Yes, diabetes is a genetic disease

With the publicity of our recent Nature Genetics paper, I have been discussing diabetes with many journalists. Almost without exception they seem surprised that I call diabetes a genetic disease - and they are not alone - even among the medical community it is standard to (incorrectly) call diabetes a lifestype disease.

The genetic basis for diabetes has been long established. It really is a shame that diabetes is so often called a "lifestyle disease". It isn't. 50% of the susceptibility to type 1 diabetes is genetic, and 70% of the susceptibility to type 2 diabetes is genetic.

Most of the remainder of the susceptibility is environmental. For example, certain types of dietary fat, such as palmitate, increase the fragility of beta cells. It is quite plausible that much of the increase in diabetes incidence in the past decades is due to changes in diet that make our beta cells more fragile. But even when we are talking about dietary factors, I think it is important to recognise that much of the effect is environmental rather than lifestyle. "Lifestyle" is easy to dismiss by blaming the patient for their own choices. Calling diabetes a lifestyle disease is one of the reasons that research and medical advances in diabetes are lagging behind, and the stigma contributes to the ill effects of diabetes (e.g., increased risk of depression, more antagonistic relationships between patients and clinicians). Recognising diet as an environmental factor takes away this stigma, is more accurate and allows us to tackle the problem using public health approaches. For example, some of the highest rates of diabetes are in the poorest neighbourhoods of America. In these areas, junk food is cheap and available everywhere, while good food is simply not practical - it is rare, expensive and takes more time to prepare than many poor families have. Likewise, the neighbourhoods may not provide the physical infrastructure that allows for a mobile lifestyle (parks for kids, urban design that promotes walking, etc). It is not a "lifestyle choice" to live in these diabetogenic environments, but it is a public policy choice to allow these environments to exist.

To really tackle the diabetes epidemic we need to recognise that the root cause is not in personal choices made by individuals. The root cause is in the social structure that we have created, in the urban design of cities, the changes in food culture, the demands placed on our time. We have made unhealthy lives the easiest to live. We can either ask individuals to make heroic efforts to overcome these obstacles to a healthy lifestyle, or we can use public policy to make our food environment and urban environment more healthy. Some of these policy changes would be immediate and easy (e.g., changing the tax structure to make good foods cheaper and junk food more expensive, or regulating the removal of the most toxic components of junk food). Other policy changes will take generations - even if we require urban planning to take into account healthy lifestyle promotion, the turnover in infrastructure is so slow that it will take a long time to occur. We certainly need major medical advances, which hopefully our study will aid, because the social changes needed will take decades to fully implement. But that is no reason not to start the public policy debate now, and even the small first steps will save the lives of millions (as well as saving billions from health care budgets).

Diabetes research in the news

Our new story on diabetes research, published in Nature Genetics, has made the news this week, with TV apperances on VRT and Kanaal Z. There are also articles in English, Dutch (here, here and here), French and Spanish media.

Nature Genetics interview

Nature Genetics has an interview with me on their blog: 

The discovery that NOD^k mice with the insHEL transgene develop diabetes is described as being serendipitous. What were your initial thoughts about this? 

At the time we first found that NOD^k.insHEL male mice developed diabetes I was actually working on immune defects in NOD mice, rather than beta cell defects. My first thoughts were that this was just another immune defect, with the immune system attacking the beta cells because they expressed the insHEL transgene. Since it fit our preconceived ideas we didn’t take too much notice, but just to be safe I set up a backcross to eradicate the adaptive immune system from the NOD^k.insHEL mice. It took a couple of years for the mice to breed and age, so I had almost forgotten about the finding when the first immune-deficient NOD^k.insHEL mice started to develop diabetes. At that point I was really startled – the cross should have eliminated diabetes if it was immune-mediated. I knew then that we were looking at some completely new biology – which took another 10 years to dissect! 

What advantages does your new mouse model bring to the field?

