New study may lead to improved treatment of type 2 diabetes

Genetic cause found for loss of beta cells during diabetes development

Worldwide, 400 million people live with diabetes, with rapid increases projected. Patients with diabetes mostly fall into one of two categories, type 1 diabetics, triggered by autoimmunity at a young age, and type 2 diabetics, caused by metabolic dysfunction of the liver. Despite being labeled a “lifestyle disease”, diabetes has a strong genetic basis. New research under the direction of Adrian Liston (VIB/KU Leuven) has discovered that a common genetic defect in beta cells may underlie both forms of diabetes. This research was published in the international scientific journal Nature Genetics.

Adrian Liston (VIB/University of Leuven): “Our research finds that genetics is critical for the survival of beta cells in the pancreas – the cells that make insulin. Thanks to our genetic make-up, some of us have beta cells that are tough and robust, while others have beta cells that are fragile and can’t handle stress. It is these people who develop diabetes, either type 1 or type 2, while others with tougher beta cells will remain healthy even in if they suffer from autoimmunity or metabolic dysfunction of the liver.”

Different pathways to diabetes development

Diabetes is a hidden killer. One out of every 11 adults is suffering from the disease, yet half of them have not even been diagnosed. Diabetes is caused by the inability of the body to lower blood glucose, a process normally driven by insulin. In patients with type 1 diabetes (T1D), this is caused by the immune system killing off the beta cells that produce insulin. In patients with type 2 diabetes (T2D), a metabolic dysfunction prevents insulin from working on the liver. In both cases, left untreated, the extra glucose in the blood can cause blindness, cardiovascular disease, diabetic nephropathy, diabetic neuropathy and death.

In this study, an international team of researchers investigated how genetic variation controls the development of diabetes. While most previous work has focused on the effect of genetics in altering the immune system (in T1D) and metabolic dysfunction of the liver (in T2D), this research found that genetics also affected the beta cells that produce insulin. Mice with fragile beta cells that were poor at repairing DNA damage would rapidly develop diabetes when those beta cells were challenged by cellular stress. Other mice, with robust beta cells that were good at repairing DNA damage, were able to stay non-diabetic for life, even when those islets were placed under severe cellular stress. The same pathways for beta cell survival and DNA damage repair were also found to be altered in diabetic patient samples, indicating that a genetic predisposition for fragile beta cells may underlie who develops diabetes.  

Adrian Liston (VIB/University of Leuven): “While genetics are really the most important factor for developing diabetes, our food environment can also play a deciding role. Even mice with genetically superior beta cells ended up as diabetic when we increased the fat in their diet.”

A new model for testing type 2 diabetes treatments

Current treatments for T2D rely on improving the metabolic response of the liver to insulin. These antidiabetic drugs, in conjunction with lifestyle interventions, can control the early stages of T2D by allowing insulin to function on the liver again. However during the late stages of T2D, the death of beta cells means that there is no longer any insulin being produced in the pancreas. At this stage, antidiabetic drugs and lifestyle interventions have poor efficacy, and medical complications arise.

Dr Lydia Makaroff (International Diabetes Federation): “The health cost for diabetes currently exceeds US$600 billion, 12% of the global health budget, and will only increase as diabetes becomes more common. Much of this health care burden is caused by late-stage type 2 diabetes, where we do not have effective treatments, so we desperately need new research into novel therapeutic approaches. This discovery dramatically improves our understanding of type 2 diabetes, which will enable the design of better strategies and medications for diabetes in the future”.

Adrian Liston (VIB/University of Leuven): “The big problem in developing drugs for late-stage T2D is that, until now, there has not been an animal model for the beta cell death stage. Previously, animal models were all based on the early stage of metabolic dysfunction in the liver, which has allowed the development of good drugs for treating early-stage T2D. This new mouse model will allow us, for the first time, to test new antidiabetic drugs that focus on preserving beta cells. There are many promising drugs under development at life sciences companies that have just been waiting for a usable animal model. Who knows, there may even be useful compounds hidden away in alternative or traditional medicines that could be found through a good testing program. If a drug is found that stops late-stage diabetes, it would really be a major medical breakthrough!”

