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Department of Pediatrics University of Florida Gainesville, Florida 32610
Jeffrey Krischer
Moffitt Cancer Research Center Tampa, Florida 33612
Jay Skyler
Department of Medicine University of Miami Miami, Florida 33136
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Introduction |
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 Top Introduction References |
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The fundamental requisites of any prevention trial are: 1) that the disease is a demonstrated burden to the individual and society; 2) that high-risk individuals can be accurately identified; and 3) that treatment is available that is safe and has soundly based potential to be effective.
Type 1 diabetes occurs worldwide with varying incidence in different parts of the world. The highest rates, more than twice that in the United States, occur in Finland and Scandinavia (4, 5). The prevalence of Type 1 diabetes in the United States is 2–3/1,000 with an annual incidence of approximately 15/100,000 children, or more than 12,000 per year (6). Their contribution to the overall morbidity and mortality statistics and health care economic burden to society is disproportionately large due to the high rate of microvascular and macrovascular complications (7). It has been estimated that diabetes consumes over 100 billion dollars annually or one in seven United States health care dollars spent. Although the Diabetes Control and Complications Trial has highlighted the strong association between tight blood glucose control and reduced risk of complications, it is clear that intensive insulin therapy is not available, applicable, or affordable for all patients with Type 1 diabetes. Furthermore, the DCCT was able to reduce but not eliminate a substantial amount of the risk for complications. At the very least, at the time of diagnosis of Type 1 diabetes, patients (most often children and adolescents) are mandated to take insulin injections, check their blood glucose several times daily, and adhere to altered nutritional and exercise practices that may alter their and their families’ lifestyles substantially. The need is, therefore, obvious to prevent the disease. Given the burden of the disease, therapies that might reduce rates by as little as 10–15% would be worthwhile. Not only would the short- and long-term burdens of the disease be lessened, but also the cost to both the individual and society would be substantially reduced.
The quest for prevention of Type 1 diabetes has been made feasible by
the unraveling of the immunogenetics of the disease and the
identification of at-risk subjects by an enhanced understanding of the
natural history of the prediabetic period (Fig. 1
) (8). The risk of developing diabetes
is clearly increased in families where a family member is affected by
Type 1 diabetes. Whereas the disease typically affects 1 in 300 persons
in the population, approximately 3–6% of relatives of Type 1 patients
will develop the disease themselves (9). The risk is highest in
monozygotic twins (30–50%) and histocompatibility leucocyte antigen
(HLA) (the major genetic influence) -identical siblings and offspring
(10). The HLA locus is the major genetic influence in diabetes
expression. The disease results from an indolent autoimmune destruction
of the pancreatic ß cells with, the peak incidence being between 5
and 15 yr of age (11). In genetically susceptible individuals, the
pathogenic process can be identified by the detection of autoantibodies
to islet cell antigens for varying, often long, periods of time before
the disease becomes clinically manifest. The presence of islet cell
autoantibodies (ICAs), autoantibodies to glutamic acid decarboxylase
(GAD65), insulin autoantibodies (IAAs), and autoantibodies directed at
a transmembrane tyrosine phosphatase (ICA512), particularly when
present in combination, at higher titers, at a younger age, and with
the high-risk HLA genes, enhance the predictability of the disease in
relatives to well over 50% over a 5-yr period (12, 13, 14). Although these
prediction studies have been done in relatives, this is most likely the
case for the general population, as well (15). Loss of first phase
insulin secretion, which occurs further along during the autoimmune
disease process, additionally enhances disease predictability (16).
Glucose intolerance, "silent" diabetes, and symptoms follow
this.
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Primary prevention of Type 1 diabetes could theoretically be implemented in two ways: 1) a population approach (i.e. altering the lifestyle and environmental determinants known to be risk factors); and 2) a high-risk approach (i.e. instituting preventive measures in individuals at high risk for developing the disease) (17). All would advocate the former approach because nearly 90% of newly diagnosed patients have no family history. Until recently, however, the least secure part of the natural history of Type 1 diabetes has been the time of life when the disease actually begins, and the inductive events that trigger this process. The BABYDIAB (German multicenter study investigating autoimmunity in offspring of diabetic parents), DIPP (Finnish Type 1 diabetes prediction and prevention project), and Diabetes Autoimmunity Study in the Young (DAISY) studies, as well as our own Gainesville studies in which newborn babies (of both affected relatives and those in the general population) are screened for the presence of high-risk HLA genes and followed prospectively for the appearance of autoantibodies, suggest that whatever the nature of the environmental factor(s), (dietary factors e.g. cow milk, viruses, toxins), they seem to operate in very early childhood (18, 19, 20, 21). The cow’s milk avoidance (TRIGR) study is based on this premise.
The long prodromal prediabetic phase of Type 1 diabetes (even more so in adults compared with children) holds hope that the clinical onset of the disease may be delayed perhaps indefinitely through therapies that can interrupt the causal disease process. Without trials, progress toward prevention cannot occur. Several studies are currently being conducted worldwide.
