[MUSIC] Hello, I'm Allan Vaag. I'm chief physician at Rigshospitalet, the Danish national state hospital, and I'm also professor of endocrinology at the Copenhagen University. The aim of my talk is to address different hot topics in our current understanding of aetiology as well as of the pathophysiology of Type Two Diabetes. I will also briefly mention upon the epidemiology of type two diabetes, and I'll talk about the definition. That is how we define the disease, and how this relates closely to the complications associated with Type two Diabetes. I will share with you our present conception of Type Two Diabetes, being both a multifactorial as well as a multiple organ disease, and this in turn has significant implications for our understanding and treatment of the different clinical phenotypes of disease. And then of course, I will talk about which underlying molecular defects are involved in the pathophysiology of Type Two Diabetes. I will focus in particular on my main research interest right now, which is the topic of fetal programming of Type Two diabetes. I will tell you about how genetic as well as epi-genetic and non-genetic mechanisms may all be involved in the complex mechanisms underlying Type Two diabetes. I will also tell you about some recent data suggesting that immature stem-cell functions are likely to play an important role for development of Type Two Diabetes, and its associated cardiometabolic disturbances. Finally, I will tell you my view about the current treatment options of disease with respect of both pharmacological as well as non-pharmacological treatment modalities. So firstly, everybody is talking about the diabetes epidemics and we know from international figures indeed that there is a very high prevalence of patients with Type Two Diabetes across the world. We know that around 400 million people have diabetes and by 2035 this figure is expected to rise to more than 500 million people. The number of patients with Type Two Diabetes is increasing in every country in the world, but in particular, the prevalence is increasing in developing countries. As for the exact number of people with diabetes in all societies, the figures are somewhat uncertain and the reason for that, is that there are very few symptoms associated with the disease, at least in its earliest stages, but it is also because the definition of the disease has actually changed over the last two decades, by lowering cut-off level criteria for defining Type Two Diabetes. For instance, the fasting plasma glucose cut-off level defining type two diabetes was previously 7.8 millimolar, and that has now within the last ten years been lowered to around, or to 7.0 millimolar. Thus, the changing criteria being somewhat more inclusive with time has also participated to the increase in prevalence. Other factors that have contributed to the increase in prevalence of the disease is very much increase in general public awareness of the disease, as well as the or including the implementation of effective population screening programs in different settings across the world. So this of course means that we have discovered many more patients with Type Two Diabetes, making it a little more difficult to compare with previous figures. To this end, the mortality of Type Two Diabetes has been decreasing over the last decade, contributing to some extent, to the increased prevalence. Having said that, however, when looking across the world there are major geographical differences in the prevalence and in the forecast for the incidence of Type Two Diabetes. In Scandinavian countries we are discussing the extent to which there is actually a true rise in the prevalence of diabetes, and recent figures from Sweden, have in fact, not supported that there is any significant increased incidence of Type Two Diabetes in the Scandinavian society. Therefore, the increase in prevalence of Type Two Diabetes in Scandinavia may at least for the major part be due to the factors I mentioned just before, but in contrast, in other areas of the world and in particular in the countries we call the growth countries, or previously called developing countries, including India, Africa, China, and South America, there are real significant increments in the incidence of Type Two Diabetes. Some forecasts have in fact suggested that within a time frame of ten to twenty years, there will be a two-fold increase, in the prevalence of Type Two Diabetes in these developing countries. Understanding the causes for these differences in prevalence of diabetes across societies is highly likely to provide us with a much better understanding of the roots of diabetes in these, and also in other parts of the world. The role of ethnicity in the development of Type Two Diabetes is illustrated, for instance, with the fact that Asian people with a BMI of 25 have the same overall risk of developing Type Two Diabetes, as Caucasian-European people have, who have an average BMI of around 30, and I will address also the potential reason for that later in my talk. To understand the reason why some people develop Type Two Diabetes, we need to address the diagnostic criteria of the disease in more details. I mentioned to you that the criteria for diagnosing type two diabetes have changed over time and that the criteria have become more inclusive. Besides lowering the cut-off level for the fasting plasma glucose concentration from 7.8 to 7.0 millimolar, Type Two diabetes can also now become diagnosed from the level of glycosylated haemoglobin (HbA1c) meaning that a person has Type Two Diabetes if the so-called HbA1c value exceeds 6.5%. HbA1c is a measure of the average level of plasma glucose over the last eight to ten weeks. The reason why the diagnostic criteria of Type Two Diabetes have changed over the years, clearly reflects the general somewhat confusion about the disease even among experts, resulting in the definition of Type Two Diabetes being an arbitrary compromise achieved as a consensus achievement among experts. The main rationale for defining a disease is based upon whether the diagnosis is associated with subjective symptoms or with the development of any associated adverse health outcomes. In the case of type two diabetes, the subjective symptoms are usually mild or absent until more severe stages of the disease, and therefore, its justification as a diagnostic disease entity is related to