[MUSIC] So in this module I'm going to continue the theme of focusing on a particular condition and exploring the genetic and molecular basis of the disease and responses to treatment. And the condition today is diabetes. Diabetes is an enormous problem worldwide. It's linked to obesity, but not everybody who is fat gets diabetes and not everybody who has diabetes gets fat. There are two types recognized. We all know that, type one and type two diabetes, and one of the lessons I'll try to teach today is that there are probably many, many other subtypes. Genetics have helped define some of those other subtypes and some of the genetic subtypes which appear to be relatively unusual right now have clear implications for therapy. And what's really interesting is that the type one and type two diabetics who behave clinically quite differently appear to have, from genome-wide association studies, from candidate gene studies, and from many, many other perspectives, very different disease mechanisms. And GWAS has actually helped illuminate some of the potential disease pathways that lead to these diseases. I'm going to start by telling you a case. And I'm not going to give you the answer until later in this module. A 16 year boy discovered incidentally to have elevated blood glucose. He is not overweight. One of the issues in dealing with a 16 year old is that that's the age where he could have type one diabetes. And it's the age where he could have type two diabetes, particularly as an evolving threat in the young who are overweight. He is not overweight, he relates a positive family history of diabetes, which is very common in type one diabetes, but his blood sugar is modestly elevated. And we'll come back to the rest of the story in a moment. Diabetes an extraordinarily common disease. There are hundreds of millions of people who carry the diagnosis. And there are probably a further couple of hundred million people who have the disease, who have not yet acquired the diagnosis. The vast, vast majority of those people have type two diabetes. Type one diabetes probably affects something like 10 million people across the world. Type two diabetes, hundreds of millions of people. Let's look at type one diabetes first. When you look at prevalence by country, well what's really quite interesting is that this is a northern European disease. Type one diabetes can occur in many, many other parts of the world, presenting classically in the young with very high blood sugars and ketoacidosis even. But that seems to be particularly prevalent in Scandinavia and other parts of Northern Europe. Even before the advent of genome-wide association studies, there was a clear association with variation in the MHC region, which controls immunity. So there was this sense that diabetes might be an autoimmune disease. What this slide shows is the effect of many, many genes that have been discovered as a predisposition alleles to diabetes. The ones in gray have been discovered by GWAS. The ones in red were discovered prior to GWAS, you can see the much larger signals from, for example, the MHC locus detected as early as the 1970s. And the y-axis here is the risk that you will get diabetes if you have a sibling with diabetes. So again this idea of familial transmission. When people started to look at genome-wide association studies, for example you can find loci on these chromosomes, and many, many others by now, that confer risk for type one diabetes. And what's interesting is the MHC locus on chromosome six carries an odds ratio of less than 10 to the minus 200th. So it's really a very, very important signal. The LOD score is like the odds ratio, it's the logarithm of the odds ratio, and this is a metric derived from family studies mainly. So I want to make a little digression here and talk about the relationship between type one diabetes as an autoimmune disease and other autoimmune diseases. So listed here are a couple of dozen loci where variation increases risk for type one diabetes. They tend to be in to be in immune signalling genes. And what's interesting is that the same variants, or at least the same loci, perhaps not the same exact variants of those genes, also confer risk for many, many other autoimmune diseases. Celiac disease notably, multiple sclerosis, MS, rheumatoid arthritis, lupus, Crohn's disease. So that's an interesting overlap that suggests that an immune diathesis can result in a variety of manifestations across diseases. There's a little bit of data. It's not very compelling. The patients, for example, with Crohn's disease, do they have a higher incidence of type one diabetes? Some say yes, some say no. Celiac disease, there's a much stronger association. Let me just digress a little bit more and talk about inflammatory bowel disease. So there have been very large genome-wide association studies looking at Crohn's disease and ulcerative colitis. Conditions that sometimes can be difficult to tell apart, but when you look at the genome-wide association signals, they tend to be in three categories. Crohn's specific, ulcerative colitis specific or overlap the inflammatory bowel disease syndromes overlap. The overlap tend to be an immune signaling in HLA, the ulcerative colitis variants tend to be in genes that are barrier functions. So those are suggested that there's something trying to get in or that the epithelium is leaky in some way. And that's a proximate contributor to the ulcerative colitis phenotype. For Crohn's there is a real problem with innate immunity. And so that suggests that there are very different pathways that make the bowel respond in a different way when manifesting with Crohn's disease or ulcerative colitis in the face of multiple exogenous stresses, as well as genetic predisposition. And one more slide about inflammatory bowel disease, again this idea of these immune diseases having overlaps at the genetic level with many other immune diseases as shown here. So, all inflammatory bowel disease is linked together and is linked to type one and type two diabetes, shown at the bottom of these slides as well is celiac disease and many, many other autoimmune conditions. And the genes