice significantly prolonged their survival. Researchers also found that in studies using doses at which metformin alone was not effective, the combination of metformin and losartan significantly prolonged mice survival. Put plainly, this study showed that an appropriate combination of the two therapeutic drugs could effectively treat the ND-CKD (Alport syndrome) mouse model.

This study raises the possibility that metformin, a proven and inexpensive diabetic drug, may delay the progression of kidney pathology in ND-CKD, including Alport syndrome. Metformin is currently available for use in patients with diabetes in clinical practice, but not in non-diabetic patients.

“This study appears to show that metformin has therapeutic effects for both diabetic and non-diabetic kidney disease,” said Professor Hirofumi Kai, who led the research project. “However, metformin is contraindicated in patients with severe renal dysfunction (eGFR < 30) due to the development of lactic acidosis as a side effect and should be administered with caution to patients with mild to moderate renal dysfunction.”

This research found that the appropriate combination of metformin and losartan significantly improved renal pathology and prolonged survival in a ND-CKD mouse model. This suggests that the old inexpensive drug metformin could become a new inexpensive drug for patients with chronic kidney disease.

This research was posted online in “Scientific Reports” on 29 March 2021.


Source:
Omachi, K., Kaseda, S., Yokota, T., Kamura, M., Teramoto, K., Kuwazuru, J., … Kai, H. (2021). Metformin ameliorates the severity of experimental Alport syndrome. Scientific Reports, 11(1). doi:10.1038/s41598-021-86109-1

[Publication URL]
https://www.nature.com/articles/s41598-021-86109-1

[Funds]
1) KAKENHI Grants from MEXT Japan, 2) The Alport Syndrome Research Funding Program of the
Alport Syndrome Foundation, 3) the Pedersen family, Kidney Foundation of Canada, 4) a grant from
the National Institutes of Health

Featured image: Low dose metformin was found to have a nephroprotective effect similar to losartan. © Professor Hirofumi Kai


Provided by Kumamoto University

GOSH-led Metformin Trial Dramatically Reduces Seizures For People With Tuberous Sclerosis (Medicine)

A team of researchers led by UCL Great Ormond Street Institute of Child Health (ICH) and Great Ormond Street Hospital (GOSH) has found that metformin – a drug commonly used to treat Type 2 diabetes – can successfully reduce symptoms associated with tuberous sclerosis complex (TSC), including reduction in the frequency of seizures and the size of brain tumours.

The study, which also included teams from Royal United Hospitals Bath NHS Foundation Trust (RUH) and University Hospitals Bristol and Weston NHS Foundation Trust, recruited 51 patients with TSC who were randomly assigned a placebo or metformin for one year on a dose similar to that given for Type 2 diabetes.

TSC is a genetic disorder characterised by the development of benign tumours due to loss of inhibitory regulation of the mTOR (mechanistic Target of Rapamycin) intracellular growth pathway. As a result, people with the condition may develop tumours (hamartomas) throughout the body that can affect the heart, kidneys, brain, skin and nails. Although some with the condition may experience few issues, for others it can be disfiguring or even have life threatening complications. As tumours can form in the brain, 75% of people with TSC will have epilepsy, which can lead to daily seizures.

Throughout the study, the research team wanted to see if metformin could limit the tumour growth and epilepsy associated with TSC.

Over the course of the year, the team found a 21% reduction in the size of brain tumours of those who were given metformin, compared to a 3% increase in tumour size for those taking the placebo. Patients with epilepsy and taking metformin saw a 44% drop in the frequency of their seizures, compared to a drop of only 3% for those on the placebo.

Metformin has been gaining attention in cancer research, with large population studies starting to show reduced rates of cancers in those regularly taking it.

Finbar O’Callaghan, professor of paediatric neuroscience at ICH and consultant paediatric neurologist at GOSH and lead investigator of the study said: “This is the first time a cheap, readily available, safe drug has been found to improve the symptoms of TSC. And we found metformin to be even more effective in treating young people. Some patients, who were having multiple seizures a day or week became seizure free after 12 months of treatment, while others are having far fewer seizures than before. We’re excited by what this could mean for the day-to day management of tuberous sclerosis patients.”

