Type 1 diabetes is an autoimmune disease in which the immune system destroys the body’s own insulin-producing beta-cells in the pancreas, leaving patients with a lifelong dependency on external insulin.

Children whose parents or siblings have type 1 diabetes have an eight- to 15-fold increased risk of developing the autoimmune disease themselves. However, this risk is not evenly distributed: the child of a mother with type 1 diabetes has a lower risk of developing type 1 diabetes than a child with a father or sibling with type 1 diabetes.

Risk differs depending on affected family member

Of interest, genetic susceptibility to type 1 diabetes has been shown to be comparable between the offspring of mothers and the offspring of fathers with type 1 diabetes. Therefore, researchers suspected that early-life epigenetic programming may be a key mechanism through which maternal type 1 diabetes confers a protective effect.

Epigenetic mechanisms such as DNA methylation determine which genes are ultimately read and expressed. By changing DNA methylation patterns, environmental influences in the womb such as smoking by the mother, medical conditions, stress, or diet can have far-reaching effects on a child’s health by switching genes on or off in the early life period and later in life.

Hence, specific environmental conditions in the womb of a mother with type 1 diabetes, the so-called intrauterine environment, may influence the child’s risk for islet autoimmunity through epigenetic modifications.

Blood methylation changes at T1D risk genes appear to protect against islet autoimmunity

“We observed DNA methylation changes at multiple type 1 diabetes susceptibility genes in children born to mothers with type 1 diabetes,” says Prof. Sandra Hummel, researcher at the Helmholtz Munich Institute for Diabetes Research and last author of the study.

Her team investigated how maternal type 1 diabetes influences the child’s epigenome. In a new epigenome-wide association study, they identified that maternal type 1 diabetes is associated with specific epigenetic marks in the form of DNA methylation in the child. These changes appear to affect the expression of several genes involved in immune function.

The paper is published in the journal Nature Metabolism.

The researchers examined blood samples from 1,752 children at around two years of age from the BABYDIAB, BABYDIET, and POInT cohorts. All children included had an increased genetic risk for type 1 diabetes. They compared DNA methylation patterns of 790 children with and 962 children without a mother affected by type 1 diabetes to identify differences linked to maternal diabetes.

“Our study identified numerous differentially methylated genetic locations, predominantly in the HOXA gene cluster and the MHC region in the offspring of mothers with type 1 diabetes. The MHC region is known to confer the major genetic susceptibility and resistance to type 1 diabetes. We observed that the epigenomic changes in these children were associated with the expression of 15 type 1 diabetes susceptibility genes,” explains Dr. Raffael Ott, lead scientist at the Institute of Diabetes Research and first author of the study.

Using 34 differentially methylated positions at type 1 diabetes susceptibility loci that best reflected exposure to maternal type 1 diabetes, the researchers created a methylation propensity score. Testing this score in children without a mother with type 1 diabetes, they found that those who developed islet autoimmunity had significantly lower scores, indicating less protective epigenetic modification.

These findings suggest that environmental factors may modulate the risk of islet autoimmunity through epigenetic changes to key susceptibility genes.

Advancing research on maternal type 1 diabetes protection

In a following project led by Sandra Hummel, the researchers will take a closer look at the relative protection of children born to mothers with type 1 diabetes.

Together with Prof. Ezio Bonifacio and colleagues from the Center for Regenerative Therapies Dresden at the TU Dresden University of Technology, the team aims to identify which type 1 diabetes susceptibility genes are epigenetically modulated by maternal type 1 diabetes and whether similar epigenetic effects occur in children born to mothers with gestational diabetes.

In collaboration with further Helmholtz Munich researchers, the project will also explore potential protein and metabolomic biomarkers linked to DNA methylation patterns and how these molecular changes contribute to protection against islet autoimmunity.

To this end, they will analyze bio-samples collected within the GPPAD trials, the BABYDIAB and the BABYDIET cohorts, and the Fr1da study.

Why do immune cells that are supposed to eliminate viruses suddenly turn against our own body? There are instances where killer T cells—which are meant to precisely remove virus-infected cells—malfunction like overheated engines, attacking even healthy cells and damaging tissues.

A KAIST research team has now identified the key mechanism that regulates this excessive activation of killer T cells, offering new insights into controlling immune overreactions and developing therapies for immune-related diseases.

The research team led by Professors Eui-Cheol Shin and Su-Hyung Park from the Graduate School of Medical Science and Engineering, in collaboration with Professor Hyuk Soo Eun from Chungnam National University College of Medicine, has uncovered the molecular basis of nonspecific activation in killer T cells and proposed a new therapeutic strategy to control it.