that highlight those overlaps are shown here. So that's the story with type one diabetes is that it appears to be an autoimmune disease. Of course there are people who are very interested in immune modulators as early interventions in patients who have just been diagnosed or who are just about to be diagnosed with type one diabetes. A very exciting area of investigation, but again, the big problem worldwide is type two diabetes. This is the prevalence of type two diabetes expressed as a percentage of the population of that country. And as part of the obesity epidemic, the United States leads the world. Probably related to obesity, but that's percentage of the population of the country. And in fact we don't lead the world. The world is led by China and India. Where the prevalence is somewhat lower, but the total population is obviously much, much higher. And so the emerging threat from Type 2 diabetes actually continues to be in the United States and somewhat in western Europe, but the big, big threat is going to come from Asia, the big threat to human health. I've shown you slides of association studies looking at diabetes or insulin sensitivity before and I highlighted in one of the earlier modules, SLC 30A8 as one of the many many signals and remember it's indicated by that red arrow on this slide. Remember that rare variation in that gene appears to protect against diabetes, at least in certain parts of the world like Iceland. And so that highlights the idea that even these modest effects sizes out of a gwASK can be clues to genetic variation that can be actually drivers for the development of new drug therapy. So if you have an inhibitor of SLC 30A8 function, you may have a drug that could prevent Type 2 diabetes as I discussed in one of the earlier modules. The other part that's really interesting about the GWAS in results in Type 2 diabetes is where the genes are. So if you had asked a diabetes researcher 20 years ago or 15 years ago, what is a fundamental defect in type two diabetes? The answer would probably be that the pancreas works just fine, secretes insulin, but those people are too fat and they have much high insulin requirements than normal. And because they have much higher insulin requirements than normal, the pancreas just sort of gets exhausted. And it turns out, at least from the gwASK data, that that explanation is probably not the whole story, and probably not in the correct direction. Most of the genes that have been identified by gwASK as conferring a predisposition to Type 2 diabetes actually are involved in insulin secretion. Not in insulin sensitivity, and some are involved in cell cycles. So the notion is that it's the beta cell mass, how many beta cells you have, and how well they are able to secrete insulin, that is the fundamental problem in Type 2 diabetes, not this idea that the end organs are gobbling it up. So that's an interesting way of thinking about it, and it makes people think differently in terms of therapeutic approaches. So come back to his boy because he seems a little unusual. And when I say a positive family history of diabetes, here's the family history. And this works like and autosomal dominant disease, with pretty high penitrants. Involves men and women, it involves many generations, it involves male to female and female to male transmission. The proband is the square on the lower right, and you can see that his mother and his maternal grandfather have diabetes and his uncle and his cousin. So what's the problem here? This is probably an example of what's called maturity onset diabetes in the young. Maturity onset diabetes being another name for Type 2 diabetes. But maturity onset diabetes in the young, MODY, M-O-D-Y. And the fundamental problem in MODY is shown on this slide. There have been now six genes in which mutations have been identified in families, such as the one I just showed you. One of the disease genes, one of the first ones discovered, is in glucokinase. Glucokinase plays a central role in beta cell functions. This is a cartoon of a beta cell and what glucokinase does is it adds a phosphate group to glucose, and that in turn results in generation of ATP, generation of ATP closes ATP sensitive. Potassium channel shown in the lower right, when they are close, the membrane depolarized and the calcium channel open and calcium entry into the cells allows insulin secretion to occur. So if you have high glucose, you have normal glucokinase activity, you get, you make Glucose 6 phosphate, that in turn results in an insulin secretion. So the cell has a way of sensing what's going on in it's outside and responding by insulin secretion. The problem in the first form of maturity onset diabetes in the MODY is loss of function variant in glucokinase. So they have decreased ability to do that sensing and therefore decreased ability to secrete insulin. And the other five genes that have been identified in families with MODY all have to do with insulin synthesis. They're all transcription factors that control insulin synthesis. So the problem in this disease is that there's just not enough insulin being secreted in response to a glucose load. The disease tends to be very, very mild. So it's important to recognize these people don't, and mild means a good long, long term prognosis. And they don't need insulin, actually, they can be managed with oral medicines. And, occasionally, oral medicines are actually the treatment of choice for these particular patients. Not surprisingly, there are rare, rare cases of families in which a child inherits an abnormal glucokinase allele from both parents. This is a family that was originally reported In 2001. And you can see the affected individual in blue, in the lower right, has two abnormal alleles, one from mom and one from dad, and mom and dad, as you can see, are first cousins. So that's the reason that a rare variant can be transmitted to a child. And that child presented with severe diabetes as a neonate. It's important to recognize that because those children do need insulin right away because they just don't have an ability to secrete insulin at all, they present with pretty profound