“We remain optimistic about the impact we’ve seen on the treatment of brain tumours and epileptic seizures, and believe this is a very promising step forward in improving quality of life for the children and adults living with TSC. Next steps for this work will be to conduct further large-scale trials in Tuberous sclerosis patients to determine the best doses to use and to demonstrate that the effect we have seen is repeatable in a larger population.”

It is estimated that between 3,700 – 11,000 people in the UK live with TSC. There is currently no cure, and only its symptoms can be treated with regular monitoring by a specialist doctor. Although the tumours in TSC patients are benign, the symptoms are not, and current treatments are not only expensive but have toxic side effects as they are immunosuppressants. GOSH treats 150 children with this condition and works closely with the two other hospitals with specialist TSC. The study team run specialist TS clinics at GOSH, the Royal United Hospital in Bath, and Bristol Royal Hospital for Children. These clinics follow up the largest number of TSC patients in the UK.

Zoe Bull, pictured above, was 18 months old when she was diagnosed with TSC, following some seizures. Doctors found benign tumours in her brain, kidneys and on her skin. After her diagnosis, Zoe was seizure-free until she had a focal-aware seizure, aged 10 on a family holiday to Disney World. “It was an unsettling wave-like sensation and what a remember feeling was a loss of control. It’s not something I could openly discuss with anyone, although eventually I was able to tell one friend and then another, until I developed a strong support network,” she said.

Zoe’s condition had been managed with medication to prevent and control her seizures but, as one of the tumours in Zoe’s kidneys was larger than 1cm, she was approached to see if she would like to be involved in the Metformin trial. Although Zoe didn’t know it at the time, she was one of the patients receiving metformin. Her results were encouraging, with a 38% reduction in brain tumour volume and a 75% reduction in seizure frequency during the course of the study.

“My hope is that medicines like this open the door for more treatment options and even a cure for TSC one day. I was fortunate enough to pass my driving test during a time when I was seizure-free but have since surrendered my licence. Hopefully, I will be able to drive again in the future, even if it was just to the shops!”


Featured image: Zoe Bull © GOSH


Reference: Sam Amin, Andrew A Mallick, Hannah Edwards et al., “The metformin in tuberous sclerosis (MiTS) study: A randomised double-blind placebo-controlled trial”, Volume 32, 100715, February 01, 2021. DOI: https://doi.org/10.1016/j.eclinm.2020.100715


Provided by GOSH for Children

Use of Goldenseal May Compromise Glucose Control in Diabetics on Metformin (Medicine)

Diabetic patients taking the natural product goldenseal while taking the prescription drug metformin may be unwittingly sabotaging their efforts to maintain healthy blood glucose levels. This concern arose from a recent study published in the journal Clinical Pharmacology & Therapeutics.

Metformin—the world’s most-prescribed oral glucose-lowering medication—was included in a cocktail of selected drugs given to participants in a clinical study led by scientists at Washington State University’s College of Pharmacy and Pharmaceutical Sciences. The study sought to determine the impact of goldenseal on specific drug transporters, proteins that facilitate absorption or expulsion of drug molecules in different tissues such as the intestine, liver and kidney.

“After six days of taking goldenseal, participants had about 25 percent less metformin in their bodies, a statistically significant change that could potentially impact glucose control in patients with type 2 diabetes,” said the study’s first author James Nguyen, a Ph.D. candidate in pharmaceutical sciences and recent Doctor of Pharmacy graduate. He said the finding serves as a caution to health care providers and patients that over-the-counter natural product use can lead to unwanted drug interactions, which may lead to negative health outcomes.