Read more: Dooley*, Tian*, Schonefeldt*, Delghingaro-Augusto*, Garcia-Perez, Pasciuto, Di Marino, Carr,Oskolkov, Lyssenko, Franckaert, Lagou, Overbergh, Vandenbussche, Allemeersch, Chabot-Roy, Dahlstrom, Laybutt, Petrovsky, Socha, Gevaert, Jetten, Lambrechts, Linterman, Goodnow, Nolan, Lesage, Schlenner**, Liston**. 'Genetic predisposition for beta cell fragility underlies type 1 and type 2 diabetes.' Nat Genet. 2016

New study provides insight into Hemophagocytic Lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a severe inflammatory disease caused by macrophage activation. Watch "Max the Angry Macrophage":

In patients with the primary (genetic) form of the disease, the underlying cause of illness is a defect in CD8 T cells which makes them inefficient at clearing viruses. The connection between this defect and the disease onset has, however, been unclear. 

Journal club: Patient diagnosed with non-human cancer

In a fascinating case report in the New England Journal of Medicine, Muehlenbachs et al identified a patient with disseminated cancer through the lungs and lymph nodes. The major oddity of the cancer was the small size of the cells, far smaller than human cells, indicating that the cancer cells were non-human. Extensive analysis identified the cancer cells as coming from Hymenolepis nana, the dwarf tapeworm. The patient was infected with tapeworms, one of which developed cancer (as can happen to any organism). These tapeworm cancer cells then metasized from the tapeworm into the host, adapted to the host and spread throughout the body as a foreign cancer. While the immune system is normally highly effective at clearing foreign organisms from the body, the tapeworm cancer cells were able to survive and disseminate throughout the body, possible for a combination of three reasons: i) tapeworms induce immune tolerance against their antigens, ii) the tumour cells were selected to be of low immunogenicity, and iii) the patient was HIV+ and immunodeficient. While this may be a one-off case, since parasite infections are so common perhaps we will find non-human cancers in other patients?

Muehlenbachs et al. 'Malignant Transformation of Hymenolepis nana in a Human Host'. New England Journal of Medicine. 2015. 373:1845

Ebastine provides relief from Irritable Bowel Syndrome

In a study published today by Gastroenterology, we demonstrate in a randomized placebo controlled trial that the anti-histimine Ebastine provides relief from the symptoms of Irritable Bowel Syndrome (IBS). The study, led by Prof Guy Boeckxstaens and in collaboration with the Translational Immunology Laboratory, tested the effect of Ebastine on pain relief. Over a 12 week course, nearly 50% of IBS patients showed considerable relief from symptoms. As Ebastine is a safe over-the-counter anti-histimine, commonly prescribed for allergy, this study could be rapidly extended to millions of IBS patients across the world.

Read more: Wouters et al. 'Histamine Receptor H1-mediated Sensitization of TRPV1 Mediates Visceral Hypersensitivity and Symptoms in Patients With Irritable Bowel Syndrome'. Gastroenterology. 2016

No separation of medical and mental health

Reporting on our research:

2005 NHMRC/RG Menzies Fellow, Professor Adrian Liston, is one of the researchers in an important study which provides new insights into the cause of irritable bowel syndrome (IBS), underscoring the connection between psychological factors and the immune system.

Adrian, who is now Professor of Translational Immunology at the University of Leuven and the VIB, Belgium says “The most important message from this research is that we cannot separate medical and mental health. The two influence each other; in our study high levels of anxiety or depression increase susceptibility to gastrointestinal infection and long-term complications.”

The findings in this latest research are based on an investigation of a drinking water contamination incident in Belgium in 2010, and have been published in the leading international medical journal Gut.