There are so many aspects to diabetes that it is often impossible to untangle the causes of disease. For example, one of the critical clinical developments in type 2 diabetes is the death of beta cells. It marks a shift from insulin-resistant diabetes (which is largely treatable), to insulin-deficient/insulin-resistant diabetes (for which there are no effective treatments). But why are the beta cells dying? From previously mouse models there were many reasonable hypotheses that were put forward – maybe it is the demand placed on the beta cell for extra insulin production, maybe it is a toxic effect of high blood glucose levels, maybe it is a side-effect of the high fat diet used to induce diabetes in the first place, or maybe it is immune-mediated. Our model has the advantage that it can strip away all of these interactions to observe the direct effects of forcing beta cells to produce too much protein – a process that results in beta cell failure. Looking forward, I see a major advantage in using this model to screen for drugs that stop the loss of beta cells in type 2 diabetes, which is really the key unmet medical need in diabetes treatment.

One of your interesting observations is the difference in diabetes incidence between the male and female mice, mediated by male sex hormones.  What parallels are there with humans and how might you use this model to explore this further?

So far we have only seen diabetes in male insHEL mice, despite challenging female insHEL mice with multiple strategies that promote diabetes in male mice (diet, autoimmunity, genetic background). At a cellular level it looks like male islets are just under more metabolic pressure than female islets, such that the insHEL stress is enough to make male mice diabetic, while female mice stay healthy. This could actually explain a lot about the epidemiology of type 1 diabetes in humans. Most autoimmune diseases have a strong female bias, while type 1 diabetes has a weak male bias. Our hypothesis is that maybe males have an intrinsic islet fragility (perhaps from supporting a larger body mass), while females have an intrinsic susceptibility to autoimmune disease. In epidemiological terms, these two effects may cancel each other out, leading to similar levels of type 1 diabetes in males and females, but at a clinical level it may mean that different individuals would respond better to different treatment strategies.   

You identified two loci linked with insHEL-induced diabetes in the NOD^k mice.  What were your expectations about what you would find? Where you excited when Xrcc4 and Glis3 were identified as candidate genes?

Geneticists have been trying to work out the basis of spontaneous diabetes in NOD mice since the strain was first published in 1980. It turns out to be a very complex problem – there are more than 20 loci that contribute to diabetes susceptibility, and each time a loci is analysed in detail it ends up being a cluster of weaker loci working together. Decades later and we are only sure about a handful of candidates genes – so I didn’t have high expectations that we would progress far when looking at the genetics of insHEL-triggered diabetes. It turns out, however, that we had several major advantages. First, the genetics ended up being much simpler, with linkage only observed on two chromosomes. Second, because we knew which cell type was important – the beta cell – we were not operating in the dark about candidates. After filtering for expression in beta cells we were left with only a handful of candidates. Seeing Xrcc4 and Glis3 on the final list was bliss – they both made perfect biological sense. GLIS3 is one of the very few genes linked to both type 1 and type 2 diabetes in humans, and here we had it on our shortlist for a model that contains aspects of both diseases! It had taken more than 10 years to get to those two genes, but then we reached one of those dream runs in the laboratory where all the data just comes together, and every experiment gave support to the candidates.

You identify beta cell failure as a common link between T1D and T2D.  Are there ways that your findings can impact the clinical understanding or management of these diseases? 

In some ways, what we have here is the laboratory catching up to the clinic. The clinical overlaps between type 1 and type 2 diabetes have been apparent from the start, yet the research on genetics and animal models has consistently emphasized the differences. We may be in the process of reconciling these two approaches. The model that I favour is one where beta cell robustness or fragility lies at the centre of both diseases. In type 1 diabetes, failures in immune tolerance promote an attack on the beta cell, while in type 2 diabetes, hepatic insulin resistance leads to beta cell stress. In both cases, however, it may be the intrinsic robustness or fragility of the beta cell that dictate whether the pressure on beta cells remains subclinical or leads to diabetes. If this model holds true in patients then it would present a golden opportunity for preventing diabetes by increasing the robustness of beta cells.

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. 

