[SOUND] Hello, my name is Ole Dragsbaek Madsen. I am an honorary professor at The Danish Center for Stem Cell Research, the transnational part and here at University of Copenhagen and at the same time I'm employed as a senior principal scientist in the company Novo Nordisk which is a pharmaceutical company devoted to improving the lives of people with diabetes. Our vision is also including the ultimate cure for diabetes. Diabetes relates to insufficient, or total lack of insulin production, but in the body and this is produced by the beta cells found in the pancreas. In this slide, the green cells show a magnification of a tissue section from the pancreas where the beta cells are visualized. In the form Type 1 diabetes which constitutes about 5-10% of all diabetes patients. This is an autoimmune disease where our beta cells become destroyed for yet unknown reasons by our own immune system. These patients are in the focus for beta cell replacement that is based upon the use of pluripotent stem cells as a source for an unlimited production and access between new beta cells. These therapeutic cells are, would be implanted in a device to eliminate the risk of the immune destruction and cell based therapy would be the topic for this talk but I will just introduce you briefly to diabetes, in general, also focusing on the beta-cell aspect of Type 2 diabetes. As mentioned, diabetes primarily comes in two major types. Type 1, as I mentioned five to ten percent. And Type 2 is the rest, 90 to 95 percent and diabetes prevalence is increasing everywhere in the world. So it is a real burden and a threat to the world's health economy because of the astronomic numbers of patients that are affected worldwide, and particularly in the poorer countries. Such as China and India, which together account for more than 40% of the world's diabetic populations, and we can see that today more than 382 million people with diabetes have been diagnosed. And an expectation of as much as 592 million by the year 2035 can be found on the IDF's webpage. So, it is really astronomic in numbers and the major issue in diabetes, is, that it is, it's association with high risk of developing devastating late complications, that actually lead to, premature death. In fact, one diabetic patient dies every six seconds while at the same time, in the same period, two new patients are diagnosed. So the complications, are among the leading causes of micro and macro vascular complications with associated neuropathy, impaired wound healing, amputations, blindness, kidney failure, and heart disease. Treatment of complications are really expensive and it's not surprising that when you look at the accumulated lifetime cost for treating diabetes, the vast majority of health care costs are actually tied towards treating the complications, while only major parts of the budget is actually for the medication and patient control. So a major focus going forward must be to change such grim forecasts and a major scientific and clinical challenge will actually be to reduce and prevent the risk of developing these complications in diabetes. By int, inter, inventing, actually, better therapy, or even being able to prevent the disease. It has been very clearly demonstrated that the only way to reduce complications, is actually to improve the glycemic control. And as you know, diabetes is hyperglycemia, meaning that you have too much sugar circulating in your blood and risk of developing complications is simply correlated to the time, that a diabetic patient has been exposed to high glucose levels in the blood. So there is stronger relation between good glucose control, good glycemia in diabetes and reduced risk of developing complications. The beauty of the insulin producing cell is that it has an unmatched accuracy by which it both can taste glucose levels and precisely those insulin accordingly to maintain a normal glycemia in a normal patient in a lifetime. In a normal human being of a normal patient. So if we can replace the beta cells, we may be able to re-install a normal glycemic condition that may actually eliminate the risk for further escalation of communications in those particular patients. The lack of adequate insulin response following glucose intake, characterizes diabetes and in other words, an insufficient function of beta cell mass leads to diabetes. Diabetes covers a multitude of diseases where I just mentioned the two major forms. Type 1, Type 2 and, and they are explained by actually two highly distinct mechanisms, but overall the point is, that in the end you have too few beta cells. The two forms, I illustrated in this particular figure, where at the lower left is indicated the size of a functional beta cell mass found in a normal individual. In Type 1, this is the lower right part of the panel, illustrates the results of the autoimmune disruption where the immune system