Described by Professor Liston as an accidental experiment, the study was set up to look at the long-term effects of an outbreak of gastroenteritis after 18,000 people came into contact with contaminated drinking water in the towns of Schelle and Hemiksem.

As reported in news-medical.net, following the patients from the initial contamination to a year after the outbreak, the researchers could assess what factors changed the risk of long-term complications. They found that individuals with higher levels of anxiety or depression prior to the water contamination developed gastrointestinal infections of increased severity. They also had greater risk of long-term IBS.

Professor Liston says there are broad applications for these research findings.

“There is a strong tendency to compartmentalise society - economy, welfare, health, education, etc. In reality, each individual moves around all these different sectors of society on a daily basis, so each influences the other.

“The Whitehall Study, a major UK study that is still ongoing, found that the degree of autonomy people experience in their jobs has a major influence on mortality. Other studies demonstrate the link between un/under-employment or social disenfranchisement on health. These effects are rarely taken into account when designing public policy. For example, a policy change to welfare that decreases financial security may save the government a few dollars in the welfare budget, but it will cause much larger increases in the health budget due to the flow-over effects of anxiety.

“What we really need is an integrated strategy that takes into account urban design, the welfare safety net, public health, employment structures and recreation”, Professor Liston said.

Anxiety increases the risk of gastrointestinal infection and long-term complications

A study in the aftermath of 2010 tap water contamination in the Belgian towns of Schelle and Hemiksem provides valuable insights into the cause of irritable bowel syndrome. A team comprised of scientists at VIB and KU Leuven has made significant progress in uncovering the connection between psychological factors and the immune system. Their findings are based on an investigation of a massive drinking water contamination incident in Schelle and Hemiksem in 2010, and are now published in the leading international medical journal Gut.

In December 2010, the Belgian communities of Schelle and Hemiksem in the province of Antwerp faced an outbreak of gastroenteritis, with more than 18,000 people exposed to contaminated drinking water. During the outbreak, VIB and KU Leuven set up a scientific task force to study the incident’s long-term effects, led by Guy Boeckxstaens and Adrian Liston.

Seizing an unexpected opportunity

Adrian Liston: “The water contamination in Schelle and Hemiksem was an ‘accidental experiment’ on a scale rarely possible in medical research. By following the patients from the initial contamination to a year after the outbreak we were able to find out what factors altered the risk of long-term complications.”

Anxiety and depression affect immune system

The scientists found that individual with higher levels of anxiety or depression prior to the water contamination developed gastrointestinal infections of increased severity. The same individuals also had an increased risk of developing the long-term complication of irritable bowel syndrome, with intermittent abdominal cramps, diarrhea or constipation a year after the initial contamination.

Guy Boeckxstaens: “Irritable Bowel Syndrome is a condition of chronic abdominal pain and altered bowel movements. This is a common condition with large socio-economic costs, yet there is so much that still remains to be discovered about the causes. Our investigation found that that anxiety or depression alters the immune response towards a gastrointestinal infection, which can result in more severe symptoms and the development of chronic irritable bowel syndrome.”

Psychological factors key in preventing long-term complications

The study’s results provide valuable new insight into the cause of irritable bowel syndrome, and underscore the connection between psychological factors and the immune system.

Adrian Liston: “These results once again emphasize the importance of mental health care and social support services. We need to understand that health, society and economics are not independent, and ignoring depression and anxiety results in higher long-term medical costs.”

For more details, see the original publication: Wouters*, Van Wanrooy*, Nguyen*, Dooley, Aguilera-Lizarraga, Van Brabant, Garcia-Perez, Van Oudenhove, Van Ranst, Verhaegen, Liston*, Boeckxstaens*. * shared authorship. Psychological comorbidity increases the risk for postinfectious IBS partly by enhanced susceptibility to develop infectious gastroenteritis. Gut. 2015, in press. 