James Nguyen

Unstable glucose levels increase patients’ risk of serious health complications, such as heart disease, kidney disease and infections. Adding to that concern, Nguyen said there are reports that diabetic patients are increasingly using goldenseal and berberine—a substance found in goldenseal—to self-treat their condition, likely based on claims that berberine helps lower glucose levels.

A perennial herb native to North America, goldenseal is often combined with Echinacea, a top-selling botanical product, in herbal remedies used to self-treat the common cold and other respiratory tract infections. Goldenseal is also commonly used to self-treat digestive issues such as diarrhea and constipation as well as rashes and other skin problems.

Establishing Best Practices

Goldenseal is one of several natural products being studied by the researchers as part of the National Institutes of Health-funded Center of Excellence for Natural Product Drug Interaction Research, a WSU-led, multidisciplinary effort to develop standardized approaches for studying interactions between natural products and pharmaceutical drugs.

Senior author and center principal investigator Mary Paine—a professor in the WSU College of Pharmacy & Pharmaceutical Sciences—noted that while the Food and Drug Administration and other regulatory agencies have well-established guidelines for studying potential interactions between drugs, no such guidelines exist for natural product-drug interactions. This gap exists because, unlike drugs, natural products are not required to be tested for potential drug interaction risks prior to entering the market.

Mary Paine © WSU

“Our work in this goldenseal study helps lay the foundation for establishing best practices for studying these interactions, with a particular niche in transporter-mediated interactions,” Paine said.

Study Tests Model Predictions

One of the overarching goals of this recently published study was to determine whether established FDA basic mathematical models for predicting transporter-mediated drug-drug interactions could be used to successfully predict natural product-drug interactions. To find out, the researchers partnered with a contract research organization to conduct test tube experiments to determine whether a goldenseal extract inhibited any of 15 different transporters. Data from those experiments were then incorporated into the models to predict whether goldenseal interacts with any of the drugs included in a drug cocktail slated to be used in the subsequent clinical study. The cocktail included low doses of three different drugs known to be transported by various transporters: furosemide (a diuretic), rosuvastatin (an anti-cholesterol drug), and metformin. The drug midazolam (a short-acting sedative) was included in the cocktail as a positive control, or a drug known to interact with goldenseal. Goldenseal inhibits the metabolic enzyme that breaks down midazolam, leading to increased midazolam in the body.

Finally, they conducted a clinical study with 16 healthy participants to see if their predictions held up. Participants were given just the drug cocktail during the baseline phase. In the goldenseal exposure phase, participants took goldenseal three times daily for five days before being given the drug cocktail and another dose of goldenseal on day six, followed by two more doses later that day. Blood and urine samples were collected at regular intervals after participants took the drug cocktail and analyzed by the researchers to compare how each drug moved through the body with or without exposure to goldenseal.

Based on their model predictions, the researchers expected to find an interaction between goldenseal and rosuvastatin in the clinical study, but it did not materialize. Surprisingly, the clinical data showed that taking goldenseal along with metformin decreased metformin blood concentrations, which the model predictions did not reveal.

These findings will help the researchers refine these models to increase prediction accuracy of future natural product-drug interaction studies. As follow-up to the research, Nguyen plans to conduct studies to determine the mechanism by which goldenseal alters metformin absorption. Based on the data, he said that this appears to happen in the intestine and may be driven by the transporter OCT1. This research could eventually lead to the discovery of other natural product-drug interactions involving goldenseal and drugs transported by OCT1.

In addition to researchers at WSU, the team includes scientists from the University of North Carolina at Greensboro, the University of Washington, the University of Pittsburgh and SOLVO Biotechnology.

The study was funded by the National Center for Complementary and Integrative Health U54 Center Grant for Natural Product-Drug Interaction Research, U54-AT008909.

