[MUSIC] My name is Torben Hansen. I'm professor at the University of Copenhagen at the Department of Novo Nordisk Foundation Center for Basic Metabolic Research. Today I will talk about genetic aspects of non-autoimmune diabetes. So the agenda for my presentation is that I will present you for the genetic basis of diabetes. I will talk about methods to identify genetic loci associating with diabetes and pre-diabetic traits. Then I will give you some examples of monogenic forms of diabetes. And finally I will discuss common forms of non-autoimmune diabetes. So diabetes was first described 1,500 years before Christ. At that time there was only one form of diabetes. And there was only one form of diabetes for many years. It was not until 1936 that Himsworth for the first time described two forms of diabetes. That was the insulin sensitive and the insulin insensitive. Since 1936, many other forms has come to knowledge, and in 2014, there are several major forms. You have heard about Type 1 diabetes, there's also forms of diabetes where you have circulating autoimmune or antibodies called LADA. There is gestational diabetes, there is specific, genetic sub types which I will talk more about and then the largest parts of diabetes is the Type 2 diabetes. But if we look at Type 2 diabetes that may be not only one form of diabetes. Do we really know what we are talking about because some diabetic patients, they are obese. Some are centrally obese. Some are peripherally obese. Some diabetic patients are lean. Some, as I mentioned previously, have circulating autoantibodies. Some have a very strong family history. Some have very early onset. Some will only be identified if you go through the community and screen for them. Some will have their presence in the clinic and there's a huge difference in the presentation between ethnic groups. For example an obese probably have a different form of Type 2 diabetes compared to a lean Japanese or Chinese diabetic patient. So we need tools to dig into the underlying pathophysiology and pathogenetics of diabetes. But is that Type 2 diabetes a genetic disease? There we have used family studies and we have used twin studies to study this. If we look at the family studies then there is what we call sibling relative risk. If one sibling has diabetes, then there is a two to four time increase risk that the other sibling also will have diabetes. In the background population, in Europeans, the prevalence of diabetes is around 10%, that means a sibling will have a 20 to 40% risk of having diabetes. If you have one parent with diabetes, you will have a 30 to 40% risk of developing diabetes yourself. If you are monozygotic twin, you'll have 50 to 90% risk of developing diabetes. We can also look at heritability estimates of prediabetic traits. And what do we mean by heritability? When I present it here, it's a fraction of the variation in a trait which is explained by genetics. And let's just look at a few traits. For example, insulin sensitivity. About one third of the variation in insulin sensitivity is explained by genetics. If we take another prediabetic trait like BMI, then more than 50% of the variation in BMI is explained by genetics and only less than 50% is explained by environmental factors. And if we take a very important trait, insulin secretion, then, again, more than 50% of the trait variation in beta cell function is explained by genetics. So there's a clear genetic component in the risk of both diabetes, but also of pre-diabetic traits. So we could look at Type 2 diabetes as a complex trait influenced by both genetic and lifestyle factors. And there is an interaction between lifestyle and genes, what we call gene lifestyle interactions. And there is probably also an important interaction between genes, gene-gene interactions. And all these complex interactions that leads to elevated obesity, to insulin resistance, and to poor beta cell function, insulin deficiency, which is the pre-runners for the development of Type 2 diabetes. And then those who have Type 2 diabetes, some of them are at increased risk of developing diabetic complications especially muscular complication and premature death. And again, here there are genetic factors influencing who are at highest risk for progressing. So why should we look at genetic factors? To understand the underlying mechanism of Type 2 diabetes. That is because we know very little about the molecular mechanisms. And if we get specific knowledge, it might help us develop novel drug targets. It might give us an ability to increase our understanding of the underlying priority. We can have tools to better classification of diabetes and we will have tools maybe to do what we call pharmacogenetics, treat patients according to their specific genetic profile. And finally, it will give us a tool for individualized genetic prediction, so that we can target prevention against subsets of individuals with a specific form of diabetes. [MUSIC]
