Insulin Prevents Diabetes -- In-Depth Doctor's Interview
William Russell, M.D., tells us about a new insulin pill that may prevent the development of type 1 diabetes
Ivanhoe Interview with
William Russell, M.D., Pediatric Endocrinologist
Vanderbilt Children's Hospital
Date of Interview: July 15, 2007
TOPIC: Preventing Type I Diabetes
What is type 1 diabetes?
Dr. Russell: Type 1 diabetes is a form of diabetes in which the patient's own body, their immune system, damages their insulin-producing cells. It results from an inability of the body to make enough insulin to maintain normal blood sugar.
Does your risk increase if a family member has type 1 diabetes?
Dr. Russell: If you have a close family member with type 1 diabetes, your risk goes up more than ten-fold compared to somebody who doesn't have a close family connection with somebody with type 1 diabetes.
A first-degree relative would be a parent, a sibling, or an offspring. With type 1 diabetes, your risk goes up significantly. If you don't have someone with type 1 diabetes in the family, the risk is about one in 240, 250, whereas if you have sibling with type 1 diabetes your risk goes up to one in 20.
What are some of the other factors that increase your risk?
Dr. Russell: Because we know what goes on in the immune system to begin this damage of the islet cells -- the insulin producing cells -- we can actually measure things in the blood that will give a very good indication if somebody is on the road to developing diabetes or not. So a blood test would be the next thing after starting with close relatives as an initial screening point.
What are the markers or indicators in the blood you are looking for?
Dr. Russell: There are a number of markers. What happens with type 1 diabetes is the immune system picks out specific proteins that are associated with the insulin producing cells, starts making antibodies against them. In addition to the antibodies, lymphocytes (white blood cells) invade the insulin producing parts of the pancreas and start to set up an inflammatory reaction.
We know what some of these antibodies are. We know many of them, probably not all, and we can measure them. By measuring specific antibodies, we can get an idea of whether this inflammatory process has started. And another thing we have to think about in these studies is that there are certain cells' surface proteins that actually protect you from developing diabetes, so we want to take that into account. If somebody has the antibodies and yet has these protective cell surface proteins -- they are called HLA proteins -- their risk is much diminished. Based on previous experience in a study called a DPT 1 and then work prior to that, we have a pretty good way of determining, depending on the level of antibodies that are present, which particular ones are present and exactly what someone's long-term risk of developing diabetes would be. For the study we're engaged in here, we are looking for those people that are considered to be at the highest risk, which is defined as more than a 50-percent chance of developing diabetes in the next five years.
Right now, is there any way to prevent type 1 diabetes?
Dr. Russell: Right now, there's not. That's the point of the oral insulin trial, to test a hypothesis. At this point it's a good hunch. There's a lot of preliminary data to back to up. But the hypothesis that we are testing is that by ingesting insulin, by taking it in by mouth, you can induce what's called tolerance, or the ability to kind of turn down the immune reaction against the islet proteins in the patient.
How do you think the pill would work in the body?
Dr. Russell: Well, it's not clear. There was a previous theory that had a lot of good experimental evidence in animals and some clinical studies in people. It said by giving injections of insulin to somebody who was in this high-risk state, you could prolong the prediabetic state and, in some cases, prevent diabetes. But that was rigorously tested and proven absolutely to be untrue.
The thinking there was that this somehow influenced the immune system, or possibly gave the islets that were there a bit of a rest because you're giving extra insulin. But that was injections of insulin. When you give it by mouth, insulin doesn't really enter your blood stream as insulin. It's broken down by the digestive system. So by this route of delivery, it's actually reprogramming the immune cells that are in the gut to turn down or to become more tolerant, to turn down the immune response or to become more tolerant to the proteins that the body's attacking. One of the major antigens or proteins that the immune system singles out is actually insulin itself. And that's one of the major proteins that we look for when screening people for TrialNet or for the oral insulin studies. They need to have high levels of anti-insulin antibodies.
Does it affect the blood sugar?
Dr. Russell: It has no effect on the blood sugar whatsoever. By the time the insulin molecule gets into the blood stream, it's been broken down into much smaller fragments that don't do anything to the blood sugar.
What form does it come in?
Dr. Russell: It's a capsule just loaded with powdered insulin.
What can you tell us about the study itself?