Featured image: Golden seal plant © Judith Van Dongen, WSU Health Sciences Spokane Office of Research


Reference: Nguyen, J.T., Tian, D.‐D., Tanna, R.S., Hadi, D.L., Bansal, S., Calamia, J.C., Arian, C.M., Shireman, L.M., Molnár, B., Horváth, M., Kellogg, J.J., Layton, M.E., White, J.R., Cech, N.B., Boyce, R.D., Unadkat, J.D., Thummel, K.E. and Paine, M.F. (2020), Assessing Transporter‐Mediated Natural Product‐Drug Interactions Via In vitro‐In Vivo Extrapolation: Clinical Evaluation With a Probe Cocktail. Clin Pharmacol Ther. https://doi.org/10.1002/cpt.2107


Provided by Washington State University

Metformin Use Reduces Risk of Death for Patients With COVID-19 and Diabetes (Medicine)

Use of the diabetes drug metformin — before a diagnosis of COVID-19 — is associated with a threefold decrease in mortality in COVID-19 patients with Type 2 diabetes, according to a racially diverse study at the University of Alabama at Birmingham. Diabetes is a significant comorbidity for COVID-19.

Use of the diabetes drug metformin — before a diagnosis of COVID-19 — was associated with a threefold decrease in mortality in COVID-19 patients with Type 2 diabetes.

“This beneficial effect remained, even after correcting for age, sex, race, obesity, and hypertension or chronic kidney disease and heart failure,” said Anath Shalev, M.D., director of UAB’s Comprehensive Diabetes Center and leader of the study.

“Since similar results have now been obtained in different populations from around the world — including China, France and a UnitedHealthcare analysis — this suggests that the observed reduction in mortality risk associated with metformin use in subjects with Type 2 diabetes and COVID-19 might be generalizable,” Shalev said.

How metformin improves prognosis in the context of COVID-19 is not known, Shalev says. The UAB findings suggest that the mechanisms may go beyond any expected improvement in glycemic control or obesity, since neither body mass index, blood glucose nor hemoglobin A1C were lower in the metformin users who survived as compared to those who died.  

“The mechanisms may involve metformin’s previously described anti-inflammatory and anti-thrombotic effects,” Shalev said.

The study — first  made available in MedRxiv and now published in the peer-reviewed journal Frontiers in Endocrinology — included 25,326 patients tested for COVID-19 at the tertiary care UAB Hospital between Feb. 25 and June 22 of last year. Of the 604 patients found to be COVID-19-positive, 311 were African Americans. 

The primary outcome in the study was mortality in COVID-19-positive subjects, and the potential association with subject characteristics or comorbidities was analyzed.

Researchers found that Blacks, who are only 26 percent of Alabama’s population, were 52 percent of those who tested positive for COVID-19, and only 30 percent of those who tested negative. In contrast, only 36 percent of the COVID-19-positive subjects were white, while whites made up 56 percent of those who tested negative, further underlining the racial disparity. Once COVID-19-positive though, no significant racial difference in mortality was observed. 

“In our cohort,” Shalev said, “being African American appeared to be primarily a risk factor for contracting COVID-19, rather than for mortality. This suggests that any racial disparity observed is likely due to exposure risk and external socioeconomic factors, including access to proper health care.”

Overall mortality for COVID-19-positive patients was 11 percent. The study found that 93 percent of deaths occurred in subjects over the age of 50, and being male or having high blood pressure was associated with a significantly elevated risk of death. Diabetes was associated with a dramatic increase in mortality, with an odds ratio of 3.62. Overall, 67 percent of deaths in the study occurred in subjects with diabetes. 

The researchers looked at the effects of diabetes treatment on adverse COVID-19 outcomes, focusing on insulin and metformin as the two most common medications for Type 2 diabetes. They found that prior insulin use did not affect mortality risk.

However, prior metformin use was a different matter. Metformin use significantly reduced the odds of dying, and the 11 percent mortality for metformin users was not only comparable to that of the general COVID-19-positive population, it was dramatically lower than the 23 percent mortality for diabetes patients not on metformin.

After controlling for other covariates, age, sex and metformin use emerged as independent factors affecting COVID-19-related mortality. Interestingly, even after controlling for all these other covariates, death was significantly less likely — with an odds ratio of 0.33 — for Type 2 diabetes subjects taking metformin, compared with those who did not take metformin.

