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1 Preventing Type 1 Diabetes

Case History

Ir^n I The parent of a 4-year-old boy with type 1 diabetes consults you wanting to know if there U^H is anything he can do to prevent a future child developing the condition. He already has an 8-year-old daughter with diabetes and there is a strong family history of autoimmune thyroid disease on both his and his wife's side of the family. They are contemplating having a third child.

Is there any evidence that type 1 diabetes is preventable? Is there any general advice the parents can usefully follow? Can we predict the onset of type 1 diabetes?


Preventing or curing type 1 diabetes is one of the holy grails for those who research autoimmune disease or treat patients with diabetes. The disease typically presents in childhood, currently necessitates lifelong use of insulin injections and exposes the indi© Atlas Medical Publishing Ltd, 2006

vidual to increased risk of vascular complications. The risk of type 1 diabetes in the general population is about 1 in 300, and this is increased up to 20-fold in first-degree relatives. Genetic markers do not provide an accurate prediction of diabetes, with only 5% of those with susceptibility markers actually developing the disease. However, the fact that the disease has a long latent period and that the pre-diabetic phase can be identified by measuring islet cell antibodies or by assessing beta cell function yields an opportunity for preventative therapy. The results of trials using non-specific immunosuppression in the 1980s were disappointing with only temporary improvements in insulin production demonstrated.

Type 1 diabetes in children became much more common in the course of the 20th century.1 In fact, available evidence suggests that the disease was quite uncommon, although generally fatal, in children during the 19th century. This, along with the geographical variation in the prevalence of childhood diabetes that is not accounted for by variations in the prevalence of susceptible genotypes, strongly suggests that environmental factors are important.2 The wide variation in incidence rates applies much more to childhood than to adult type 1 diabetes.3 It is not surprising that there has been intensive research into environmental triggers for diabetes that might be modified, or into safe and effective nutritional or immunological manipulations that might decrease risk of developing the disease (Figure 1.1). Recent evidence suggests that most parents of children at risk of type 1 diabetes will attempt preventative measures,4 and it is increasingly important for health professionals to be able to enter into a balanced discussion with parents and would-be parents.

Both macronutrient and micronutrient components of the diet have received atten-tion.5 A protective effect of breast-feeding has been proposed, but not confirmed in all

Factors Predisposing To Type 1 Diabetes Level of Evidence

Genetic (including HLA) Non-breast-fed Early exposure to cows' milk Low vitamin D status Viral infection

Rapid weight gain in childhood

The Following Do Not Appear To Modify Risk

Childhood vaccination Treatment with nicotinamide Oral insulin therapy

Strong evidence supported by multiple well-conducted and randomized clinical studies Reasonable evidence supported by clinical studies (not randomized) Some evidence supported by observational studies and expert opinion

Fig.1.1 Factors predisposing to type 1 diabetes. HLA = human leucocyte antigen.

studies. Breast-feeding may afford protection through early oral exposure to human milk (inducing tolerance to insulin; see below), through protection against infectious agents, and by decreasing the risk of excessive weight gain in infancy. The latter is also probably a trigger for diabetes during adolescence. On the other hand, early exposure to cows' milk may increase risk through exposure to bovine insulin or (3-casein, the latter being a known immunomodulatory protein contained in cows' milk. Bottle-feeding can also be associated with excessive weight gain. Amongst micronutrient components of the diet, nitroso compounds (related to streptozotocin), nitrates and nitrites, all used as preservatives in meat products, have been considered. Variations in vitamin D status may be another reason for the geographical variation in the incidence of type 1 diabetes. Vitamin D has important regulatory effects on the immune system. A protective effect of cod liver oil (a source of both vitamin D and long-chain n-3 fatty acids, which are also anti-inflammatory) was shown against childhood diabetes in the recent study reported by the Norwegian Childhood Diabetes Study Group.6

Certain infectious agents, including enteroviruses, have been associated with development of diabetes in animal models and in rare cases of human diabetes. This has led to worries that childhood vaccination, particularly with live attenuated vaccines, may be a risk factor for type 1 diabetes. A Danish study, along with other recent evidence, has gone a long way to dispel worries on this score; Hviid and colleagues7 studied a cohort including all Danish children born between 1990 and 2000, and found no evidence of any association between childhood vaccinations and diabetes. On the contrary, the vaccines may be protective by limiting the effect of potentially diabetogenic infections, particularly rubella.

