Metformin Mechanism Different Than Previously Thought

Previous lab findings do not tell the complete story of how the diabetes drug metformin works to limit the level of glucose in the blood, suggests a Mayo Clinic study. Researchers there found that metformin does not actually limit the action of the hormone glucagon, specifically glucagon-stimulated glucose production from the liver.

Metformin’s action is typically involved with the release of glucose from the liver.

The liver releases glucose when prodded by a pancreatic hormone called glucagon. Glucagon is released when blood glucose levels drop. Metformin is thought to limit the action of glucagon, the substances used to make it, or affect the level of enzymes used to make it.

“In our clinical trial, metformin treatment appeared to trigger a compensatory increase of glucagon that may mitigate the ability of metformin to lower glucose production in prediabetic individuals and prevent the likelihood of hypoglycemia,”

explained K. Sreekumaran Nair, M.D., Ph.D., Mayo Clinic endocrinologist and senior author of the article.

In their double-blind study of nine prediabetic individuals, the researchers found that for the six individuals with fasting (basal) glucagon levels of less than 150 picograms/milliliter, metformin treatment decreased the liver’s production of glucose as expected. But for the three individuals with basal levels greater than 150 pg/mL, levels of glucose produced by the liver in fact increased after metformin treatment.

The difference in findings could be due to both the study design and participants. Unlike previous preclinical metformin research, this study used human participants and metformin at therapeutic doses. Studies in animal or cellular models have examined higher doses, or used drugs in the same class as metformin that are not approved for use in humans.

Also, unlike many other human studies based on participants with type 2 diabetes, the current report is based on prediabetic individuals. Further research on a larger and more diverse group of patients is needed before the findings can be widely applied.

Study: Hyperglucagonemia Mitigates the Effect of Metformin on Glucose Production in Prediabetes

Image: fickleandfreckled/Flickr

How Taste And Odor Perception Is Altered In Pregnancy

It’s well known that perception of different tastes and smells and tastes can change when a woman is pregnant. But did you know this is also true for flies?

Not only that, but just how these changes are triggered is not really known, either for mammals or insects. But now, scientists from the Max Planck Institute of Neurobiology in Martinsried have shown that the concentration of a certain receptor increases in the sensory organs of pregnant fruit fly females.

Because of this, the taste and odor of important nutrients, known as polyamines, are processed differently in the brain. Pregnant flies favor nutrition that is rich in polyamines and so increase their reproductive success.

Ilona Grunwald Kadow, Research Group Leader at the Max Planck Institute of Neurobiology, said:

“We wanted to find out whether and how expectant mothers can sense the nutrients they need.”

uterus of the female fly
Part of the reproductive system with the uterus of the female fly. Credit: MPI of Neurobiology/ Friedrich

Pregnancy has a huge impact on a mother’s body. To give the best nutrition for the developing offspring, her nutrition must be adapted to the altered requirements.

Polyamines

Polyamines can be made by both the body itself and by intestinal bacteria, but some of the required polyamines must be obtained from food.

With advancing age, the consumption of polyamines through food increases in importance, as the body’s own production declines. Polyamines play a role in numerous cell processes and a polyamine deficiency can have a negative impact on health, cognition, reproduction and life expectancy.

chemosensory neurons
SPR/MIP signaling in chemosensory neurons adjusts female preference behavior upon mating. PLoS Biol

An excess of polyamines can also be harmful, however. The intake of polyamines therefore need to be adapted to the body’s current needs. Neurobiologists at Max Planck demonstrated that, after mating, female fruit flies show a preference for food with a high polyamine content.

Behavioural studies and physiological tests revealed that the change in the appeal of polyamines to flies before and after mating is triggered by a neuropeptide receptor known as the sex peptide receptor (SPR) and its neuropeptide binding partner.

“It was already known that the SPR boosts egg production in mated flies,” explains Ashiq Hussain, one of two first authors. “But we were surprised to discover that the SPR also regulates the activity of the sensory neurons that recognize the taste and smell of polyamines.”

Many more sex peptide receptors are integrated into the surfaces of the chemosensory neurons in pregnant females. This increase in neuropeptide signalling modifies the reaction of the sensory neurons to the odour and taste. The thereby intensified odour and taste perception therefore occurs at a very early stage in the nervous system.

