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Dr. Eshki: Thank you for this very informative presentation. I have witnessed the condition in the neonatal intensive care unit in which infants develop diabetes because they have been given diets inappropriate for their age. There are several studies looking at infant diet and type-1 diabetes [1, 2]. Does your theory cover such factors?

Dr. T. Wilkin: Insulin resistance is a post receptor defect, and the child who grows up to become a type-1 child lives in exactly the same obesogenic environment as a child who grows up to become a type-2 individual. We tended to think of two separate populations, type-2 insulin resistance, type-1 autoimmune, but they live in the same obesogenic world. They have exactly the same experiences which lead to increased insulin resistance. There is no reason to believe that there would be a different insulin resistance in the type-1 than there would be in the type-2 individual.

Dr. Eshki: It is just because insulin is formed in a different area than the insulin receptors, that is what I was looking at. So maybe the formation of insulin receptors could also be a factor where perhaps in some cases it is not well enough formed for them to provide the insulin available.

Dr. T. Wilkin: I think current understanding would lead us to the argument that insulin resistance is indeed a post-receptor issue.

Dr. Chiasson: It is a very provocative and interesting hypothesis. I agree that it is interesting that perhaps with a different paradigm we will approach the prevention of type-1 differently, and we may be able to delay the development of type-1 diabetes, be it type-1 or type-2. Now in type-2 diabetes insulin resistance is mostly an environmentally induced factor. It is very likely, yet it still has to be proven, that the major genetic defect in type-2 is the p-cell, maybe the p-cell mass or the p-cell susceptibility to whatever environmental factor, obesity, decreased physical activity, and insulin resistance. Now the fact that insulin resistance or obesity or both, because usually one correlates with the other, would tend to increase or accelerate the development of type-1 in subjects susceptible for type-1 is not unexpected because the p-cells are under strain. If they have whatever the problem at the p-cell level then obesity would accelerate, would increase the stress on the p-cell. So to me, the insulin resistance per se will accelerate both type-1 and type-2, but that doesn't necessarily mean that the problem at the p-cell level is the same. As you said, correlations are always interesting but do not prove a cause and effect relationship. So I challenge the hypothesis.

Dr. T. Wilkin: I think what we will always find that the individual who is more immune-susceptible, that is to say whose HLA genes instruct a more reactive response, will always present first. The accelerator hypothesis I see as revolving around a gradient of p-cell loss, which we are all subject to. Most of us live our lives and p-cell loss is never sufficient to cause us diabetes. From that point on there are accelerators. One of those accelerators, as I think we agree, is insulin resistance which has mechanisms which are increasingly being understood. The second of these, which is my accelerator number 3, is the immune response which is graded according to immune response genes. Now I believe all that is doing is to accelerate the rate, so that of a group of individuals who is going to get diabetes, those in whom it is most accelerated, will inevitably be children, and those in whom it is least accelerated may well die before it ever happens. I don't look outside that paradigm for an answer at the moment because I think that insulin resistance is driving both the non-immune and the immune component of p-cell damage.

Dr. Chiasson: I am not an immunologist, but I understand that the HLA genes are not diabetic genes. There are a number of genes that have been identified, but whether it is in the same area, I don't know. The genes themselves as well as the antibodies that we are looking at do not necessarily cover everything. That must be left open. Also in type-2, there are going to be a number of genes related to the p-cell function as well as perhaps insulin action. At least in the prevention studies that we have done so far, the only thing that we have been able to modify is the insulin action, insulin sensitivity, not p-cell function.

Dr. T. Wilkin: Are you talking of type-2 prevention studies, or type-1?

Dr. Chiasson: Type-1 would most likely be the same. At the present time I don't think that in type-1 we have any tools that can help us to modify the susceptibility of the p-cell, assuming that it is different than the susceptibility in type-2. We don't have any data one way or the other, but it is clear to me that they are susceptible, pheno-typically they are different. As a matter of fact Dr. Slama told me that a lean type-2 is a type-1 who is ignoring himself. So more and more we find antibodies in those lean type-2 individuals, and they evolve differently over time, and the insulin resistance is different. The insulin resistance in type-1 exists; it does not compare to type-2.

Dr. T. Wilkin: Again I would answer by saying that you have two fundamental contributors to the probability of disease, one of them is insulin resistance and one of them is HLA genetic. In order to develop diabetes you would need to have a higher insulin resistance if you don't have the genetic contribution. In type-1 diabetes you would need less insulin resistance to have the same effect because you have the help of the third accelerator which is the immune response.

Dr. Slama: I found your hypothesis very clever. I accept your hypothesis that there are some accelerators in the phenomenon. But I have two arguments. First of all you have also to show not only that the patients are a bit overweight as compared to normal but they do have insulin resistance. When insulin resistance has been studied by glucose clamp in type-1 diabetics it was found that it is really insulin resistance at the beginning where the blood glucose is very high but declining to normal very quickly when blood glucose is normalized, making this phenomenon an accelerator but not a causal factor. My second argument: if you try to find out if there is vitamin B12 deficiency in a large population, you will find a prevalence of X. Then in the same community there will be iron deficiency, much more anemia in this population, and the more iron deficiency the less you will find a role for autoimmune disease in this community. Does that mean that the disease is the same as iron deficiency, of course not. When you say that genetics is decreasing, it is decreasing relatively but in absolute value it does not change. So I accept your hypothesis of the accelerator, but I do not accept that because the accelerator might be verified that the original disease has disappeared.