its associated vascular complications. For instance, the diagnostic criteria of Type Two Diabetes as determined during oral glucose tolerance tests, is based on epidemiological associations with increased prevalence of microvascular complications, being retinopathy, nephropathy and neuropathy, with values above 11.0 millimolar two hours after the ingestion of 75 gram glucose. Similarly, the reason for lowering the criteria for fasting plasma glucose concentration in the definition of type two diabetes from a level of 7.8 to 7.0 milimollar was that cross sectional, as well as longitudinal, observational, epidemiological studies, have found an association between increased mortality from cardiovascular disease, also in the window of glucose values between 7.0 and 7.8 milimollar in the fasting state. Even among patients treated for type two diabetes in developing countries or in developed countries, such as Denmark, their risk of dying from cardiovascular disease is at least twofold elevated compared with the background population. In fact, being almost exactly the same as that seen among people without diabetes, who have suffered from a previous myocardial infarction. So, this is why Type Two Diabetes is commonly referred to as a cardiovascular disease equivalent. Oral glucose tolerance tests are performed in people after an overnight fast. Blood samples are obtained from a vein in the forearm in the fasting state, and two hours after the ingestion of a solution consisting of water and 75 gram glucose. The blood is immediately centrifugated to remove circulating cells and thereby isolating the fluid component of blood, called the plasma. The glucose concentration of plasma is subsequently measured using an enzymatic method. It is important not to leave the blood sample with its cellular components too long after the sample has been taken to avoid that the glucose concentration decreases as a result of ongoing metabolism of glucose in the cellular components of the blood. Implementing the consensus diagnostic criteria for Type Two Diabetes based on the cut-off levels mentioned above directly or indirectly implies that the lowering plasma glucose levels below these cut-off levels will also be associated with an effective prevention of both microvascular as well as macrovascular complications. This however, may not necessarily be the case for all vascular complications associated with Type Two Diabetes, including cardiovascular mortality, which is why the criteria actually is still far from complete and why they probably may also be modified again in the future. Illustrating the utmost contemporary relevance of this topic, a prominent British diabetologist, Edwin Gale, recently published a very provocative article in The Lancet entitled "Is Type Two Diabetes a category error?" The main point argued in this article was that our present definition of Type Two Diabetes is in no way based upon a distinct knowledge about the exact origin of the underlying pathophysiological disease mechanisms or for that instance, on exact knowledge of the cutoff levels for plasma glucose by which the disease is defined as mentioned above. It was argued that Type Two Diabetes is a more plastic and dynamic state, where the diagnosis may be present or absent at different time points depending on a number of conditions including diet, level of physical activity, as well as the presence of comorbidities, etc. As for comorbidities in Type Two Diabetes, there are some that may occur as a direct consequence of the elevated plasma glucose, which in particular is the case for the microvascular complications, however, other comorbidities may occur as a result of a common underlying aetiology and/or as a result of inverse causality with the comorbidity actually being the cause of the elevated plasma glucose and/or Type Two Diabetes per se. Examples of comorbidities that at least theoretically may occur as a result of common underlying aetiology includes hypertension, dyslipidemia and cardiovascular disease, which all to some extent may be caused by an adverse intrauterine environment. Examples of comorbidities that may cause Type Two Diabetes also include cancer, heart insufficiency, infections, immune diseases requiring glucocorticoid treatment, as well as hyperfunctioning endocrine diseases such as thyreotoxicosis, pheochromocytomes and increased growth hormone secretion. Indeed, we lack evidence to show that patients with Type Two Diabetes, due to different underlying causes, should be treated the same way and using similar treatment targets and/or treatment modalities. To illustrate our challenge defining Type Two Diabetes as a distinct disease entity, you can compare with the definition of Type One Diabetes. Type One Diabetes is a very distinct disease entity caused by totally absent or very low insulin secretion from the pancreas. Based on the distinct underlying pathology, people with Type One Diabetes have an absolute need for insulin treatment to ensure survival on a short-term respect perspective, in fact, this is the exact definition of Type One Diabetes. In contrast to type one diabetes, type two diabetes is actually more of an exclusion diagnosis, being the diabetes disease which you have, when you do not have Type One Diabetes, and when the state of diabetes is not caused as a result of distinct genetic mutation or as a result of pregnancy induced by insulin resistance, the latter also called gestational diabetes. The importance of being able correctly to classify Type Two Diabetes is illustrated by the fact that the vast majority of all patients with diabetes in total, estimated to be more than 80%, belong to this category. Compared with Type One Diabetes, the pathophysiological mechanisms involved in Type Two Diabetes are more complicated involving in fact multiple organ dysfunctions. Besides being a multiple organ disease, Type Two Diabetes is also a multi-factorial disease, with different patients having different types of combinations of causes and even metabolic defects causing the disease. What we need to know about in the future, is what is the most instrumental definition of Type Two Diabetes in terms of actually defining and finding those patients who may benefit the most from intensive focus and intensive treatment. We know today, that not all patients with Type Two Diabetes benefit to the same extent from intensive glucose lowering