“Because smell and taste are processed in a similar way in insects and mammals, a corresponding mechanism in humans could also ensure an optimal nutritional supply for the developing life,” said Habibe Üc̗punar, second first author.

Study: Neuropeptides Modulate Female Chemosensory Processing upon Mating in Drosophila

Viral Infections Can Increase Children’s Diabetes Risk

In an analysis of data on children, a team of scientists at the Helmholtz Zentrum München has found that viral respiratory infections during the first six months of life are associated with an increased risk for type 1 diabetes.

Led by Prof. Dr. Anette-Gabriele Ziegler, Director of the Institute of Diabetes Research (IDF) at Helmholtz, the scientists examined anonymized data from almost 300,000 children born in Bavaria between 2005 and 2007. This is 85 percent of all newborns in Bavaria during this period. The data material was provided by The Kassenärztliche Vereinigung Bayern (KVB – Bavarian Association of Statutory Health Insurance Physicians) for research purposes.

The infections were categorized by location of symptoms (such as dermal, eye, gastrointestinal or respiratory infections), causes (bacterial, viral or mycoses) and age (quarter-yearly from birth). Dr. Ziegler’s team systematically evaluated all available data on infections with respect to the later development of type 1 diabetes.

Explains Dr. Andreas Beyerlein, the study’s first author:

“Our findings show that viral respiratory tract disorders during the first six months of life significantly increase the risk of children developing type 1 diabetes.”

Infections that happened later or that involved other organs were not associated with a significantly higher risk. For the researchers, these findings are a further piece in the puzzle of learning how type 1 diabetes develops. The interaction of genetic and environmental factors in diabetes is still largely unclear.

Up until now there were only relatively inconsistent indications from studies with children with a genetically higher risk of type 1 diabetes regarding the influence of infections.

“Now for the first time we were able to confirm this in a population-based dataset of almost 300,000 children. In particular, we found strong indications that the first six months are an especially sensitive stage in life,” explains lead scientist Ziegler. “This is also consistent with other results that we have published based on data from children with increased familial risk, which already suggested that the first half year of life is crucial for the development of the immune system and of autoimmune diseases such as type 1 diabetes.”

Moving forward, the team would like to determine if there is in fact a causal relationship and if so, precisely which pathogens are involved and how they trigger this effect. The results could then create a basis for trying to develop an appropriate vaccine.

Study: Infections in Early Life and Development of Type 1 Diabetes

Image: Razza Mathadsa/Flickr

Research May Lead To Personalized Breast Cancer Treatment

Five new genes associated with breast cancer have been uncovered by the largest-ever study to sequence the whole genomes of breast cancers. The study also found 13 new mutational signatures that influence tumor development.

The findings also uncover what genetic variations exist in breast cancers and where in the genome they occur. The results also provide evidence that breast cancer genomes are highly individual.

This international collaboration was led by Dr Serena Nik-Zainal of the Wellcome Trust Sanger Institute. The study involved analysis of 560 breast cancer genomes; 556 from women and four from men, and included breast cancer patients from around the world, including the USA, Europe and Asia.

Each person’s cancer genome is an exhaustive historical record of the genetic changes acquired throughout their life. As a person develops from a fertilised egg into adulthood, the DNA in their cells collect genetic changes along the way.

In fact, human DNA is constantly being damaged by things in the environment or simply from wear and tear in the cell. These mutations form patterns, or mutational signatures, that scientists can detect and read for clues about the causes of cancer.

Personalised Healthcare For Cancer

Dr Nik-Zainal’s team searched for mutations that embolden cancers to grow, and looked for mutational signatures in each patient’s tumor.

They found that women who carry the BRCA1 or BRCA2 gene, and so have increased risk of developing breast and ovarian cancer, had whole cancer genome profiles that were highly distinctive from each other and were also very different to other breast cancers. This discovery could be used to classify patients more accurately for treatment.

Dr Nik-Zainal says:

“In the future, we’d like to be able to profile individual cancer genomes so that we can identify the treatment most likely to be successful for a woman or man diagnosed with breast cancer. It is a step closer to personalised healthcare for cancer.”