Update on Wednesday, July 8, 2015 at 7:33PM by Adrian Liston

An article written in Healio on our study

(Yet another) reason to vaccinate your child

Vaccination may be one of the greatest scientific breakthroughs of all time. Smallpox eradication alone probably saves 3 million lives a year, and the routine childhood vaccines save another 3 million lives a year. Vaccines are so effective and successful, in fact, that they are no longer seen with the awe they deserve. The virulent fear of infectious disease has faded so completely forgotten that clueless celebrities are happy to campaign against vaccines based on the incorrect claims of a discredited  fraud.

Take measles, for example. While often dismissed as a harmless childhood disease, measles can be a killer. It is extremely infectious virus, putting most other viruses to shame for just how incredibly infectious it is. For children or adults in poor health (immunocompromised or malnourished), measles has a mortality rate of 30%. Even under the best scenario, measles can cause blindness and brain damage and kill 0.2% of those infected. 0.2% doesn't sound that much, but consider that in the USA without vaccination we would have 3-4 million cases a year - that is 8000 infant deaths being prevented every year.

Well, it turns out that measles is probably even worse than this. A new study demonstrates that measles infection increases the risk of dying of other diseases (scientific paper here, lay verion here). When measles vaccines are introduced, it is not only deaths from measles that are eliminated - deaths from a wide set of childhood infections dramatically drop. In fact, rather than "what doesn't kill you makes you stronger", surviving measles seems to suppress the immune system for several years, making children more likely to die from alternative diseases. Vaccination gives protection against measles without the risks of infection and without the immunosuppression of infection - a great "win-win" situation.

Chronisch Vermoeidheidssyndroom Uitgelicht

CVS, wat als het u overkomt?

(interview by Veto)

New cause for early-onset lupus discovered

In a new study out by the Autoimmune Genetics Laboratory, we have discovered a new genetic cause for early-onset systemic lupus erythematosus - mutation in the gene IFIH1. In 2014, mutations of this gene were independently found to cause the neurodegenerative disease Aicardi-Goutières syndrome (AGS). Despite lupus and AGS manifesting as clinically different symptoms, this study shows that mutation in the same gene causes both diseases. The mutation in IFIH1 works via driving excessive production of the cytokine IFN alpha, so this discovery opens up the possibility for treatment once anti-IFN alpha antibodies (currently in development) are approved for use. 

Read more: Van Eyck, De Somer, Pombal, Bornschein, Frans, Humblet-Baron, Moens, de Zegher, Bossuyt, Wouters* & Liston*. IFIH1 mutation causes systemic lupus erythematosus with selective IgA-deficiency. Arthritis Rheumatol. 2015, in press.

If you would like to support our clinical research, and allow us to take on more cases like this one, you can make a tax-deductable donation the Ped IMID fund, by transferring to IBAN-number BE45 7340 1941 7789, BIC-code: KREDBEBB with the label "voor EBD-FOPIIA-O2010".

New fund to support translational research into paediatric inflammatory diseases

A new fund has been set up to drive bench-to-bedside research for children with inflammatory immune diseases. The Ped IMID fund (Fonds Pediatrische Immuun-inflammatoire Aandoeningen) was set up by Prof Carine Wouters (Pediatric Rheumatology), Prof Patrick Matthys (Immunobiology) and Prof Adrian Liston (Autoimmune Genetics) to build on our strong research cooperation. More than merely "translational research", where basic science is pushed into the clinic, our group performs "dialog research", where we meet regularly to discuss the clinic and the science of the most difficult-to-treat patients. We use the clinic to inform the research and the research to inform the clinic, and have already had multiple break-throughs in understanding and treating children with rare inflammatory diseases. 

If you would like to support our research, and allow us to take on more cases, you can transfer a tax-deductable donation to IBAN-number BE45 7340 1941 7789, BIC-code: KREDBEBB with the label "voor EBD-FOPIIA-O2010".