Anath Shalev, M.D. © UAB

“These results suggest that, while diabetes is an independent risk factor for COVID-19-related mortality,” Shalev said, “this risk is dramatically reduced in subjects taking metformin — raising the possibility that metformin may provide a protective approach in this high-risk population.” 

The researchers say future studies will need to explore how metformin is protective, as well as assess the risks and benefits of metformin treatment and the indications for its use in the face of the ongoing COVID-19 pandemic. 

This study is part of a new Precision Diabetes Program, a collaboration between the UAB Comprehensive Diabetes Center and the Hugh Kaul Precision Medicine Institute at UAB. 

Co-authors with Shalev for the paper, “Metformin use is associated with reduced mortality in a diverse population with COVID-19 and diabetes,” are Andrew B. Crouse and Matthew Might, the Hugh Kaul Precision Medicine Institute at UAB; Tiffany Grimes and Fernando Ovalle, the Comprehensive Diabetes Center and the Department of Medicine Division of Endocrinology, Diabetes and Metabolism at UAB; and Peng Li, UAB School of Nursing

Support came from National Institutes of Health grants DK078752, DK120379 and TR001417.

Shalev is a professor in the UAB Department of Medicine Division of Endocrinology, Diabetes and Metabolism, and she holds the Nancy R. and Eugene C. Gwaltney Family Endowed Chair in Juvenile Diabetes Research.

Reference: Andrew Crouse, Tiffany Grimes, Peng Li, Matthew Might et al., “Metformin Use Is Associated With Reduced Mortality in a Diverse Population With COVID-19 and Diabetes”, Front. Endocrinol., 13 January 2021 | https://doi.org/10.3389/fendo.2020.600439 https://www.frontiersin.org/articles/10.3389/fendo.2020.600439/full?&utm_source=Email_to_authors_&utm_medium=Email&utm_content=T1_11.5e1_author&utm_campaign=Email_publication&field=&journalName=Frontiers_in_Endocrinology&id=600439

Provided by University of Alabama at Birmingham

A Molecule From Gut Bacteria Reduces Effect Of Diabetes Medication (Medicine)

The action of metformin, the classic drug used to treat diabetes by stabilizing blood sugar, can be blocked by a molecule from the bacteria in our intestines, a University of Gothenburg study shows.

©Ara Koh et al.

Metformin is the primary treatment option for type 2 diabetes, but there are major variations in how individuals respond to this drug. In some people it lowers blood glucose (sugar) and delays the course of the disease, while in others its effects are less favorable.

An article published in the journal Cell Metabolism now clarifies one underlying factor that explain why metformin action can be blocked. This blocking is preceded by processes in the gut bacteria — the intestinal microbiota — in which the molecule imidazole propionate is produced.

The change in gut microbiota associated with type 2 diabetes has been demonstrated in previous research under the leadership of Fredrik Backhed, Professor of Molecular Medicine at Sahlgrenska Academy, University of Gothenburg.

He has also shown that the altered gut microbiota brings about a change in metabolism of the amino acid histidine. This, in turn, leads to an increase in the production of imidazole propionate, a molecule that inhibits the effects of insulin in lowering blood glucose.

The present study shows that, besides blocking the effects of insulin, imidazole propionate also reduces the efficacy of metformin in lowering blood glucose. In type 2 diabetes patients, high imidazole propionate levels proved to be associated with impaired metformin action, and vice versa.

The study also shows that imidazole propionate impairs the glucose-lowering effect of metformin in mice.

“Our study demonstrates clearly that imidazole propionate not only inhibits the effects of insulin but may also reduce the therapeutic action of the metformin,” Backhed says.

“Since imidazole propionate has also been linked to inflammation in the gut, and metformin has several side effects in the form of intestinal problems, it’s conceivable that imidazole propionate both blocks the treatment effect and contributes to side effects of metformin. But new studies are needed to verify this hypothesis.”