Working moms have more successful daughters and more caring sons

Not necessarily restricted to women in science, but well worth a read. It is not a choice between career and family - being a successful career woman actually provides a wonderful role-model to your children. So don't feel guilty about hiring a baby-sitter or even (shock! horror!) asking the father to do some parenting.

...and yet we still have kids

Great job by PhD student in the lab, Dean Frankaert, on VTM news last night - Belgian TV star! 

Our research on the shaping of the human immune system has also had a lot of international media attention the last few days. New Scientist has a great article on the work, and I have to give a special call out to the Daily Mail, since the journalist who wrote this article was savvy enough to ask about Pathogen-Associated Molecular Patterns. It is also fun to read quotes from yourself in German or Italian. My personal favourite, however, would have to be the Australian media:

If you had to rate how hard parenting is, where would you put it on a scale from "perfectly fine" to "worse than suffering from extreme vomiting and diarrhoea"?

If you answered "somewhere in between", you might be surprised to hear the truth is even more extreme – because new research has discovered that parenting hits your immune system harder than travellers' gastroenteritis.

Yes, that's right – raising children is as hard on your body as projectile vomiting in a foreign airport.

It's funny because it is true.

Een kind verandert alles, vooral je immuunsysteem

Voor welke ziektekiemen we vatbaar zijn, hangt af van onze genen, ons gewicht en hoe goed we ons in ons vel voelen. Maar het belangrijkste effect hebben kinderen.

Het immuunsysteem beschermt ons tegen ziekten. Tegen welke ziektekiemen het lichaam precies gewapend is, verschilt sterk van persoon tot persoon. Een onderzoeksteam van de Leuvense tak van het Vlaams Instituut voor Biotechnologie en het Britse Babraham Institute vond in het bloed van 670 proefpersonen aanwijzingen dat mensen elkaars immuunsysteem sterk beïnvloeden. Adrian Liston leidde het onderzoek.

Professor Liston, veel jonge ouders worden ziek, zodra hun kindje naar de crèche gaat. U hebt vastgesteld dat een kind grootbrengen het immuunsysteem van de ouders verandert. Ten slechte?

‘Niet per se. We zien dat personen die samenwonen, op den duur immuunsystemen hebben die sterk op elkaar lijken. Terwijl voorheen de ene misschien zeer vatbaar was voor bacteriële ziektes en minder voor virale aandoeningen, kan hij van de ander de weerbaarheid tegen virussen overnemen. Hij is dan voortaan wel, net als zijn partner, kwetsbaar voor bacteriën. Het risico op bepaalde ziektes neemt dus door het samenleven toe, het risico op andere dan weer af.’

‘Samen een kind grootbrengen blijkt dat effect te versterken. Ons onderzoek bij kinderen en volwassenen uit België en het Verenigd Koninkrijk toont aan dat een kind voor je immuunsysteem zelfs een belangrijkere rol speelt dan je genen, je gewicht, je geslacht of hoe je je voelt.’

Hoe komt dat?

‘Als je gedurende tien seconden kust, wissel je zo’n 80 miljoen bacteriën uit. Op een gegeven moment draag je dus dezelfde bacteriën als je partner en daar reageert je immuunsysteem op. Als twee volwassenen samen voor hun kindje zorgen, wisselen ze ook via het kindje bacteriën en virussen uit.’

Als de ene ouder ziek wordt, is de ander dus ook buiten strijd?

‘Ja. Maar dat is op zich niet zorgwekkend bij personen die voor de rest gezond zijn.’

‘In een rusthuis is dat iets anders. De bewoners hebben geen intieme relatie met elkaar, maar ze wonen wel allemaal samen. Mogelijk lijken hun immuunsystemen sterk op elkaar en is de groep zeer vatbaar voor uitbraken, bijvoorbeeld van griep. Dat zouden we graag in detail verder onderzoeken.’

Courtesy of De Staandard

Think twice before you have kids!

Prof Michelle Linterman, co-lead author on our recent study on the effect of children on the immune system, has been hitting the airwaves today:

Interested? Listen here for a recap of the BBC World Service (conversation runs from 08.53-12.40), or here for the Today show (45.07).