invades and kills your beta cells. The autoimmune memory is life long and beta cells are never coming back in Type 1 diabetes. So these patients are stuck in a situation where life can only be sustained by exogenous insulin injections. So as a Type I patient, you will have to rely on insulin therapy for the rest of your life. In Type 2 diabetes, the disease is mostly associated to westernized lifestyle, characterize by excess caloric intake and also, reduced physical exercise that is leading to obesity and associated with that is, development of peripheral insulin resistance that could be explained as a shielding of the body against the bombardment of the excess calories. This means that when the beta cell of an obese person is sensing glucose, then the normal amount of insulin that should be released is probably not enough and therefore, during insulin resistance, the beta cell will have to work harder to secrete more insulin to actually keep the blood glucose in check. Now in order to further meet the increased demands the beta cell mass actually undergoes expansion to enlarge the capacity for it's insulin production and this is illustrated in the upper corner the upper left corner of this diagram, where it has been demonstrated that obese people that still have no diabetes and this is still 80% of obese people do not develop Type 2 diabetes. So they are able to cope with increased insulin resistance because the produce more insulin. So, if this compensatory upregulation actually, hence failing then you develop Type 2 Diabetes. It means that in Type 2 Diabetes, you still have insulin production, but you have, actually have a relative lack of beta cells to produce enough insulin. While, in Type 1, you will have an absolute lack of beta cells. The final outcome is the same if you do not have enough insulin, you become hypoglycemic and diabetic. There is also a group of patients that are residing in between the two types where a slow engagement with the immune system is some unknown way is further involved in eliminating beta cells in the so called Type 1 and half diabetes. It's also called latent autoimmune diabetes of the adult, or LARA. So it's a slow progression from might, what might have been diagnosed as a Type 2 diabetes that moves towards the Type 1 diabetes that eventually becomes entirely dependent on exogenous insulin injections. So the major challenge going forward, as I mentioned is to interfere, block or revert these red arrows and I, I wanted to highlight the for, that for Type 2 diabetes, phenomenally, promising data have very recently been published from a clinical trial called the Dual Trial that illustrates that when you combine therapies of using long acting insulin, known here is IDeg and a long acting GLP-1, known here as Liraglutide actually leads to the normalization of hemoglobin A1C over time. And glycosylated or glycated hemoglobin reflects the long-term control of glucose control and you could say glycosylation of proteins, or glycations of proteins, is sort of an directly proportional with the levels of glucose in the blood. So if you have high glycosylated, gly, glycated levels of hemoglobin A1C, you will also have an indication that you have had hyperglycemia for the past period. When you look at the lower curve. It is all the way into the normal area which is a, below the 6.5 horizontal line on the slide. So it, in these patients, you could say it glycosylated insulin, oh, sorry, glycosylation of hemoglobin A1C levels all the way back to approach to normal levels and one could speculate that if, although this is a clinical trial, one could speculate that if these patients were continued in this, therapy that they may actually be, prevented from developing complications. So in conclusion there maybe a window of prevention by the combined use of long acting insulin and GLP1, and we know from beta cell biology studies, that this cocktail of two of these two drugs, is actually possibly optimal to nurse, and protect, and enhance the apparent functionality of the beta cell mass. Possibly one of the explanations, to restart on normal glycemic levels, in Type 2 diabetes. Also, now [UNKNOWN] the drugs, to interfere with obesity, may in the long term, be the most effective tools to actually prevent progression to once diabetes. For the reversal of the arrow regarding Type 1 diabetes cell replacement therapy, as illustrated by organ donor islets transplantation's from the Edmonton protocol, has proven effective in attempts to establish and normalize blood glucose regulation when combined with immunosuppression. This pioneering work of Dr. Shapiro at the University of Edmonton has led us to very, to very strong worldwide commitments in trying to make alternative sources to possibly replace this [UNKNOWN] organ donors and providing the islets of Langerhans. This is the focus of the remaining talk. [MUSIC]