How imidazole propionate obstructs the efficacy of metformin in regulating blood glucose has been thoroughly investigated through applied biochemistry and molecular biology. Ara Koh is the first author of the study.

“We found out that imidazole propionate interacts with AMPK, the same molecule as metformin. But instead of activating AMPK, imidazole propionate inhibits metformin-induced AMPK activation,” she relates.

By blocking another protein, p38gamma, which is required to enable imidazole propionate to block AMPK (AMP-activated protein kinase), the researchers were able to inhibit the effects of imidazole propionate.

The research group works at the Wallenberg Laboratory for Cardiovascular and Metabolic Research at the University of Gothenburg, and the present study was conducted in collaboration with Sahlgrenska University Hospital.

“The work demonstrates the robustness of the translational research carried out at the Wallenberg Lab. There, observations of patients can be explained in molecular terms, which can give rise to new therapies,” Fredrik Backhed concludes.

References: Ara Koh, Louise Mannerås-Holm, Na-Oh Yunn, Rosie Perkins, J. Gustav Smith et al., “Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation”, VOLUME 32, ISSUE 4, P643-653.E4, OCTOBER 06, 2020. DOI:https://doi.org/10.1016/j.cmet.2020.07.012 link: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30370-3?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1550413120303703%3Fshowall%3Dtrue

Cell Ageing Can Be Slowed By Oxidants (Biology)

At high concentrations, reactive oxygen species – known as oxidants – are harmful to cells in all organisms and have been linked to ageing. But a study from Chalmers University of Technology, Sweden, has now shown that low levels of the oxidant hydrogen peroxide can stimulate an enzyme that helps slow down the ageing of yeast cells.

Yeast can be grown on both solid and liquid nutrition medium and is a good model system for studying ageing. Yeast cells share many molecular mechanisms with cells in more complex organisms, yet it is easy to change their DNA and study different genes’ functions. Yeast also produces many generations in a short time. ©Martina Butorac/Chalmers University of Technology

One benefit of antioxidants, such as vitamins C and E, is that they neutralise reactive oxygen species – known as oxidants – which may otherwise react with important molecules in the body and destroy their biological functions. Larger amounts of oxidants can cause serious damage to DNA, cell membranes and proteins for example. Our cells have therefore developed powerful defence mechanisms to get rid of these oxidants, which are formed in our normal metabolism.

It was previously believed that oxidants were only harmful, but recently we have begun to understand that they also have positive functions. Now, the new research from Chalmers University of Technology shows that the well-known oxidant hydrogen peroxide can actually slow down the ageing of yeast cells. Hydrogen peroxide is a chemical used for hair and tooth whitening, among other things. It is also one of the oxidants formed in our metabolism that is harmful at higher concentrations.

The Chalmers researchers studied the enzyme Tsa1, which is part of a group of antioxidants called peroxiredoxins.

“Previous studies of these enzymes have shown that they participate in yeast cells’ defences against harmful oxidants,” says Mikael Molin, who leads the research group at Chalmers’ Department of Biology and Biological Engineering. “But the peroxiredoxins also help extend the life span of cells when they are subjected to calorie restriction. The mechanisms behind these functions have not yet been fully understood.”

It is already known that reduced calorie intake can significantly extend the life span of a variety of organisms, from yeast to monkeys. Several research groups, including Mikael Molin’s, have also shown that stimulation of peroxiredoxin activity in particular is what slows down the ageing of cells, in organisms such as yeast, flies and worms, when they receive fewer calories than normal through their food.