Killer T cells (CD8⁺ T cells) selectively eliminate infected cells to prevent viral spread. However, when excessively activated, they can attack uninfected cells, causing inflammation and tissue damage. Such overactive immune responses can lead to severe viral infections and autoimmune diseases.

In 2018, Professor Shin’s team was the first in the world to discover that killer T cells can be nonspecifically activated by cytokines and randomly attack host cells—a phenomenon they termed “bystander activation of T cells.” The current study builds on that discovery by revealing the molecular mechanism driving this abnormal process.

The team focused on a cytokine called interleukin-15 (IL-15). Experiments showed that IL-15 can abnormally excite killer T cells by a bystander activation mechanism, causing them to attack uninfected host cells. However, when there is a concurrent antigen-specific stimulation, IL-15-induced bystander activation is suppressed.

The researchers further identified that this suppression occurs through an intracellular signaling process. When the concentration of calcium ions (Ca²⁺) changes, a protein called calcineurin activates, which in turn triggers a regulatory protein known as NFAT, suppressing IL-15-induced bystander activation of killer T cells. In other words, the calcineurin–NFAT pathway activated by antigen stimulation acts as a brake on overactivation by a bystander mechanism.

The team also discovered that some immunosuppressants, which are known to block the calcineurin pathway, may not always suppress immune responses—in certain contexts, they can instead promote IL-15-induced bystander activation of killer T cells. This finding underscores that not all immunosuppressants work the same way and that treatments must be carefully tailored to each patient’s immune response.

Through gene expression analysis, the researchers identified a gene set that increased only in abnormally activated killer T cells induced by IL-15 as markers. They further confirmed that these same markers were elevated in bystander killer T cells from patients with acute hepatitis A, suggesting that the markers could be used for disease diagnosis.

This study, now published in the journal Immunity, provides crucial clues for understanding the pathogenesis of various immune-related diseases, including severe viral infections, chronic inflammatory disorders, autoimmune diseases, and organ transplant rejection. It also paves the way for developing novel immunoregulatory therapies targeting IL-15 signaling.

Professor Eui-Cheol Shin explained, “This study shows that killer T cells are not merely defenders—they can transform into ‘nonspecific attackers’ depending on the inflammatory environment. By precisely regulating this abnormal activation, we may be able to develop new treatments for intractable immune diseases.”

It seems contradictory: the pills you’re taking for headaches might actually be perpetuating them. Medication-overuse headache is a well-documented medical phenomenon, but the good news is it’s often reversible once identified.

Over 10 million people in the UK regularly get headaches, making up about one in every 25 visits to a GP. Most headaches are harmless and not a sign of a serious problem. Although many people worry they might have a brain tumor, less than 1% of those with headaches actually do.

Because there are so many possible causes of headaches, GPs must play detective. A detailed medical history and examination are essential, sometimes followed by specialist referral.

The challenge lies in determining whether a headache signals a serious underlying cause, or is benign. Even benign headaches, however, can greatly affect a person’s daily life and still need proper care.

Treatment depends on the type of headache. For example, migraines may be treated with anti-sickness medicine or beta blockers, while headaches related to anxiety or depression might improve with mental health support. Lifestyle changes, such as dietary changes and exercise, can also help manage many types of long-term headache.

However, doctors often see another type of persistent headache that has a clear pattern. Patients report getting repeated headaches that started or got worse after taking painkillers regularly for three months or longer.

This can happen in people with migraines, tension headache, or other painful conditions like back or joint pain. Some may take several types of medication, often more and more frequently, and end up stuck in a frustrating cycle that doesn’t seem to make sense at first.

The probable diagnosis is medication-overuse headaches. This condition is thought to affect about 1–2% of people and is three-to-four times more common in women.

The culprit is often the painkillers themselves. Opiates like codeine, used to treat moderate pain from injuries or after surgery, come with a long list of side-effects including constipation, drowsiness, nausea, hallucinations—and headaches.

It’s not just strong opiate-based medications that can cause headaches. Common painkillers like paracetamol and NSAIDs (non-steroidal anti-inflammatories, such as ibuprofen) can also play a role. Some medications even combine paracetamol with an opiate, such as co-codamol.

Paracetamol has a simpler side-effect profile compared with drugs like codeine. When taken within the recommended daily limits—which depend on age and weight—it is generally a safe and effective painkiller. This has contributed to its widespread use and easy availability.

However, taking more than the recommended dose or using it too often can be very dangerous. This can lead to serious—sometimes fatal—complications, such as liver failure.