Professor Sir Mike Stratton, Director of the Wellcome Trust Sanger Institute, said:

“All cancers are due to mutations that occur in all of us in the DNA of our cells during the course of our lifetimes. Finding these mutations is crucial to understanding the causes of cancer and to developing improved therapies.

This huge study, examining in great detail the many thousands of mutations present in each of the genomes of 560 cases brings us much closer to a complete description of the changes in DNA in breast cancer and thus to a comprehensive understanding of the causes of the disease and the opportunities for new treatments.”

Nik-Zainal S et al.
Landscape of somatic mutations in 560 breast cancer whole genome sequencesis
Nature 2016 DOI: 10.1038/nature17676

Photo: Ed Uthman/Flickr

Erythropoietin Could Prevent Birth Damage In High-risk Newborns

A synthetic version of the hormone erythropoietin may protect newborns at high risk for brain damage, found a multi-site trial led by researchers at UC San Francisco.

Every year over 800,000 deaths worldwide and many thousands of cases of permanent brain damage in the U.S. are attributed to hypoxic-ischemic encephalopathy (HIE). HIE is a dysfunction of the nervous system caused by birth complications resulting in a drop in oxygen supply and inadequate blood flow to the brain and other organs.

Lead author Yvonne Wu, a child neurologist and professor of Neurology and Pediatrics at UCSF Benioff Children’s Hospital San Francisco, said:

“More than 40 percent of infants will die or suffer moderate to severe disabilities, including cerebral palsy, intellectual impairment and epilepsy. We wanted to find something that could amplify effectiveness.”

The standard care for HIE is hypothermia in which the head or whole body is cooled to 33.5ºC (92.3ºF) in order to accelerate healing. Hypothermia treatment however, doesn’t save all patients.

In a phase II trial done at seven hospitals throughout the nation, the researchers compared outcomes in 26 full-term newborns with HIE, who were treated with hypothermia and placebo, to 24 who were treated with both hypothermia and five infusions of EPO, or erythropoietin, a man-made version of a natural hormone that stimulates the production of red blood cells.

Fewer Incidences of Brain Injury

The drug was approved by the Food and Drug Administration in 1989 to treat anemia in patients with chronic renal failure. It was later prescribed for children and infants.

Previous studies have shown that EPO is an anti-inflammatory and fights apoptosis or cell death. It has also been shown to promote the development of nervous tissue and tissue remodeling after oxygen deprivation.

MRIs of the treated newborns were examined at an average 5 days of age, and eight in the EPO group (33.3 percent) were found to have no brain injury, versus three in the placebo group (11.5 percent). One infant in the EPO group had a severe or moderate injury compared with 11 such injuries in the placebo group.

Two deaths occurred in the EPO-treated newborns, versus five in the placebo group – a difference that was not clinically significant due to the low number of infants in the trial. Serious adverse effects were reported in nine newborns, but were evenly distributed in both groups and none were attributed to EPO, said Wu.

Senior author of the study, published in the journal Pediatrics, Roberta Ballard, MD, a neonatologist and professor of Pediatrics at UCSF Benioff Children’s Hospital San Francisco, said:

“It is clear that this therapy is safe as used in this study and there is a strong suggestion that the patients are doing better than would be expected long term. It would be very encouraging if we find that an inexpensive old drug, costing $60 per infusion, rather than a new drug that costs more than $2 billion to develop may prevent untold suffering.

A larger trial will allow a definitive answer to whether there should be a change in clinical care for this devastating condition.”

HIE occurs in 1 to 3 per 1,000 full-term births. It accounts for 22 percent of annual neonatal deaths worldwide, totaling 814,000 deaths in 2008, according to the Child Health Epidemiology Reference Group of the World Health Organization and the United Nations Children’s Fund.

Original Study

Image: Anthea Sieveking , Wellcome Images

EZH2 Gene Mutation Drives Lymphoma And Melanoma

Researchers at University of North Carolina at Chapel Hill have recently shown how a genetic mutation can drive the most common type of lymphoma as well as melanoma, the deadliest form of skin cancer.

Their work centered on a specific mutation of EZH2, a gene previously known to regulate cell fate. The team also tested an investigational drug to block a protein made by the gene.