Yeast is a good model system for studying ageing. The researchers can easily determine the age of the cells by counting the bud scars, formed when they divide and form new cells by budding (left). As the yeast cells age, you can examine, for example, how proteins are damaged and aggregate (light spots in the image to the right), a process that in higher organisms can be linked to the degeneration of nerve or brain cells in, for example, Alzheimer’s or Parkinson’s disease. ©Mikael Molin/Chalmers University of Technology

“Now we have found a new function of Tsa1,” says Cecilia Picazo, postdoctoral researcher at the Division of Systems and Synthetic Biology at Chalmers. “Previously, we thought that this enzyme simply neutralises reactive oxygen species. But now we have shown that Tsa1 actually requires a certain amount of hydrogen peroxide to be triggered in order to participate in the process of slowing down the ageing of yeast cells.”

Surprisingly, the study shows that Tsa1 does not affect the levels of hydrogen peroxide in aged yeast cells. On the contrary, Tsa1 uses small amounts of hydrogen peroxide to reduce the activity of a central signalling pathway when cells are getting fewer calories. The effects of this ultimately lead to a slowdown in cell division and processes linked to the formation of the cells’ building blocks. The cells’ defences against stress are also stimulated – which causes them to age more slowly.

“Signal pathways which are affected by calorie intake may play a central role in ageing by sensing the status of many cellular processes and controlling them,” says Mikael Molin. “By studying this, we hope to understand the molecular causes behind why the occurrence of many common diseases such as cancer, Alzheimer’s disease, and diabetes shows a sharp increase with age.”

The fact that researchers have now come a step closer to understanding the mechanisms behind how oxidants can actually slow down the ageing process could lead to new studies, for example looking for peroxiredoxin-stimulating drugs, or testing whether age-related diseases can be slowed by other drugs that enhance the positive effects of oxidants in the body.

More about: The mechanism of slowed ageing by the enzyme Tsa1:

The Chalmers researchers have shown a mechanism for how the peroxiredoxin enzyme Tsa1 directly controls a central signalling pathway. It slows down ageing by oxidising an amino acid in another enzyme, protein kinase A, which is important for metabolic regulation. The oxidation reduces the activity of protein kinase A by destabilising a portion of the enzyme that binds to other molecules. Thus, nutrient signalling via protein kinase A is reduced, which in turn downregulates the division of cells and stimulates their defence against stress.

More about: Related results from other research groups:

Other studies have also shown that low levels of reactive oxygen species can be linked to several positive health effects. These oxidants are formed in the mitochondria, the ‘powerhouse’ of a cell, and the process, called mitohormesis, can be observed in many organisms, from yeast to mice. In mice, tumour growth is slowed by mitohormesis, while in roundworms it has been possible to link both peroxiredoxins and mitohormesis to the ability of the type 2 diabetes drug metformin to slow cellular ageing.

Metformin is also relevant in the hunt for drugs that can reduce the risk of older people being severely affected by Covid-19. Studies in China and the United States have yielded some promising results, and one theory is that metformin may counteract the deterioration of the immune system caused by ageing.

Reference: Friederike Roger, Cecilia Picazo, Wolfgang Reiter, Marouane Libiad, Chikako Asami, Sarah Hanzén, Chunxia Gao, Gilles Lagniel, Niek Welkenhuysen, Jean Labarre, Thomas Nyström, Morten Grøtli, Markus Hartl, Michel B Toledano, Mikael Molin, “Peroxiredoxin promotes longevity and H2O2-resistance in yeast through redox-modulation of protein kinase A”, Biochemistry and Chemical Biology, 2020. Doi: https://doi.org/10.7554/eLife.60346 link: https://elifesciences.org/articles/60346

Provided by Chalmers University Of Technology

New Research Provides Fresh Hope For Children Suffering From Rare Muscle Diseases (Medicine)

Results of an international study published today in Autophagy and led by researchers from Monash University, School of Biological Sciences, provides renewed hope for children suffering from a progressive and devastating muscle disease.

Stephen Greenspan and Laura Zah were devastated when they learned their son Alexander had a rare genetic mutation, which causes a deadly neuromuscular disease with no known treatment or cure.