treatment, and there is currently a risk of becoming somewhat defaitistic with respect to how and with what intensity Type Two Diabetes patients should be treated, most notably when it comes to which glycemic target we are aiming for. With the large amount of Type Two Diabetes patients in the world, it is a major demand for both the patients, as well as healthcare systems if we are treating all type two diabetes patients aiming to normalize glucose control, blood pressure, as well as lipid levels. Besides the need for regular controls with the doctor, this requires multiple and commonly less effective drugs, intensive lifestyle treatment, a very high motivation and compliance for the patients, adverse effects on life quality, high expenses, and much time used for home monitoring of for instance glucose etc. As a consequence of that, today and in many areas of medicine we are talking about how to achieve more individualized treatment modalities, as well as treatment goals of different diseases, and in that sense, Type Two Diabetes is a perfect example of a disease where we definitely need individualization. Thus indeed, there are some patients that need very intensive care and on the other side there are also patients that may not need so intensive care, where we should rather reduce the burden of treatment for the patient and the society, and instead focus on other aspects in life. With the recognition of a need for more individualized treatment in Type Two Diabetes, it helps us understanding why it is such a high priority for us to discuss the definition of the disease, and even in provocative manners like claiming that it might be a category error. As said already, having Type Two Diabetes is often not associated with any major symptoms beside tiredness, of course, if the glucose level is very high, you have symptoms like polydipsia, and a high degree of thirst and water intake, and you also have weight loss, infections, blurred vision, and so on and so forth. But the majority of diabetes patients with the Type Two diagnosis they only have vague symptoms. So, why is it that Type Two Diabetes is such an important disease? As for the long term complications, one type of complications in Type Two Diabetes is the same as seen in patients with Type One Diabetes, namely, microvascular disease and its complications which includes retinopathy, meaning risk of blindness, neuropathy with altered sensing in the peripheral nerves, causing increased risk of foot ulcers, as well as nephropathy, where you have a risk of developing end-stage kidney disease, causing a need for dialysis, and also eventually a potential need for kidney transplantation. Indeed, the risk of microvascular complications in Type Two Diabetes is closely associated with the duration of the disease, and also with the duration and the degree of hyperglycemia in the individual patients. Given that these complications develop very slowly, it means that the oldest patients with Type Two Diabetes, who may not have a long life expectancy, may to some extent be at a low risk of developing microvascular complications, as opposed to the younger patients with Type Two Diabetes, who are expected to live with the disease for many decades, and therefore also are at risk of these microvascular complications on a long term perspective. This of course, has significant direct implications for the treatment of diabetes. Besides the microvascular complications, we have the macrovascular complications that all occur as a result of atherosclerosis. These states include ischaemic heart disease including angina pectoris, and myocardial infarction, stroke, as well as peripheral arterial insufficiency, particularly affecting the lower limbs and therefore also involve a risk of severe a foot ulcers, and eventually amputations. Patients with Type Two Diabetes have an around twofold increased mortality compared to patients who do not have Type Two Diabetes. While glucose-lowering treatment is the hall mark for the prevention of microvascular complications in Type Two Diabetes, prevention of macrovascular complications needs multifactorial interventions, including intensive blood pressure and lipid lowering treatments as well as platelet aggregation inhibitors and smoking cessation. Lifestyle intervention with low-energy and low-fat contents as well as low contents of simple carbohydrates is a cornerstone in Type Two Diabetes to reduce weight, plasma glucose, as well as channel cardiovascular risk. The famous Steno two study shows that multifactorial treatment in Type Two Diabetes patients with all of these treatment modalities in combination was associated with a significantly reduced but not normalized mortality in these patients. However, large scale studies and meta analyses have now provided conclusive evidence for that intensive glucose-lowering treatment in itself compared with conventional glucose lowering treatment, aiming for HbA1c values between 7.5 and 8.0, does actually not reduce mortality in Type Two Diabetes. It has been suggested that intensive glucose lowering treatment in newly diagnosed Type Two Diabetes patients may have long lasting beneficial implications for survival due to the so called "legacy effect". However, the putative physiological mechanisms underlying such an effect are lacking, and the idea of the legacy effect having been derived from observational data neglecting that many type two diabetes patients have elevated plasma glucose levels actually for years before the diagnosis actually makes the support for this legacy effect hypothesis rather sparse at least for the time being. I told you before that type two diabetes is both a multifactorial as well as a multiple organ disease. Illustrating the multiple organ systems affected by Type Two Diabetes, Type Two Diabetes is also a central component of the so-called metabolic syndrome. The metabolic syndrome defines a clustering of cardiovascular risk factors including glucose intolerance, abdominal obesity, hypertension and dyslipidemia. The common denominator of all of these components is that they are associated with insulin resistance, as well as their status of being associated with elevated risk of developing cardiovascular disease. However, the exact reason why these factors are clustering is still a mystery, but one possibility may be that they all have their roots in the fetal environment. [MUSIC]