In the United States, the Diabetes Prevention Trial (DPT-1) was launched in 1994 with the goal of determining whether antigen-based therapies using insulin would prevent or delay the onset of diabetes in at-risk relatives. Intensive insulin therapy prolongs the honeymoon period in new-onset patients and prevents diabetes and reduces the severity of insulitis in rodent models (22, 23, 24). Pilot studies in high-risk relatives given prophylactic parenteral insulin injections revealed promising results (25). In NOD mice, oral insulin delays the onset of disease (26, 27). In the DPT-1 trial, low-dose parenteral insulin therapy (annual iv insulin infusions, followed by daily sc injections) is given to a high-risk group of relatives (>50% over 5 yr) who are matched with an untreated, but closely monitored, experimental group. Oral insulin vs. placebo is given in a double-blind study to relatives at intermediate risk (25–50% over 5 yr). Over 60,000 relatives have been screened, to date, with over 278 (target 360) randomized to the high-risk arm and 223 (target 490) to the intermediate risk group. No major safety concerns have been identified, and initial outcome data are expected early in the next millennium
Enrollment for the European Nicotinamide Diabetes Intervention Trial (ENDIT) is now complete. Five hundred fifty-two relatives of Type 1 probands have now been randomized to either nicotinamide or placebo. In NOD mice, nicotinamide, a free radical scavenger, prevents diabetes, and in a population based study in New Zealand the drug seemed to have a protective effect (2, 28). Although it does not seem to have efficacy in either newly diagnosed patients, or, as was shown in the smaller DENNIS (Deutsche Nicotinamide Intervention Study) study of a high-risk group of young relatives, the outcome of the larger ENDIT study of relatives (with potentially greater insulin reserve), too, is anticipated in the next few years (29). No major side effects have been reported. Based on epidemiological studies in humans, suggesting that prolonged breast feeding of infants and the delayed introduction of cow’s milk into their diets led to decreased frequency of the disease, studies in animal models linking cow’s milk to disease frequency, as well as debated immunological studies, the TRIGR (Trial to Reduce Diabetes in the Genetically at-Risk) study was launched (3, 20, 30). Initially piloted in Finland, but now with several collaborative sites in Europe and North America, the study seeks to determine whether genetically at-risk infants who are not exposed to cow’s milk for the first 6 months of life will be protected from the subsequent development of diabetes. Preliminary data in this randomized study reveals that there may be a decrease in autoimmunity, as evidenced by lower frequencies of islet autoantibodies in the experimental compared to control groups. As reported at the recent meetings of the American Diabetes Association, 3 of 84 in the experimental arm have evidence of autoimmunity compared with 10 of 89 of controls (P = 0.06.)
Promising trials using inhaled insulin to prevent diabetes are currently being conducted in Finland and Australia (31, 32).
To date, the greatest single barrier toward wide-scale population screening and prevention of the disease is the hitherto lack of an effective intervention. Pilot studies and clinical trials have, to date, been carried out only in high-risk relatives. The Helsinki Declaration affirms that a "doctor must be free to use a new diagnostic and therapeutic measure if, in his or her judgment, it offers hope at saving life, re- establishing health or alleviating suffering" (33). Pilot studies should be seen as exploratory, and if a new therapy is shown to be clinically effective, then a larger study with sufficient power to determine efficacy, as well as safety, must be undertaken, or it cannot be ethically applied. Such is the case with the major prevention trials currently in progress. The studies are prospective, randomized controlled studies with appropriate statistical power and objective endpoints in which the benefit to the individual and society is immense.
It is unlikely that any current therapy will be the magic bullet that stops the disease process in its tracks akin to penicillin/pharyngitis and the prevention of rheumatic fever and rheumatic heart disease. Additional pilot studies are clearly needed using promising agents with known safety profiles, alone or in combination, with demonstrated efficacy in the rodent models. The current prevention trials have generated outstanding collaborative interactions across and between continents. Such cooperative group structures need to be established (akin to the childhood cancer cooperative groups) so that in the very near future multiple pilot studies involving primary and secondary prevention strategies in different population groups at different stages of the disease process can be undertaken. Not only will these studies ascertain potential efficacy, but also should lead to greater insight into both the pathogenesis of the disease and mechanism of the disease strategy. There is no turning back; great strides have already been made, rendering cautious optimism that the day is not too far away when Type 1 diabetes can be safely prevented.
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References |
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TopIntroductionReferences |
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This article has been cited by other articles:
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  L. F. Ross Minimizing Risks: The Ethics of Predictive Diabetes Mellitus Screening Research in Newborns Arch Pediatr Adolesc Med, January 1, 2003; 157(1): 89 - 95. [Abstract] [Full Text] [PDF]
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 A. L. Rosenbloom Prevention of Type 1 Diabetes: Perspectives J. Clin. Endocrinol. Metab., February 1, 2000; 85(2): 494 - 495. [Full Text]
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