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Progress in Rat Studies: Learning to Make a Rat Really Diabetic
October 10th, 2010
What is worse than seeking something with a flashlight that does not work? I would say seeking something with a flashlight that may not be working!
If you are reading this it is likely that you are interested in the promise and prospects for the Islet Sheet. Naturally there is great interest in our studies of Islet Sheets in diabetic rats. A couple of months ago I published partial results from an ongoing experiment. Here is the promised update.
The figure shows the complete series of blood sugars for the rat reported previously. The point of the experiment was to find out if an Islet Sheet could normalize blood sugar in a diabetic rat.
In this experiment, a laboratory rat was made diabetic with a drug that kills insulin-producing beta cells. In the diagram, the drug was injected in day -3, and the rat immediately had elevated blood sugar. On day zero an Islet Sheet made with rat islets was implanted in the rat which had been diabetic for three days. Immediately, boosted only by a single dose of insulin, the blood sugars normalized. And with only two exceptions it remained ‘cured’ for 84 days. Impressive for a first try.
Actually, the series is even more impressive. In this series of 23 rats, from May through August, 13 of 23 responded to Islet Sheet implants, and the source of the islets (rat, pig, dog) did not seem to make a difference. And in one heroic experiment, an Islet Sheet that functioned by 21 days in one diabetic rat was removed and implanted into a second diabetic rat. In the second rat it functioned for 18 days!
Call the New York Times! Diabetes cured!
But we are trying to cure diabetes, not get headlines, so here is the bad news. The rats were indeed diabetic, but not fully diabetic. So the Islet Sheet allows the islets inside to function but we have not proved that it would work in a diabetic rat with no insulin secretion of its own.
One lesson for me is, don’t post experimental results on the web before the experiment is complete! We don’t want to offer false hope. But on the other hand my readers surely know we offer the truth as we come to know it.
An advantage of the Islet Sheet is that it can be removed intact. For a diabetic human, this will mean that when the islets in the Islet Sheet lose their function, the Islet Sheet can be retrieved and replaced. And in diabetic animals, we can remove the sheet and observe that the animals’ cure reverses, that is, diabetes reappears.
So we decided to keep some of the 23 rats in this first series alive after we removed the sheet. Blood sugars did rise, but not to the high levels expected for an untreated type 1 diabetic rat.
The frustrating reality is that there is no good model for type 1 diabetes in rodents; all models have deficiencies. The drug streptozotocin is a sugar analog that is highly toxic and particularly toxic to beta cells. An injection kills most of the beta cells, but not all. This difference with human diabetes is, the human disease appears where the immune system has killed most of the islets. The so-called honeymoon in diabetes is when, in the presence of the first injected insulin, the remaining beta cells recover and control blood sugar for a while. But the immune attack continues, and the remaining beta cells die, the honeymoon ends, and the human with diabetes has close to zero insulin secretion: fully developed type 1 diabetes (or as we call it on this site, autoimmune diabetes).
This does not happen in the streptozotocin-treated rats. They get diabetes, as you can see in the diagram, but when the insulin from the Islet Sheets floods the rat with insulin the surviving beta cells recover and appear to regenerate. Humans with autoimmune diabetes inevitably develop full type 1 diabetes in months because their islets degenerate, not regenerate. We have just shown that streptozotocin-treated rats recover. In effect they demonstrate a robust honeymoon.
We will repeat the Islet Sheet implant experiments in Really Diabetic rats. The group at UCI led by Dr. Li is making progress on methods to make the rats really diabetic. We will treat those rats with our Islet Sheet. Then we will remove the Islet Sheets from some of them and show that they remain really diabetic.
Is this a setback? Not really; we are in exploratory research. It does show that we (along with others in the field) had too much faith in this particular model. But we have learned the truth about the model and are fixing the problem. (Of course we will report this so that others who have found similar results with STZ-rats will know that their therapy may not have really worked.)
We will start clinical research with the Islet Sheet as soon as possible. But we will wait until we have learned all we can from the best models available, even if we have to develop and prove new models.
Next time: The Animal Models of Autoimmune Diabetes
Unfortunately, there are limits to the value of all animal models of human type 1 diabetes. (M. Atkinson and E. Leiter, “The NOD Mouse Model of Type 1 Diabetes: As Good as it Gets?” Nature Medicine, vol. 5, p. 601 (1998)) Until tests can ethically be done on human subjects, the case for any intervention will always remain unclear. Too bad the days when Banting and Best could just give themselves a low dose of insulin to test it for basic toxicity, or when they could give their diabetic friend, Dr. Fitzgerald, a larger dose with no worse legal consequences than his being arrested during a hypoglycemic episode by the Toronto police for public drunkenness, are now long gone.
JP, the equivalent today is to do such things in countries outside the United States. Or on a ship on the open ocean. Or secretly. I too miss the boldness that was once reckoned a virtue.
How do I get on the waiting list to get my diabetes cured?
We still need permission to perform a clinical study from the authorities, then recruiting will begin.