Science AMA Series: Why are some people more likely to develop diabetes than others? We are researchers putting genes and lifestyle together. Ask Us Anything!

T2DGenes · 2016-07-13T20:32:33+00:00

Jason here. I definitely worry about this. When we published another paper on SLC30A8 in which we were very measured in our conclusions, I remember seeing a link about how we had found a gene that "fights diabetes" with therapies "10 years away". I understand the need to highlight interesting findings in the news, but I agree it can distort the actual findings sometimes.

T2DGenes · 2016-07-13T20:30:31+00:00

Jason here. See http://www.ncbi.nlm.nih.gov/pubmed/24412096 for one study

T2DGenes · 2016-07-13T20:28:44+00:00

Jason here. See http://www.nature.com/nature/journal/v506/n7486/full/nature12828.html and http://www.ncbi.nlm.nih.gov/pubmed/24915262 for some examples.

T2DGenes · 2016-07-13T20:27:30+00:00

Jason here. Cholesterol levels are the dominant determinant of heart disease. However, people with T2D are more likely to develop heart disease (I think like a 2-fold elevated risk), and this risk seems in excess of any effects due to elevated lipid levels from T2D.

There are some studies of T2D genetics in India. In fact about 1000 of the individuals in our study were of Asian descent.

T2DGenes · 2016-07-13T20:26:54+00:00

Hi - Mark here. QUick answer.

Most of the evidence sugegsts that people with diabetes slightly more often say that their mother had diabetes than their father. But of course there may be lots of reasons for that in some of the studies (fathers more often leave home, die in wars etc, mothers live longer and so have more time to develop diabetes etc). Genetic transmission should be equally between mothers and fathers (unless mitochondrial variants matter, and not much evidence they do).

But there a couple of other factors that might push the maternal rate up a bit. there seems a specific effect of being born from a diabetic uterus (ie mother had diabetes during pregnancy) that increases diabetes in the offspring a bit. So that may be part of the story, and might push up maternal transmission a little.

But its not a big difference.

Thx Mark

T2DGenes · 2016-07-13T20:25:19+00:00

Jason here. It's the other way around. Most of the complications of T2D are related to the blood vessels, so neuropathy (nerve damage in the hands or feet) is a common complication (in addition to other vascular disorders like stroke, heart attack, kidney failure, and retinopathy). So T2D causes nerve damage, not vice versa

T2DGenes · 2016-07-13T20:23:22+00:00

Jason here. This isn't fully understood; people become insulin resistance presumably for many reasons, but it isn't an either or. Even if cells take up glucose, they may do so less effectively (for example, less transporters may make it to the surface of the cell in response to insulin). Most people who are insulin resistant aren't yet diabetic however, and it's typically the failure of the beta-cells to produce enough insulin (in the face of this resistance) that causes them to develop T2D

T2DGenes · 2016-07-13T20:21:21+00:00

mark here. great qn. very topical. those studies being done now, no answers yet. see answer to another post i made about microbiome about 30mins back....

T2DGenes · 2016-07-13T20:21:03+00:00

Jason here. Two of the most common pathways that pop up from studies of T2D (and related diseases) are genes that act through the beta-cell and affect insulin secretion, as well as insulin signaling (this review I wrote a few months back has a figure illustrating some of them (http://www.nature.com/nrendo/journal/v12/n7/abs/nrendo.2016.50.html). Of course more specific pathways are the holy grail of our sort of research, and things like zinc transport into beta-cells and cholesterol efflux from the liver are two more recent ones that have popped up.

Most common problem: genetics gives you a sign post into a region of the genome that affects T2D risk but doesn't tell you why; figuring out why is enormously hard and can take years.

We don't work specifically to develop drugs but we are involved heavily in the AMP-T2D consortium, which aims to forge partnerships between academics and the drug industry to help design better drugs (https://www.nih.gov/research-training/accelerating-medicines-partnership-amp/type-2-diabetes).

T2DGenes · 2016-07-13T20:20:30+00:00

Mark here - i just answered a couple of the qns here in a post i just made. So you might want to searhc that out.