Norman Sharpless M.D, director of the University of North Carolina Lineberger Comprehensive Cancer Center, explained:

“We have shown that the biology of tumors driven by this mutation is distinct from other types of lymphoma and melanoma, and that these tumors require persistent malfunction of EZH2 for growth. And with our collaborators, we have shown that a potential new drug designed to target EZH2 mutations in such cancers is very active in our laboratory models.”

This particular mutation is a relatively common event in diverse cancers, occurring in approximately 20 percent of B-cell lymphomas, 5 percent of melanomas, and at lower frequency in a variety of other cancers, Sharpless adds. The findings suggest that thousands of people in the United States annually develop cancer driven by this mutation.

The researchers determined that a mutation in the EZH2 gene alone is sufficient to drive B-cell lymphoma. In contrast, for melanoma, the EZH2 mutation occurs in combination with mutations of the BRAF gene, which occurs in about half of melanoma patients.

First author George P. Souroullas, a research scientist at UNC Lineberger and the UNC School of Medicine genetics department, says the findings could have important implications for both treatment and further drug development.

More concretely, their findings in melanoma indicate that inhibitors of the protein created by the EZH2 gene might work well in combination with inhibitors of BRAF, which are already approved by the US Food and Drug Administration as melanoma therapy.

Furthermore, their findings suggest that EZH2 inhibitors could be an effective strategy in some patients with melanoma or B-cell lymphoma, he adds.

“While there has been significant progress in recent years against cancers such as lymphoma and melanoma, many patients still fail these newer therapies and need further options for therapy,” Sharpless says.

Original Study: An oncogenic Ezh2 mutation induces tumors through global redistribution of histone 3 lysine 27 trimethylation

Image: Wellcome Photo Library, Wellcome Images

Ibrutinib Shows Added Benefits For Refractory Mantle Cell Lymphoma

Ibrutinib, trade name Imbruvica, is approved by the FDA to treat chronic lymphocytic leukemia in patients who have already received other treatment, mantle cell lymphoma in patients who have already received other treatment, and Waldenström macroglobulinemia, a form of non-Hodgkin lymphoma.

Upon a request from the German Federal Joint Committee (G-BA), Johnson & Johnson’s Janssen Pharmaceutical division, the manufacturer of Ibrutinib, has now submitted a new dossier. This is because the turnover of the drug in the statutory health insurance exceeded 50 million euros in the preceding 12 months.

The German Institute for Quality and Efficiency in Health Care (IQWiG) therefore examined in an early benefit assessment whether the drug offers an added benefit for patients with these diseases in comparison with the respective appropriate comparator therapies.

As per the findings, there is no added benefit in chronic lymphocytic leukemia (CLL) and Waldenström macroglobulinaemia.

In the case of refractory mantle cell lymphoma, however, there is an indication of major added benefit of ibrutinib for patients for whom temsirolimus is the individually optimized treatment option. An added benefit is not proven for patients for whom temsirolimus is no or only a secondary option.

Refractory Mantle Cell Lymphoma

MCL is an aggressive type of B-cell non-Hodgkin lymphoma (NHL) that usually occurs in older adults. The disease typically begins in the lymph nodes, but can spread to other tissues, such as bone marrow and the liver. Ibrutinib targets the B-cell receptor pathway, an important pathway in malignant B-cell growth and proliferation.

In the United States, there are approximately 5,000 new cases of MCL each year.

The G-BA separated relapsed or refractory MCL patients into two subpopulations. Those were patients for whom temsirolimus is the individually optimized treatment, and patients for whom this is not the case.

Because of a lack of data, added benefit of ibrutinib is not proven for patients for whom temsirolimus is no or only a secondary treatment option.

For the other patient group, however, the manufacturer presented data from the study MCL3001, in which ibrutinib was compared with temsirolimus. There was no statistically significant difference between the study arms regarding overall survival.

Ibrutinib had positive effects in the outcomes “health status” and “side effects,” which were not offset by negative effects in other outcomes. Overall, there is therefore an indication of major added benefit for patients for whom temsirolimus constitutes the individually optimized treatment.

According to the Wall Street Journal, in January 2016 ibrutinib, a specialty drug, cost US$116,600 to $155,400 a year wholesale in the United States. In spite of discounts and medical insurance, the prohibitive price causes some patients to not fill their prescriptions.