Dr. T. Wilkin: Let me take the first question. I would give the same response as I did to Dr. Chiasson, that the amount of the insulin resistance you would require to develop a diabetes is going to be less if the contribution that it makes is helped by an immune accelerator being present as well. The second question is an interesting one because your implication is that even though childhood diabetes is increasing, and it undoubtedly is, you will always have conventional type-1 diabetes because in absolute terms it has not changed. I actually don't agree with that, I think you will lose the phe-notype of a type-1 diabetic because I think he will become overweight, acanthotic, seropositive, T-cell reactive and quite impossible to distinguish from what we know now as a type-2. I think there will be a convergence because the slim type-1 diabetic, as we have known him in the past, is now obese.

Dr. Slama: How can you say so when you say you will find T-cell activation and you will not be able to separate them? There is T-cell stimulation, so they are different. Perhaps our tools are not fine enough to distinguish this very well, but it doesn't mean that it doesn't exist.

Dr. T. Wilkin: There is T-cell stimulation for both groups now which there wasn't previously. We never knew type-2 diabetes in childhood 30 years ago. The real evidence comes from the slide that I showed twice in which there is a secular rise in the weight at diagnosis of children who are labeled type-1, and that has been linear since the 1980s. The variance at each time point is much the same, the mean has progressively risen, we are progressively losing sight of the cachectic, scrawny, low body weight child that is often portrayed as the characteristic presentation of type-1 diabetes. I think we will lose it completely if things go on the way they are.

Dr Schiffrin: If I remember correctly, the genetic susceptibility for diabetes type-1 and celiac disease shows a strong overlap. There are Swedish studies showing that the two diseases coexist in some patients. Now if I got your paradigm right, if the insulin resistance or the environment is becoming so important, the coexistence of type-2 diabetes should be less associated with celiac disease if the genetic background is less important. Is that right?

Dr. T. Wilkin: You are absolutely correct about the association between celiac disease and type-1 diabetes, but the connection there is genetic. If the phenotype of type-1 changes as Dr. Slama was saying, there will always be the same genetic distribution within the population. I have no doubt that there will always be an association of celiac disease with a proportion of individuals who have diabetes. But that is a genetic association, it is not an association with the phenotype of a disease which I think is becoming indistinguishable for the reasons that I have indicated.

Dr. Golay: I come from the type-2 research field, and we are more and more able to prove that we have a p-cell defect in type-2. I propose a third type (half type-1) between a clear type-1 (complete insulin defect) and type-2 with insulin resistance and a slow partial defect.

Dr. T. Wilkin: I understand what you are saying, but I am not sure I would give it that explanation.

Dr. Golay: We have a third group of diabetic patients instead of having the same disease for type-1 and type-2.

Dr. T. Wilkin: The rates at which conversion occurs from type-2 to type-1 is a function of the third accelerator. I think that conversion occurs very rapidly in childhood and the earlier in childhood the more rapid, and that is because the tempo is so telescoped in childhood by the intensity of the immune response; that would be my argument. When you have got through childhood you have, as it were, used up the population with that particular genotype of extremely intense reactivity. Teenagers who develop type-1 have a different genotype distribution than those who are 2 or 3 years old when they develop type-1. When you move from teenagers into adulthood, the genotype changes again. When you come to adults, where the third accelerator is contributing very little, then the tempo of conversion is very slow, but I see no fundamental conceptual difference in the two.

Dr. Metzger: There are two points I wanted to make. One, I don't believe that your analogy of the cachectic type-1 patient is very strong evidence because that represented the long-term symptomatic uncontrolled state of diabetes, and we tend to see a diagnosis made much earlier now. In analogy we see very few sustained long-term symptomatic patients with Graves disease before we make a diagnosis, whereas 30 years ago it was very different. It seems to me that the acceleration in the onset of type-1 diabetes would not necessarily increase the true incidence of type-1 diabetes. We may simply be seeing a shift to the left in onset, and whether the lifetime risk of type-1 diabetes has changed in the last 30 years I think would be an interesting part of evaluating the status of type-1 diabetes.

Dr. T. Wilkin: There is some evidence that would help on that as well. There are at least two, possibly three reports in the literature which would suggest that there is indeed a shift. I think the accelerator hypothesis would predict just that, that there is a group in the population with higher susceptibility genes who will accelerate faster if given the stimulus through insulin resistance. But they would borrow from the older group as a result, so that you would see a shift to an earlier age at onset, and earlier age at onset is very much the observation that we make in type-1 diabetes.

Dr. Bantle: I think there is evidence that if you treat people with early type-1 diabetes with insulin and control glucose, you cause weight gain. Presumably you increase insulin resistance but, at the same time, you preserve insulin production for some time. Would the accelerator hypothesis be able to explain how that would happen?

Dr. T. Wilkin: I think it would. I think it might predict that if you give an external source of insulin you would rest the endogenous p-cell so it would be less antigenic because it would be less metabolically upregulated, and as a less antigenic p-cell it would invite a less intense immune response and therefore might survive longer. That is speculation but I think it was the premise on which the DPT-1 study was based on using low dose insulin to try and preserve the p-cell.


1 Strotmeyer ES, Yang Z, LaPorte RE, et al: Infant diet and type 1 diabetes in China. Diabetes Res Clin Pract 2004;65:283-292.

2 Paronen J, Knip M, Savilahti E, et al: Effect of cow's milk exposure and maternal type 1 diabetes on cellular and humoral immunization to dietary insulin in infants at genetic risk for type 1 diabetes. Finnish Trial to Reduce IDDM in the Genetically at Risk Study Group. Diabetes 2000;49:1657-1665.

Bantle JP, Slama G (eds): Nutritional Management of Diabetes Mellitus and Dysmetabolic Syndrome. Nestlé Nutr Workshop Ser Clin Perform Program, vol 11, pp 155-169, Nestec Ltd., Vevey/S. Karger AG, Basel, © 2006.

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