The most striking evidence of a non-genetic contribution to Type 1 diabetes relates to the fact
The Epidemiology of Diabetes Mellitus. An International Perspective. Edited by Jean-Marie Ekoe, Paul Zimmet and Rhys Williams. © 2001 John Wiley & Sons Ltd.
that the concordance rate in monozygotic twins is far below unity (1,2,3). Since monozygotic twin partners have identical genes, this difference can only be attributed to the influence of non-genetic exposures. Two additional lines of evidence provide support for the non-genetic contribution. First, the huge variation in the incidence of Type 1 diabetes between Caucasian populations (16) cannot be explained by the geographical distribution of susceptibility genes. Second, the rising incidence of Type 1 diabetes, as observed in many European populations (17), cannot possibly be explained by increased size of the pool of susceptibility genes (18) and must be attributed to increased susceptibility in individuals at genetic risk and/or the introduction of environmental causative agents in these populations.
The search for non-genetic determinants of Type 1 diabetes has been intensified over the last decade and has focused on viral infections, nutritional factors, stressful life events, and socio-economic status (19,20) and recently also on the intrauterine environment (21).
Virus infections have for a long time been implicated in the causation of Type 1 diabetes (22). It has been demonstrated that congenital rubella infection is associated with a high risk of subsequent development of Type 1 diabetes (23). The development of Type 1 diabetes has also been associated with cytomegalovirus infection, mumps and Coxsackie B infections (24). The mechanisms by which infectious agents cause ,3-cell destruction by immune-mediated mechanisms are largely unknown although various hypotheses have been presented recently (25,26). It may also be possible that viral infections are associated with clinical precipitation of Type 1 diabetes in subjects suffering from ongoing ,3-cell destruction.
Following the results from animal studies that dietary changes influence the incidence of diabetes (27), several studies in humans have focused on the possible role of dietary factors in Type 1 diabetes.
A study from Iceland suggested that exposure to nitrosamines in women at the time of conception may increase the risk of Type 1 diabetes in the male offspring (28). Some support to this concept has come from the case-control studies in Sweden (29, 30) and Finland (31), but the finding needs confirmation and does not explain the high Type 1 diabetes incidence level in populations where exposure to nitrosamines is less common than in Iceland.
The association between Type 1 diabetes and breastfeeding has been extensively studied since a Danish study (32) found that reduced length of breastfeeding during infancy seems to be associated with increased risk of developing Type 1 diabetes. The literature on cow's milk exposure and Type 1 diabetes has been reviewed extensively (33,34). In general, the associations described have been weak and, if causal, can explain the development of diabetes in only a limited number of cases. Also, changes in breast feeding habits over time as well as recall biases are potential confounders that are difficult to control.
The possible association between reduced breastfeeding and Type 1 diabetes risk may reflect an aetiological role of cow's milk protein, as indicated by a much higher occurrence of antibodies to cow's milk protein in newly onset diabetic children as compared with control subjects (35,36). This possible association is in accordance with migrant studies from New Zealand, demonstrating that Samoan children in New Zealand, following introduction to milk formula, increased their risk of Type 1 diabetes as compared with children in Samoa (37). Accordingly, the increased Type 1 diabetes risk among children with lack of or with reduced duration of breastfeeding might be explained by early introduction to a protein that acts as a trigger for the immunological destruction of the ^-cells, possibly by cross-reaction with a membrane protein(s) of the £-cell (38).
A few studies have addressed the possible aetiological role of psychological factors and stressful life events in the period preceding clinical onset of disease. Although with rather weak associations, several reports have provided consistent evidence of such possible influences (39,40,41). It is possible that stressful life events and psychological dysfunction, through elevated stress hormone levels, increase the demand for endogenous insulin production and thereby accelerate clinical precipitation of Type 1 diabetes in individuals with ongoing ,3-cell destruction.
Conflicting results have been reported regarding the associations between socio-economic status and Type 1 diabetes. A Danish study (42), in the Copenhagen area, found higher incidence of Type 1 diabetes in regions with relatively low average income level, whereas a study in North America found an opposite trend (43). In both studies, the associations were rather modest only. In a Swedish case-control study (19) a positive, but rather weak association between Type 1 diabetes and low educational and income level was found. Such associations are probably explained by unknown events and factors in lifestyle that may influence the risk of developing Type 1 diabetes as well as the socio-economic status (19).
Low weight at birth or weight at one year of age are associated with increased risk of subsequent development of impaired glucose tolerance and Type 2 diabetes, maybe because intrauterine malnutrition during critical periods of fetal life and infancy will lead to a suboptimal development of the endocrine pancreas. This could theoretically have implications for the pathogenesis of Type 1 diabetes as well. However, the small number of studies performed have not found evidence of an association between low birthweight and Type 1 diabetes (44). On the contrary, a Swedish case-control study (21) found that the risk of developing Type 1 diabetes was lowest in children small for gestational age and highest in children large for gestational age. In our own twin study there was no association between birthweight and Type 1 diabetes, and variables related to birthweight and length could not explain why some pairs are concordant while other remain discordant (44).
may accelerate the process to the precipitation of clinical disease. If so, this aetiological heterogeneity implies severe difficulties in finding a unified approach to prediction and prevention of Type 1 diabetes which may apply to all subjects at risk in different populations.
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