A German version of the extract of dossier assessment can be found here.

Image: Michele Angelo Petrone, Wellcome Images

Unexplained Lower Back Pain? It Could Be Ankylosing Spondylitis

Lower back pain is common and many of those who have suffered it can identify, or at least guess, the event that led to their back injury. Perhaps it was weekend sport or a garden project. Often a trip to the GP or physiotherapist will confirm suspicions and a suitable treatment regime follows.

For others, the cause is less certain. Roughly a quarter of patients under 45 years suffering ongoing lower-back pain (three months or more) without an obvious other cause will have the disease ankylosing spondylitis. This somewhat daunting name essentially means “fused and inflamed spine”.

Ankylosing spondylitis is quite different to other forms of lower back pain: it is not a result of mechanical or muscular injury.

Ankylosing spondylitis is a disease of chronic, inappropriate inflammation. In much the same way as other autoimmune diseases (such as rheumatoid arthritis or type 1 diabetes), sustained inflammation leads to tissue damage and a reduction in normal function.

ankylosing spondylitis symptoms
A and B show side-on and front-to-back views of the lumbar spine in a patient without ankylosing spondylitis. C and D show the lumbar spine in a patient with ankylosing spondylitis ‘bamboo spine’. Note the bone joining (‘ankylosing’) the vertebrae together (arrowed). Author provided

A stark example in patients with severe ankylosing spondylitis is “bamboo spine”, the disturbingly vivid name for fused vertebrae; joined as a result of inflammation-induced bone growth.

Patients with less dramatic ankylosing spondylitis symptoms can still suffer terribly, and the impact on everyday activities and routine tasks can be quite major. Friendships, family relationships and sexual activity can all be affected as a result of fatigue, stiffness and pain.

The most common symptoms are chronic lower back pain and stiffness, often waking sufferers during the night, and typically being worse in the mornings. Alternating buttock pain is also a common sign.

People with ankylosing spondylitis can additionally experience pain and stiffness in their shoulders, chest, upper back, hips, knees and feet, and the disease can affect other organs, commonly the eyes.

In Australia, about 0.5% of the population suffer from ankylosing spondylitis and it is more commonly diagnosed in men; up to three times more often.

Ankylosing spondylitis is a serious disease and left untreated it can lead to prolonged suffering and permanent changes of the spine. The symptoms of ankylosing spondylitis appear gradually, usually when patients are in their late teens or early 20s.

Ankylosing Spondylitis Diagnosis

There is no cure for ankylosing spondylitis, but there are good management options, especially when patients are diagnosed early in the course of the disease and the destructive inflammation can be restrained.

But herein lies the problem: a sizeable fraction of people with ankylosing spondylitis are only finally diagnosed after the disease has wreaked considerable damage.

It is not uncommon for ankylosing spondylitis patients to endure a decade between disease onset and definitive diagnosis, living with a great deal of hardship in the meantime. This is because chronic back pain is common in the community, and often caused by conditions other than ankylosing spondylitis, so the correct diagnosis is often overlooked.

Ankylosing spondylitis patients with more advanced forms of the disease will not only face reduced physical capacity and a decline in general well-being, they will also be much less responsive to treatment, because of the damage the disease has already caused to their spines.

The possibility of ankylosing spondylitis needs to be in the mind of GPs and physiotherapists when managing younger patients with persistent lower-back pain. Most of these patients won’t have ankylosing spondylitis, but a significant proportion do, and it’s important they are diagnosed correctly.

Increasing awareness of ankylosing spondylitis, and the appropriate care pathways, should be a priority of ongoing professional training.

Public awareness campaigns also have a role, such as the availability of online screening tools for back pain sufferers to assess the chances their own problems are due to ankylosing spondylitis. If ankylosing spondylitis is suspected, patients can be referred to a rheumatologist and, if a diagnosis of ankylosing spondylitis is made, management can start early.

Treatment

There are good treatment options for relieving the pain of ankylosing spondylitis sufferers. Current management includes patient education about the condition, how it may affect patients, and what sufferers can do to help themselves deal with the disease. Lifestyle adjustments such as changes to work patterns, a specific exercise program, and appropriate drugs can all be effective.