Recent Developments

1 Vitamin B3 (niacin) consists of nicotinic acid and nicotinamide. The latter is tolerated in high doses, and has been shown to decrease the incidence of diabetes in streptozo-tocin-treated animals, and in non-obese diabetic mice. Some early preclinical studies showed promise for the agent. The vitamin inhibits poly-ADP-ribose polymerase (PARP), an enzyme involved in DNA repair. Activation of PARP leads to depletion of intracellular nicotinamide adenine dinucleotide. This depletion of cellular energy stores may predispose to cell damage, including in the pancreatic beta cell. The European Nicotinamide Diabetes Intervention Trial (ENDIT)8 was a randomized, double-blind, placebo-controlled trial in which 552 islet cell antibody-positive first-degree relatives of patients with diabetes took either nicotinamide or placebo. There was no difference in the incidence of diabetes during the five years of the trial (82 vs 77 cases, respectively).

2 Autoimmunity directed at insulin epitopes is one of the critical driving forces in the pathogenesis of type 1 diabetes. In animal models, exposure to mucosal insulin induces tolerance and thus decreases risk of diabetes. This mechanism is of particular interest because of the recent developments of insulin formulations which are active after oral or nasal administration. The Diabetes Prevention Trial-Type 1 reported recently.9 In this trial, a large number of first- and second-degree relatives of patients with diabetes were screened for pre-diabetes. Those found to be positive were ran-

^^^ §01 Prevention and Diagnosis domized to receive either oral insulin or placebo. Again, there was no difference in the incidence of new diabetes between the control and the treatment groups.

3 The prospects of gene therapy for diabetes are improving rapidly. Approaches to introduce a functioning insulin-producing mechanism in glucose-responsive cells have been considered. The genetic susceptibility to diabetes is mainly through class II histocompatibility alleles. Recent experiments in non-obese diabetic mice have been carried out to replace diabetes-prone genes with those that are protective.10

Conclusion ceptibility by up to 20-fold, and there might be a slight bias towards males developing diabetes. Epidemiological data strongly support a role for environmental influences, especially for childhood diabetes. There is no evidence currently to support specific preventative measures. Breast-feeding should be promoted for its possible role in preventing type 1 diabetes, as well as its other health benefits. Efforts to limit excessive weight gain in infancy and adolescence should be promoted, as high body weight at these times may favour development of type 1 diabetes. Among the other nutritional factors, the best evidence is for a protective effect of vitamin D and supplementation should be considered (perhaps as cod liver oil) in areas where sunlight exposure is low. Finally, parents should be encouraged to have their children vaccinated as per normal childhood schedules— there is no evidence that vaccination predisposes to diabetes and it may be that, by decreasing infection with some agents, it actually protects.

There is not, currently, any way to accurately predict which individuals are going to get diabetes, or to prevent its occurrence. Family history is a major risk factor, increasing sus-

Further Reading

Geographical variation in risk HLA-DQB1 genotypes for type 1 diabetes and signs of beta-cell autoimmunity in a high-incidence country. Diabetes Care 2004; 27:676-81.

3 Kyvik KO, Nystrom L, Gorus F, Songini M, Oestman J, Castell C, Green A, Guyrus E, Ionescu-Tirgoviste C, McKinney PA, Michalkova D, Ostrauskas R, Raymond NT. The epidemiology of Type 1 diabetes mellitus is not the same in young adults as in children. Diabetologia 2004; 47: 377-84.

4 Baughcum AE, Johnson SB, Carmichael SK, Lewin AB, She JX, Schatz DA. Maternal efforts to prevent type 1 diabetes in at-risk children. Diabetes Care2005; 28:916-21.

5 Virtanen SM, Knip M. Nutritional risk predictors of beta cell autoimmunity and type 1 diabetes at a young age. Am J Clin Nutr 2003; 78:1053-67.

6 Stene LC, Joner G, Norwegian Childhood Diabetes Study Group. Use of cod liver oil during the first year of life is associated with lower risk of childhood-onset type 1 diabetes: a large, population-based, case-control study. Am J Clin Nutr 2003; 78:1128-34.

7 Hviid A, Stellfeld M,Wohlfahrt J, Melbye M. Childhood vaccination and type 1 diabetes. NEngl J Med 2004; 350:1398-1404.

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