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September 5th, 2012
After a long period of laboratory and small-animal studies, at last we have begun the crucial large-animal studies of the Islet Sheet’s safety and efficacy — second in importance only to clinical trials themselves. As I have discussed previously, large-animal studies are needed to determine whether the Islet Sheet will perform well in humans with diabetes.
After spending years on small animal and laboratory studies, the reality of large-animal studies is a bit shocking. We knew it would be expensive. We are learning that it is difficult. I cannot report the results yet, but I can tell you that we’re happy with our progress.
We are doing this study with Jonathan Lakey’s group at UC Irvine. The first step was to select the animal to be used. We had planned to use the canine model, which is the best metabolic model to compare with humans, and a good model for transplantation. Using dogs turned out to be even more expensive and complicated than anticipated, however, in part because of growing concerns about animal experimentation protests. So we have changed course and are studying the Islet Sheet in the pig model. All steps of the process can be performed at the University of California – Irvine, which helps simplify the logistics.
The pig is suitable for these studies for several reasons. Its metabolism is similar to that of humans (both species are omnivores), and its insulin requirements are similar, ~0.75 U/kg. Pigs are less expensive to use in a lab setting than dogs. And they can be easy to work with: after a relatively short time they become comfortable around humans, and even affectionate. Winston Churchill once remarked, “I am fond of pigs. Dogs look up to us. Cats look down on us. Pigs treat us as equals.” We’ve chosen the Yucatán minipig to be the subject of these experiments. It is smaller than a market pig with mature weight of 40 to 50 kg.
The process remains challenging. Type I (autoimmune) diabetes does not occur spontaneously in any large animal. You must make the animal diabetic through a procedure. There are two ways to do this: by administering the drug streptozotocin or by surgical removal of the pancreas. Dr. Lakey and his staff have mastered the canine pancreatectomy and now are working to develop a method for surgical removal of the pig pancreas. But other researchers report that, due to the vascular anatomy of the pig pancreas, total pancreatectomy often leads to serious complications. So in the meantime we are using the proven drug method.
Streptozotocin is toxic to the beta cells in the islets. As they die, the beta cells release insulin into the blood. The blood sugar drops; then, when the beta cell death is complete, blood sugar rises. Over the next couple of days the pig becomes frankly diabetic with high blood sugar. Then the use of insulin begins in an effort to control the pig’s blood sugar as well as we are able to control the blood sugar of a human with type 1 diabetes. The diagram below shows this process in pig 151:
Now we enter a phase that will be familiar to you if you help your child manage diabetes with insulin, or manage your own diabetes, as I do. And that is getting the insulin dose right, twice a day. We are using both a short-acting and a long-acting insulin. (We don’t think the pig would tolerate a pump.)
Our team has learned to control the pig diabetes faster and better than I have ever seen done before. In addition to the regular stick BGs (green in the diagram), we are using Dexcom CGM (red in the diagram). For insulin dosing management we are using the tools developed by Dr. Andrew Drexler and Carolyn Robertson, CDE, of the Gonda Diabetes Center at the University of California, Los Angeles. This means that we can change the dose of fast-acting and long-acting insulin every two days toward our goal of stable blood sugar with injected insulin.
In addition to obtaining twice-daily blood sugars and the data from continuous glucose monitoring, the pig’s insulin secretions are evaluated with intravenous glucose tolerance tests (IVGTT). The first one is done before the animal has received any therapy; the next is done after diabetes is established. Then further IVGTTs are done after implantation of the Islet Sheets. The final test will be done after the sheets are removed, to prove that the animal has remained diabetic while Islet Sheets have been delivering insulin.
As I write this, one pig has received an implant of several Islet Sheets after being diabetic for weeks. A second pig has been made diabetic and its insulin administration is being fine-tuned. This animal is expected to receive its Islet Sheet implant later in September.
I must praise everyone’s devotion to this project. Management of a diabetic pig is as relentless as managing diabetes in a child. Dr. Lakey’s group members are coming in twice on weekends to measure BGs and administer insulin, as well as providing standard pig care and feeding. Robert Boock at Dexcom has been very helpful. Marilyn Ader, Associate Director of the Diabetes and Obesity Research Institute at Cedars-Sinai, is teaching best practices in metabolic procedures. We are all learning very rapidly. I am pleased to have a day-to-day role myself, helping to manage our little diabetic pig. Thirty years of managing the disease in a large omnivore (myself) is proving useful.
It is customary and expected among academic researchers that results will be reported at a scientific meeting before being released to the public. Dr. Lakey will present progress reports on these pig studies at scientific meetings over the coming months. With his permission, when he presents these interim results to his colleagues, Hanuman Medical Foundation will release them on this website.