Even though side-effects are less common, studies have shown that regular use of paracetamol alone can also trigger chronic headaches in some people.

Other drugs besides painkillers can also cause problems. Using triptans too often—medications to stop migraine attacks—can also lead to medication-overuse headaches.

The term “overuse” might make it sound like patients are taking more than the recommended daily dose, which can happen and brings its own serious risks. However, in many cases of medication-overuse headaches, patients are neither exceeding dose limits nor taking the medication every single day.

For paracetamol or NSAIDs, medication-overuse headaches may develop if they are taken on 15 or more days per month. With opiates, headaches can appear with even less frequent use—sometimes after just ten days a month.

That’s why it’s important to talk to a doctor if you need to use any painkiller, even over-the-counter ones, for a long time. Not everyone will develop medication-overuse headaches, and the risk seems to differ from person to person, meaning individual susceptibility plays a big role.

Treatment

Treating these headaches can be challenging. It’s often hard for patients to recognize on their own that their medication is causing the problem. The usual approach involves gradually stopping the medication under guidance, eventually stopping it completely.

This can seem unfathomable to patients, especially since they expect painkillers like paracetamol to relieve their headaches. Some worry their pain will get worse as they cut back. That’s why working closely with a doctor is essential—to confirm the diagnosis, monitor progress and plan the next steps in treatment.

If you’re having headaches on more than 15 days a month, it’s important to see your GP. Talking it through can help identify underlying causes and explain these often debilitating symptom patterns. Keeping a headache diary—noting symptoms and daily details—can also support the diagnosis.

Why some medicines, especially painkillers, can make headaches worse isn’t fully understood. However, it’s important to be aware of this now well-established link and seek medical advice.

Only when some patients stop taking certain medications altogether do they discover the uncomfortable truth: that their pain was being fueled by the very drugs they depended on.

This article is republished from The Conversation under a Creative Commons license. Read the original article.

The drug finerenone has a positive effect on patients with type 1 diabetes and chronic kidney disease. The drug reduces the amount of proteins excreted in the urine of these patients. This reduction indicates that the degree of kidney damage is reduced and that the drug has a protective effect on kidney function.

Clinical pharmacologist Hiddo Lambers Heerspink of the UMCG led a large international study into the effect of this drug. He presented the initial results of this study at the American Society of Nephrology conference in Houston.

First effective and safe drug in 30 years for patients with type 1 diabetes

Although many new drugs have been discovered in recent years for the treatment of kidney disease in patients with type 2 diabetes, this is not the case for patients with type 1 diabetes. This is mainly because patients with type 1 diabetes were often excluded from participating in studies due to possible side effects.

As a result, kidney disease in people with type 1 diabetes is still treated with blood pressure-lowering drugs dating back to research conducted more than 30 years ago.

Finerenone is now the first new drug in more than 30 years that is effective and safe for this patient group. It is expected that the drug can now be registered in the guidelines for the treatment of type 1 diabetes.

Best possible endpoint is protein loss in urine

Previous research by Heerspink showed that protein loss in urine (albuminuria) is the best possible indicator of early, measurable kidney protection. The more traditional endpoint in clinical drug studies, such as the onset of dialysis and kidney transplantation, only become apparent at a late stage and require large, long-term studies.

Because there are far fewer patients with type 1 diabetes and kidney disease compared to type 2 diabetes and kidney disease, drug studies with traditional endpoints are practically impossible to conduct. That is why Heerspink and his research team found an alternative and investigated the effect of the drug finerenone on protein excretion.

Positive effect of finerenone

In the study, Heerspink investigated the effect of the drug finerenone, which blocks the receptor for the hormone aldosterone. Aldosterone is a hormone produced in the adrenal glands that regulates salt and water balance to maintain blood pressure.

It had previously been shown that this drug had a positive effect in patients with type 2 diabetes in slowing down kidney function loss and protecting the heart.

Heerspink investigated whether the drug led to less protein in the urine and whether it was well tolerated in 242 patients with type 1 diabetes and chronic kidney disease.

The patients were followed for six months and the amount of protein in their urine was found to have decreased by about a quarter. This is very likely to translate to less kidney failure in these patients. Finerenone was also safe and well tolerated, except for a slightly elevated potassium level in the blood.

About the research

Eighty-two hospitals from nine countries in Asia, Europe and North America participated in the study. According to Heerspink, the results of this study offer hope for patients with type 1 diabetes. At the same time, it encourages researchers to conduct more research into the effect of new medications in these patients at high risk of kidney and heart diseases.