[MUSIC]. The Edmonton protocol was published back in year 2000 by the team of scientists led by James Shapiro from University of Edmonton. And the major breakthrough that they actually published at that time was that you could normalize blood glucose without insulin injections. And the first study was published, including seven patients that were treated with islet transplantation from organ donors. So the focus is cell replacement and organ donation of islet of langerhans. As illustrated, you isolate only the islets of langerhans out of the big organ of the pancreas and then you simply inject, or infuse the islet cells into the portal vein of the recipient where the islets become trapped in the calip eh, capillary system of the liver. And they will start to resume their ability to sense the glucose and secrete adequate amounts of insulin to sustain glycemia at normal levels. [BLANK_AUDIO] The major breakthrough by the Edmonton group was that these seven patients all came off insulin for the initial period. And remember, they were continuously receiving immunosuppression to prevent rejection or destruction of the donor islet cells. The patient group enrolled in such studies are representing the most severe form of type one diabetes, also eh, at least in the United States, called brittle diabetes. And it is almost impossible to control their diabetes adequately by conventional insulin injections. They have recurrent hypoglycemic episodes. And hypoglycemia is identified as probably one of the worst experiences by a patient. And it's due to over insulinization. Furthermore the also have no detectable C-peptide levels. And C-peptide is a split product of pro-insulin that indicates that whenever insulin is secreted, C-peptide is also secreted. So, C-peptide lack of C-peptide means that there is no endogenous beta-cell left in these patients. Therefore, these patients have a very high risk of developing complications. The patients actually receive multiple islet donor infusions, at least two up to three and they received a glucocorticoid-free immunosuppression, part of the explaining the success of the first publication. The diagram at the left shows the wide range of glucose fluctuations before the transplantation, which is typical for this group of diabetics. Strikingly after the transplant, these fluctuations are narrowed again down to actually be within the normal range of non-diabetic people. Indicating, and this is again indicated by the horizontal lines stipulated lines that indicate the normal area of again, black oscillated hemoglobin A1C. So this is in fact taken as a proof of concept that cell replacement therapy can really work in type one diabetes. So if you can protect against the immune destruction, and you can repeat, replace the missing beta cells, you can actually restore a normal glucose regulation in the blood. As mentioned, the most severe experience for diabetics not only the brittle, but many diabet, most type one diabetics and also type two, is when you receive too much insulin, the blood sugar drops down to dangerously low levels. As I mentioned, called hypoglycemia, in contrast to hyperglycemia, which is diabetes. And hypoglycemia is a situation where the glucose is so low that the brain cannot function. It is equivalent to shutting off the battery of a computer. It stops functioning, and it is actually a lethal condition for the brain if it's prolonged, and it may result in coma and death. Fortunately, most diabetic patients can actually feel when they are approaching the dangerous situation. But those who lose this ability called the suffering of hypoglycemia unawareness, are highly vulnerable to increases in their severe hypoglycemic episodes, and they are also at the deterioration of their quality of life. It is likely the strongest force preventing diabetic patients to comply with an optimal insulin injection regimen to control their blood, their blood glucose in, in the most optimal fashion. to, which is required to prevent complications. And, and this experience when you get the hypoglycemic episodes, actually is a no go for many patients and they would rather take less insulin, be less stringent with their diabetes, have more hyperglycemia to avoid the hypo situation. As I mentioned, the Edmonton Protocol propri, provides proof of principle for cell therapy in type one diabetes. And possibly, most importantly, it's, it effectively protects against hypoglycemic episodes. Thus, eliminating the biggest fear of diabetic patients. The lower graph, in this panel, is illustrating that actually after five years follow-up following transplantation, there's only 7.5% of patients that are still off insulin. And they have not experienced hyperglycemia, nor hypoglycemia in this period, and have thus remained normal in their blood glucose regulation. The hemoglobin A1C is the left side of the curve and it's a surrogate mark of a blood glucose regulation. So the higher level, the higher spontaneous glycation reactions you have in your blood, and that is again directly related to the time of exposure to high sugar levels in your blood. So, the higher level of hemoglobin A1C you have in your body, the more indication it is that you have in the past three months been exposed to high blood glucose. So these patients, that have the lower curve, is actually within the normal range of non-diabetic persons. The middle curve represents a large group of patients, this is the curve with the open circles, that are actually now back on insulin in order to keep blood glucose regulation. But they still have some C-peptides circulating in their bodies, and this is a surrogate marker that there are still grafted eyelet cells surviving in their body from the transplantation. There's just not enough functioning beta cells to sustain normal glycemia, so they need to topped up, be topped up with insulin injections. However, the most interesting aspect about this group of patients is that despite the fact that they are now back on insulin injections, they are still cured for their previous dreadful recurrent hypoglycemia. The curve is then the upper curve is then, the unfortunate group of patients that have been able to fully reject and kill off all of the grafted cells. So they have no further C-peptide secretion, and they are fully back on previous insulin dosing, and they are also actually as poorly manageable as they were before the transplantation. So in those patients, the therapy did not work. But in conclusion, islet transplantation has greatly improved the quality for the patients with severe type one diabetes in those patients that retain functioning cells. And this is by relieving the glucose instability and problems with hypoglycemia, as long as the graft survives. Furthermore, it has been suggested that the scarce availability of the organ donor islets should rather be distributed among more patients, with the indications to primarily prevent recurrent hypoglycemia, rather than achieving the full independence of insulin injections. [MUSIC]