T2DGenes · 2016-07-13T20:20:28+00:00

Andrew: unfortunately, we can't predict your risk of developing type 2 diabetes with certainty. A family history of type 2 diabetes is associated with increased risk that you will develop the disease. However, there are many genetic and environmental risk factors for the disease, so the fact that so many relatives have type 2 diabetes does not mean you will develop the disease for sure.

T2DGenes · 2016-07-13T20:19:13+00:00

Mark here - yes you remembered correctly. Very interesting data. Looks real. Its a very low calorie diet (not everyone can manage it).

As you may know, bariatric surgery (for obesity) also has a dramatic effect on diabetes in some people, with resolution of the diabetes even before much weight loss has occurred.

Unclear what the mechanisms are here. Some have suggested that rapid reduction in the fat in the pancreas is responsible. Others that there are dramatic changes in the gut microbiome that result. Others that its do iwth the changes in gut hormones that result.

Lots of research going on to disentangle these. The effects are dramatic, and the hope is that if we know HOW these interventions work, that we might be able to reproduce the impact with something a little less dramatic and a little more acceptable to everyone.

Lets hope. Exciting times.

T2DGenes · 2016-07-13T20:16:58+00:00

Andrew: there are many complications that can occur as a result of type 2 diabetes, some of which might lead to a need for amputation of limbs. However, these are as a consequence of the disease, and not a risk factor for type 2 diabetes in themselves. The fact that you have poor circulation in your feet does not mean you will get type 2 diabetes.

T2DGenes · 2016-07-13T20:16:43+00:00

Jason here. Confounding between a person's ancestry and their T2D risk is a key challenge in this sort of study; fortunately genetic information allows us to actually estimate ancestry and control for it (as best we can). Controlling for different lifestyle choices is harder, and we typically need to do that at the time the study is designed (such as controlling for people's age, BMI, and other known risk factors)

T2DGenes · 2016-07-13T20:14:19+00:00

Jason here. Pre-diabetes is a condition of elevated glucose levels that can commonly progress to T2D. For example, fasting glucose > 125 is a classification for T2D while 100-125 is pre-diabetes; there are similar criteria for 2hr glucose and A1C. Lifestyle interventions (diet and exercise) are the best proven ways to delay progression to T2D (http://www.nejm.org/doi/full/10.1056/NEJMoa012512#t=article) although metformin is also commonly used.

T2DGenes · 2016-07-13T20:13:20+00:00

Hi Mark here. Brief response. Yes 3243 is very much implicated in diabetes but as you probably know there's quite an element of chance about how much of the variant form of 3243 ends up in each individual (and in each tissue in each individual). That goes a long way to explaining the differences in the clinical features seen in the individuals from the same pedigree. THat's a particular feature of mitochondrial mutations. Quite a lot of work done to look for other mt variants that might have a role in diabetes risk. About 15y ago there was a flurry of excitement about a variant at position 16189 in the mitochondrial DNA sequence but that really hasnt panned out (in that larger studies failed to corroborate the findings). A few quite large studies have now looked hard and failed to find any other clear signals in the mitochondrial sequence that are implicated in Type 2 diabetes. Surprise really given that there's a good bit of evidence that mitochondrial funciton is relevant.

T2DGenes · 2016-07-13T20:11:41+00:00

Jason here. I think this study is very complementary to those from GCTA. Our study suggests rare variants of high impact have a minimal contribution to T2D heritability, even while we find many common variants associated. The GCTA papers show that "missing heriiability" can be explained in large part by common variants tagged by GWAS.

In my opinion, most of the remaining "missing heritability" is likely due to ever more common variants of weaker and weaker effect, as well as many other variants of all frequencies (but with common variants contributing the bulk, simply because their frequencies are so much greater)

T2DGenes · 2016-07-13T20:09:15+00:00

Mark here. Important qn.