Most ankylosing spondylitis patients respond well to non-steroidal anti-inflammatory drugs, showing a reduction in both pain and inflammation. Those who don’t respond to non-steroidal anti-inflammatory drugs can often experience positive outcomes when treated with tumour necrosis factor inhibitor drugs.

These medications block tumour necrosis factor, a protein that is one of the main causes of inflammation in ankylosing spondylitis, and greatly reduce pain and other ankylosing spondylitis associated symptoms.

The most important thing is that health-care professionals become more aware of this disease so it doesn’t take so long to diagnose. With early diagnosis, treatment will be more effective, and sufferers can look forward to getting on with their lives.The Conversation

Authors: Matt Brown, Professor and Director of Genetics, Queensland University of Technology and Murray Hargrave, Technical Writer and Ethics Officer, Queensland University of Technology

This article was originally published on The Conversation. Top Photo: Jean/Flickr

Temporal Self-Continuity Across The Life Span

Understanding your present self depends not only on thoughts, feelings, and activities, but also on experiences and recollections of the past and the vision of yourself into the future. In other words, it all depends on where you’ve been, and where you’re going.

A new study explores how people view themselves over different time spans. The work sheds new light on individual differences in people’s perceptions of themselves and the degrees to which they change over time.

For most people, the sense of connection with their past and future selves declines with increasing distance from the present. In fact, when we’re thinking of ourselves in the distant past or future, it almost feels like we’re thinking about a different person.

Joshua Rutt, now a postdoctoral researcher at the University of Zurich, and Corinna Loeckenhoff, professor of human development in Cornell University’s College of Human Ecology, asked people how much their present selves overlapped with their past and expected future selves and whether the same personality traits described them in past, present, and future.

Past And Future Self-continuity

The study was the first to assess both past and future self-continuity and to include a variety of time intervals ranging from 1 month to 10 years.

“Let any one try, I will not say to arrest, but to notice or attend to, the present moment of time. One of the most baffling experiences occurs. Where is it, this present? It has melted in our grasp, fled ere we could touch it, gone in the instant of becoming.”

– William James, The Principles of Psychology (1890)

The researchers found that past and future self-continuity are symmetrical—that is, people who feel more similar to their past are also more connected to their future. They did the measuring two ways: explicitly (responses to a direct question) and implicitly (completing a task that tapped into their self-continuity).

“We extracted two different measures,” Rutt says. “One of them was the extent to which their future and past personality trait ratings agreed with their present ones, and the other was simply reaction time. How fast did they press the button to answer the question? How long did they have to think about their answer?”

Rutt and Loeckenhoff also found that self-continuity decreases fairly quickly as one thinks a few months into the past or future, but continues to drop off, although more gradually, for longer intervals.

We see ourselves, they contend, as gradually emerging from the past, then slowly slipping away into the future.

There are considerable differences in self-continuity across people, Rutt and Loeckenhoff say. Perhaps most interestingly, they found that older adults are more likely to view themselves as living in an extended present as opposed to younger adults who tend to live a temporary state suspended between a distant past and an unknown future.

Back in the Saddle Again

Prior research suggests that feeling disconnected from our past and future selves could lead to poor decision-making regarding things like finances and health care. On the other hand, a greater sense of self-continuity might make one less susceptible to such issues, but at the same time more resistant to making necessary changes in health behavior.

For example, older adults’ high levels of self-continuity could lead them to accept treatable conditions as a permanent part of their identity.

Their results put Loeckenhoff in the mind of William James, a pioneer in the study of psychology, who said, “The practically cognized present is no knife-edge, but a saddle-back, with a certain breadth of its own on which we sit perched, and from which we look in two directions into time.”

“From an objective point of view, the present flips into the future in an instant,” Loeckenhoff says. “There is the past and the future, but the present isn’t really there.

“But from a subjective point of view,” she adds, “there is an extended present, and we’re sitting on that like it’s a saddle. In fact, when Josh brought me the first graphs of the data we collected, it really did look like a saddle-back.”

[alert-note]Rutt, Joshua L.; Löckenhoff, Corinna E.
From Past to Future: Temporal Self-Continuity Across the Life Span
Psychology and Aging, Apr 11 , 2016[/alert-note]

Photo: Moyan Brenn/Flickr