hyperglycemia. So let me come back to this idea of the interplay between the ATP sensitive potassium channel and the calcium channel, because I have a different story to tell you. So again, the cartoon on the left side shows the normal function. There's potassium inside the cells, potassium outside the cells, and when ATP levels are low, the channels is open. When the channel opens, potassium flows out. And when ATP levels rise the channel closes, so it's an ATP inhibited channel. The channel closes, potassium no longer flows out, membrane depolarizes, calcium enters the cell, and that results insulin secretion. That's the way the things normally worked. Now, if you at this cartoon you wondered to yourself, could there be mutations in the genes that encode the ATP sensitive potassium channel itself. Of course I wouldn't be telling you this story if that wasn't the case. The ATP sensitive potassium channel, you can see in the cartoon, has a blue core, and an orange coating around the core. The blue core are the potassium channels. And there are four proteins that make up one potassium channel. And the orange coat is a sub unit that goes around the potassium channels to regulate their function. So what happens in a person who has A mutation in the ATP sensitive potassium channel, is that the channel is open and it refuses to close. And when it refuses to close, the signal to tell people to secrete insulin, the signal through the calcium channel, is no longer there. So insulin is not secreted and the patient is hyperglycemic. Interestingly, I didn't tell you the name of the subunit of the potassium channel. So the orange coating around the potassium channel is called SUR1, and that stands for sulfonylurea receptor 1, and that is the specific target of the sulfonylurea class of drugs. You give the sulfonylurea's and you specifically correct this defect. So this so-called gain of function defect in SUR, and there are also mutations reported in the potassium channel, can be specifically reversed and managed by the administration of sulfonylurea drugs. These are patients who have hyperglycemia, they do not need insulin. What they need is a drug that corrects the fundamental defect, the fundamental defect here being a channel that doesn't close appropriately in response to high blood sugar. So here is a cartoon of the channel. I told you there is four potassium channel proteins that assemble together to make the little pore through which potassium flows. And then there's this outer coating called the sulfonylurea receptor that channels, and the name of the channel is KIR6.1 and the name of the sulfonylurea receptor gene is SUR1. And gain-of-function mutations, in either the SUR1 or the potassium channel gene, result in diabetes. Loss-of-function variance do the exact opposite. And loss-of-function variance results in profound neonatal hypoglycemia. Because they have too much insulin secretion. So this is an example, again, where understanding the molecular basis of the disease leads to direct therapies. The hypoglycemic patients could be managed by drugs that activate the channel complex. The most commonly used is a drug called Diazoxide which in normal individuals, [COUGH] is an anti-hypertensive with a side effect of increase in blood sugar. But of course in this instance you want it to increase blood sugar. So I told you before, the prevalence of type ii diabetes is enormous around the world. The drug of first choice is metformin. And there is a little bit of data that suggests that variability and response in metformin is also genetically driven. So here is one example. This is a group of normal subjects who were given a glucose load and blood sugars were followed over time on the left hand panel in the absence of metformin. There are two groups of subjects. These are normal subjects. One who have wild-type OCT1. OCT1 is a transporter. That is responsible for moving metformin out of the blood, into the liver cell, which is where it does its work. And the other group are people who have lost a function variant in oft one. So there in the absence of drug, they look exactly the same. They have the same response to glucose load. But you then give them metformin and perform the glucose load again. In the presence of metformin and the transporter that will suck the drug up into the liver and allow it to work, blood glucose is lowered. That's the black dots. But in the presence of a variant in opt one you can see that the metformin effect is much less prominent. And those patients look like they're not taking any drug at all. So this transporter, polymorphism, is one explanation for variability in response to metformin and there other genetic variants that are now being described that contribute to variability in metformin effects. Again, what does all this have to do with personalizing medicine in diabetes and across medicine? Okay once again I keep on coming back to this message understanding the mechanisms of disease allows you to personalize therapy. So type 1, type 2 diabetes that 's an important distinction. But there are other sub-types that are pretty rare right now, but hopefully will become more common. Which will have specific therapies attached to them. There is variability in this response to commonly used treatments and genetics does play a role. We recognize type 1 and type 2 diabetes. Those classifications are almost certainly over simplifications. And an interesting challenge that we have now is not simply to identify who is going to get diabetes. That's actually pretty difficult, and you would think that understanding the genetics of the disease could allow you to use genetics to identify patients ahead of time. But the genetics don't contribute enough to risk to allow us to do that. The real challenge in clinical medicine right now, is to identify the hundreds of millions of patients around the world who have diabetes, who are suffering the vascular complications of diabetes, and don't yet know it. So that's going to be an interesting public health challenge that has everything to do with personalizing medicine and not much to do with genetics. [INAUDIBLE] [MUSIC] [SOUND] [APPLAUSE]