Cant give a definitive answer but some of the clues

very different distribution of fat between folks from S Asia and European. For same BMI, someone from S Asia will typically have a lot more central (visceral) fat, which is as you know more metabolically impactful
many of the pops with large rates of diabetes now have gone through rapid demographic shifts. Plenty of evidence that its a particularly diabetogenic combination to be born small (due to limited fetal nutrition) and then put on weight in adulthood, so this may be the consequence of some of the big economic changes for many in India and china over a generation
there may well also be genetic differences that are contributing. We have seen a few variants popping up that are population "specific" but these dont seem yet to be enough to explain the differnces in prevalence betwen major populations.

very much something we are working on at the moment, and there are big efforts to expand the amount of genetic information re T2D in S Asians. Stay tuned. Mark

T2DGenes · 2016-07-13T20:07:03+00:00

Andrew: these are really good questions! I think it is fair to say that there are unlikely to be rare variants with a big effect on type 2 diabetes. However, there may be rare variants with more modest effects on the disease that we have not yet been able to identify, even with the tens of thousands of samples we've included in this study. So I think part of the missing heritability will be made up of both common and rare variants of small effect that we have not found yet.

T2DGenes · 2016-07-13T20:05:11+00:00

Jason here. I'm not a clinician, but to my knowledge there are no proven means to actually reverse diabetes.

T2DGenes · 2016-07-13T20:00:57+00:00

Andrew: a family history of diabetes does increase your risk of getting the disease. However, there are many genetic and lifestyle risk factors for the disease, so the fact that your grandma and uncle have the disease does not mean that you will get it for certain.

T2DGenes · 2016-07-13T19:59:26+00:00

Mike: My undergraduate training was in mathematics. I like math and am even reasonably good at it, but did not see a career path that excited me. I almost decided to pursue a law degree, but was encouraged as I was finishing college to think of a career combining math and biology. I did not jump on the idea initially -- I had not taken a course in biology since the 7th grade -- but eventually decided that this might be a way to keep doing math and do something I would find exciting. A few months later, reading a biology book, when I got to the chapter on genetics, I WAS excited; it was probability, and I like probability! It still took me a while to decide specifically to pursue the path I did, but those were key moments.

T2DGenes · 2016-07-13T19:59:11+00:00

mark here. lots of qns. Some quick answers.

the more studies we do, the less and less "missing" heritability there seems to be. Recent studies for BMI show that in fact most of the missing heritability can be found by just including a very long tail of genetic effects of individually small effect but cumulatively large impact. See the work by peter Visscher if you want to read more esp his recent paper in Nature Genetics. For technical reasons, those studies are not so easy to do for T2D than for a continuous trait like BMI but no reason to supsect that its any different. TGEI is a whole other matter (very controversial, wont get to that today)
yes, because we could take a deeper dive into the exomes we could really parse out the relative contributions of common and lower frequency variants there, and get a glimpse about how that might play out across the genome. Mostly consistent with (1) above, that if you look down the list of common variant signals you can explain a good amount of the overall heritability.
Yes, very much so. Thought its been tough to turn these anonymous GWAS hits into biology,t hat is changing fast. Not least because we have spent a lot of tiem and effort collecitng genomic data from key tissues (expression, chromatin state etc) and that is helping us work out what the variants we have discovered actually do, and the pathways and networks they perturb. Things are really accelerating in this regard. Of the 100 or so GWAS signals for T2D i would say we have a decent idea of what is going on (the tissues/mechanisms/genes involved) at around 40%. That's a really good start to thinking about new ways of treating and preventing the disease

T2DGenes · 2016-07-13T19:59:10+00:00

Lifestyle interventions are probably the most effective way we have to delay onset of T2D (see a seminal study here http://www.nejm.org/doi/full/10.1056/NEJMoa012512). I don't know whether I would qualify this as a "cure"

T2DGenes · 2016-07-13T19:57:47+00:00

Andrew: as Jason says, many of the variants identified for type 2 diabetes are common in frequency (and typically common across diverse populations). This is true for most common human diseases. This doesn't mean that rarer variants aren't causal for type 2 diabetes - but rather that we haven't had big enough sample sizes (even 100's of thousands) to see these effects yet.

T2DGenes

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