[MUSIC] Welcome to this module on inflammatory beta cell destruction in diabetes. I am Thomas Mandrup-Poulsen of the Department of Biomedical Sciences, University of Copenhagen. So in this module, I'd like to discuss the following topics. I'd like to start off with discussing diabetes as diseases of the pancreatic beta cell. And then I'd like to go on with causes of beta cell failure in type 1 and type 2 diabetes. I'll then discuss the innate immune system and beta cell failure. And then inflammatory mediators as a therapeutic targets of type 1 and type 2 diabetes. I'd like to end off with two examples of recent developments from our own laboratory. That is, novel approaches to prevent inflammatory beta cell failure and a question which has been nagging us for quite some time and that is why is only the islets beta-cell destroyed by inflammation. So diabetes does not arise without impaired insulin secretion. With the very rare exceptions of mutations in the insulin molecule or the insulin receptor that prevents insulin signaling, all forms of diabetes are caused by failure of the beta cell to compensate for insulin resistance. So in type 1 diabetes as you probably know, there is an autoimmune destruction of pancreatic beta cells that leads to an absolute insulin deficiency. Whereas in type 2 diabetes, there is relative insulin deficiency when compared to the bodily needs that is increased most often due to insulin resistance. So that type 2 diabetes is not just a matter of insulin resistance. Is very clearly shown by the discrepancy in the prevalences of obesity and diabetes. If you take figures from the United States the prevalence of obesity varies between approximately 20%, up to about 30% in certain areas of the United States. Whereas the prevalence of diabetes is only of approximately 5 to 10%. In other words, if you ask patients that are obese whether they have diabetes or not, only every second to third patient will answer a yes to that particular question. Insulin resistance may, in fact, by some researchers be believed to be a mechanism of protection from morbid obesity and immobilization. If you have strong and healthy beta cells that can compensate for insulin resistance, because that would lead to an ever-increasing weight gain. So, in normal glucose homeostasis, as insulin resistance increases, there is normally a compensation of insulin secretion that is proportional to that insulin resistance. So when insulin resistance sets in, it is registered by the beta cells by an increasing blood glucose within the normal level. And that will trigger apart from insulin secretion also insulin biosynthesis. It will cause recruitment of quiescent beta cells and if long lasting even proliferation and generation of a novel beta cell mass. A typical example of these normal physiological compensatory mechanisms are those that occur in pregnancy and in puberty in states of growth where the bodily needs eventually are now increased and where the beta cells are fully able to compensate for those increased needs. However, in the situation of diabetes with increasing insulin resistance as a consequence of obesity, the pancreatic beta cell mass is unable to compensate for that increased need leading first to impaired glucose tolerance, then overt diabetes. And in the case of overt diabetes as diabetes is lasting for several years, a progressive failure of insulin secretion relative to insulin resistance. So on this figure, you can see what we call the starling curve of the beta cell. The term is derived from an analogy to the Frank Starling mechanism of the heart that as you probably know relates cardiac output to the diastolic filling volume, that is that the cardiac output increases with the volume inside the heart ventricle. So on the y axis, you see the beta cell function depicted as insulin secretion, and on the x axis, there is the insulin action as an expression of insulin sensitivity. In the blue curve, you can see the normal physiological homeostatic action of the relationship between insulin sensitivity and beta cell function. In normal individuals, with decreasing insulin sensitivity, there is a proportionally increasing beta cell secretory function, however. In case of diabetes, you can see that the white arrow pointing downward indicates that as beta cell decompensation occurs, the person is undergoing transition from normal glucose tolerance, NGT, to impaired glucose tolerance, IGT. And then to overt diabetes, DIA. So does the notion that diabetes are beta-cell diseases implicate that insulin resistance is unimportant? By no means. Of course, insulin resistance in the face of beta-cell compensation causes the metabolic syndrome of hypertension and dyslipidemia, which are components of the metabolic syndrome and cardiovascular disease. Insulin resistance is the most common driver of beta-cell decompensation. And thus, restoring insulin sensitivity and normalizing caloric intake may reestablish beta-cell compensation and alleviate diabetes. Therefore, insulin sensitisation is an important therapeutic target. But this does not change the fact that you do not get diabetes if you have strong beta cells. And beta cells are therefore, at the center of diabetes pathophysiology. How is beta cell mass then reduced in type 1 and type 2 diabetes? In type 1 diabetes, I mentioned that the underlying cause is an autoimmune destruction of the pancreatic beta cell mass where infiltrating immune cells induce a process of programmed cell death in the beta cells called beta cell apoptosis. In type 2 diabetes, we have discussed that the disease is caused by inadequate insulin secretion to compensate for insulin resistance. And it was long believed that beta cell mass was normal when compared to lean normal glycemic subjects. However, relatively recent comparisons with obese have shown that their clearly is a reduction in beta cell mass in type 2 diabetes. And then, what are the causes of this reduction in mass? It has been supposed that the reduction in mass is also due to program cell deaths, or beta cell but in this case produced by metabolic factors. And relatively recent discoveries have shown that, as in type 1 diabetes, there is in fact infiltrating immune cells into the pancreatic islets in type 2 diabetic patients. And that activation of inflammatory pathways In both beta cells, and in intra-eyelid macrophages contribute to beta cell apoptosis in type 2 diabetes. [MUSIC]