Metformin rescues muscle function in BAG3 myofibrillar myopathy models. ©Taylor & Francis

But the results of an international study published today in Autophagy and led by researchers from Monash University, School of Biological Sciences, provides renewed hope for children suffering from the progressive and devastating muscle disease. Known as myofibrillar myopathies, these rare genetic diseases lead to progressive muscle wasting, affecting muscle function and causing weakness.

Using the tiny zebrafish, Associate Professor Robert Bryson-Richardson from the School of Biological Sciences and his team of researchers were able to show that a defect in protein quality control contributes to the symptoms of the diseases.

“We tested 75 drugs that promote the removal of damaged proteins in our zebrafish model and identified nine that were effective” explained first author Dr Avnika Ruparelia, who completed her student and post-doctoral training in the team working on the disease. “Importantly two of these are already approved for human use in other conditions.”

“We found that one of the drugs, metformin, which is normally used to treat diabetes, removed the accumulating damaged protein in the fish, prevented muscle disintegration and restored their swimming ability,” said Associate Professor Bryson-Richardson, who led the study.

The most severe form of the myofibrillar myopathy, caused by a mutation in the gene BAG3, starts to affect children between 6 and 8 years of age. The disease is usually fatal before the age of 25 due to respiratory or cardiac failure.

In the case of Alexander (who was born in 2003) clinicians were able to draw on the study’s information to prescribe metformin – which is so far proving positive.

“Initially, we were devastated by our son’s diagnosis. Alexander has a rare mutation that causes a deadly neuromuscular disease. No treatment or cure was known. In desperation we formed the charitable organization, Alexander’s Way, to promote and sponsor research into this disease. Upon learning of our awful problem, A/Prof Bryson-Richardson was compassionate, and found a way to share with us his pre-publication results about the disease and metformin. The research conducted by Robert Bryson-Richardson and Avnika Ruparelia has given us hope, and we thank them deeply for their work and compassion,” said Alexander’s father, Stephen.

“This is a wonderful outcome, as initially we thought that because of the rarity of the mutation, it was unlikely that there would ever be a treatment or therapeutic intervention available,” said Alexander’s mother, Laura Zah. “Compared to previous case studies, the progression of our son’s disease has been slower, likely due to metformin. Another boy, Marco, who is affected by this disease also takes metformin, and is presently judged by his mother to be stable. Metformin may have given us more time with our boys and more time to work for a cure.”

Associate Professor Bryson-Richardson said the repurposing of existing drugs provided a very rapid route to clinical use, as there was already existing safety data for the drug. This is especially important for these rare diseases as the patient numbers are low, meaning it might not be possible to do clinical trials with novel drugs.

“We have identified metformin as a strong candidate to treat BAG3 myofibrillar myopathy, and also myofibrillar myopathy due to mutations in other genes (we showed similar defects in protein quality control in three other forms) and in cardiomyopathy due to mutations in BAG3,” he said.

“Given that metformin is taken by millions of people for diabetes and known to be very safe this makes clinical translation highly feasible, and in fact many patients are now taking it.”

Stephen and Laura Zah are the founders of the charitable organisation Alexander’s Way Research Fund which they established to promote and sponsor research into myofibrillar myopathies.

“The research conducted by Monash scientists has given us hope, and we thank them deeply for their compassion – they have given us time,” said Laura Zah.

References: Avnika A. Ruparelia , Emily A. McKaige, Caitlin Williams, Keith E. Schulze, Margit Fuchs , Viola Oorschot, Emmanuelle Lacene , Mirella Meregalli , Clara Lee , Rita J. Serrano , Emily C. Baxter , Keyne Monro , Yvan Torrente , Georg Ramm, Tanya Stojkovic , Josée N. Lavoie & Robert J. Bryson-Richardson, “Metformin rescues muscle function in BAG3 myofibrillar myopathy models”, Journal Autophagy, doi: https://doi.org/10.1080/15548627.2020.1833500 link: https://www.tandfonline.com/doi/full/10.1080/15548627.2020.1833500

Provided by Taylor And Francis Group