Dr. Russell: Nationally, the goal is to enroll somewhere around 450 subjects in the study. To get to that point, the feeling is that we are going to have to be screening about 20,000 people a year nationally in order to identify those people who are at high risk. The good news in all this is that if you take people who are close relatives of somebody with type 1 diabetes, 95 percent of the time or more, they turn out not to have any evidence of immune inflammation that's damaging the pancreas, and they're pretty much off the hook. The younger ones that we screen, we suggest that they be rescreened yearly until they turn 18 because there is still a chance that it could develop a bit later. But for the most part, we find most of these relatives are free of inflammatory process and at very low risk. We'll have to start with a very large number in order to get enough subjects in the study to actually decide whether this insulin capsule will delay the progression to diabetes. In order to really test that, half the subjects in the study will be getting insulin. The other half will be getting a placebo, just a powder that has no effect whatsoever and has no insulin in it. We don't know, the subjects don't know until the end of the study who is getting what. The results will be monitored essentially until it's clear what the answer is, until enough data has been accumulated to make a very clear case. If it's a very strong effect, then it will take fewer subjects to say, "Okay, we have a definitive answer and we can stop the study." If it's not such a strong effect, if it's maybe significant but not very major effect, it may take longer. That's the way the study goes. Once somebody is enrolled in the study, once they are either getting the placebo or the oral insulin capsule, they come back three months after the first part of study, but then every six months. They have their glucose tolerance -- their ability to handle a glucose load -- assessed to pick up diabetes before it ever becomes troublesome, before they develop severe clinical signs where they become sick, start to lose weight, vomit, and some of the other things that can happen with type 1 diabetes.
Do you continue to monitor them after that?
Dr. Russell: Very closely. Basically every six months, as long as they are in the study, until we have an answer.
What did the preliminary animal data tell you?
Dr. Russell: It has been done in animals. There is a strain of mice that spontaneously develop an autoimmune diabetes very much like the kind humans get. In those mice, feeding them insulin seems to have prolonged the period before they actually develop diabetes and perhaps, in some instances, even prevented it from happening since mice live shorter lives than humans. But more significantly, in a previous study -- the DPT 1 -- where they were testing whether injections of insulin would delay the onset of diabetes, there was a subgroup of subjects who actually got insulin capsules or placebo like we were doing here. It wasn't the primary goal of the study to answer the question about oral insulin. The primary goal was the injectable insulin. But when they went back and analyzed the data from that, it seemed that the people who had the highest levels of insulin antibodies in their blood were the ones that seemed to have a very beneficial effect of the oral insulin. It looked like it prolonged the onset of diabetes by four to five years.
How important is that onset delay?
Dr. Russell: In the span of a lifetime, four or five years may not look like it's so long, but when you think of the fact that the primary age group that develops type 1 diabetes is children and young adults and, in a pediatric center like ours where we see infants and toddlers with developing type 1 diabetes, if we did nothing more than delay that until they were older, maybe adolescents, that would be a major step. Obviously, the other thinking is that there are going to be other approaches to this. If we can delay it with oral insulin and then some other agents come along that might have a similar effect, that might prolong it even further. Or if the two combined -- oral insulin plus something else -- that might delay it much longer. That would be great. When you're around families with diabetes, when you take care of kids with diabetes, everybody wants a cure. That's been everybody's goal so that these kids don't have to take shots, so that they can live a normal life and they don't have to prick their fingers. It's a life-altering experience to have type 1 diabetes. On the other hand, it's great to have a cure, but we know that once we cure everybody with diabetes, there are still kids. At our center, we get about 250 children a year newly diagnosed with diabetes. It would really, really mean a lot to us, who take care of these kids, and to the families where these kids are born into, if we could prevent it from happening. A cure is very important, but it's kind of like the old adage: an ounce of prevention is definitely worth a pound of cure, in this instance. There are not many diseases like this where you have the hope of actually preventing them from happening. This would be a very important breakthrough if we could start out small, delay it and ultimately prevent it. It would be miraculous.
Is this concept of pill prevention a new idea?
Dr. Russell: Well, it's been tested in some other autoimmune diseases: rheumatoid arthritis and I think in multiple sclerosis. There has been some evidence suggesting that taking the antigen -- the protein that's being attacked by the body -- by mouth will prolong the development of disease, or make it a much milder form of the disease and possibly even prevent it. So this is an area that's not just limited to diabetes, but other autoimmune diseases as well.
Are there any side effects of the insulin pill?
Dr. Russell: Based on the experience in the preliminary studies, there seem to be absolutely none. People who take it can't taste the difference and it certainly has no bad effect on their blood sugar or any other problems that have been encountered so far. People have looked very carefully for these.
How exciting is this for you as a doctor?
Dr. Russell: Oh, I think this is a tremendous step. As I mentioned, we've been looking for a cure for a long time. It's always around the corner and it may be awhile yet. I know there will be one. To be able to prevent diabetes to coming anew into these families is a tremendous advance. It's a little bit like realizing that smoking causes lung cancer. If you could stop smoking, you would prevent most lung cancer. That's a fairly easy one, theoretically, to do. From a social policy standpoint, it's been a little harder to get that accomplished. But when you know that there is one fairly simple thing you can do like taking a pill a day that will prevent you a lifetime of misery and potentially life-threatening complications later, it's a tremendous advance. I'm very excited.
END OF INTERVIEW
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