In this analysis of children at increased genetic risk for type 1 diabetes, greater height growth velocity was associated with earlier IA development in healthy children, and was even more strongly associated with more rapid progression to type 1 diabetes in autoimmune children. Shorter height was weakly associated with IA development, but was not associated with progression to type 1 diabetes in IA positive children. Weight, BMI, and growth velocities of weight and BMI were not associated with either IA development or progression to type 1 diabetes.
Many of the previous studies had used SD scores for height, weight, and BMI, calculated from general population data for the analysis of association with type 1 diabetes, using a case-control design. However, since the DAISY cohort is selected to be at increased genetic risk for type 1 diabetes, and therefore is not expected to be representative of the general population, and because we have an excellent comparison group embedded within our cohort (i.e., the higher risk children who did not develop the outcome), it was not necessary to calculate SD scores to examine the association between body size and the development of islet autoimmunity and type 1 diabetes. Prospective follow-up of our cohort produced longitudinal data on size, which gave us the opportunity to examine velocity of growth. We note that our results regarding height velocity are consistent with what has been reported, even though other studies had used other statistical approaches and had used SD scores for their measure of height. Our analyses extend the previous findings by suggesting that the velocity of linear growth, rather than attained height or change in height (growth), may be the operative factor.
The mean difference in height growth velocity between DAISY children who did and did not develop IA is 0.18 cm per year (). It is not clear whether an increase in growth velocity of this small of a magnitude is biologically relevant. However, the difference in height growth velocity between those autoimmune children who did and did not develop diabetes is much larger. IA-positive children that subsequently developed type 1 diabetes had a mean height growth velocity that was 0.54 cm per year greater than IA-positive DAISY children that did not develop type 1 diabetes. The consistency of the associations between greater height growth velocity and more rapid development of both IA and type 1 diabetes is intriguing. Our findings may offer preliminary support for the Overload Hypothesis (7
), which suggests that high growth rate may exacerbate the autoimmune process via beta cell overload. A causal link between rapid linear growth rate and greater risk of IA and subsequent type 1 diabetes development could be postulated. However, we acknowledge that greater height growth velocity may simply be a side effect of the underlying biologic mechanisms that drive the autoimmune disease process.
One potential explanation for our findings is that increased linear growth velocity, perhaps associated with higher levels of IGF-1, may result in greater insulin secretion and insulin resistance, which have also been shown to be associated with greater IGF-1 levels (34
). Insulin resistance may increase demands on the beta cell, and has been shown to precede type 1 diabetes development (41
), especially when coupled with reduced insulin secretion (42
). However, there is currently little evidence supporting a role of insulin resistance in predicting islet autoimmunity. Finally, we cannot rule out a primary increase in insulin levels as the explanation for the more rapid linear growth. Chronic hyperinsulinemia, perhaps due to a genetic tendency for hyperinsulinemia, would result both in greater growth rate (43
) and greater demands for insulin from the beta cell. The class III allele of the INS
gene, which is considered to be protective against type 1 diabetes (44
), is also associated with lower BMI and lower fat mass in children with rapid infant growth (45
), possibly through lower insulin secretion. Thus, exploration of the role of the insulin (INS
) gene and its effect on insulin secretion may further our understanding of the association between rapid linear growth velocity and progression through the autoimmune disease process. In considering potential genetic influences on the observed associations between increased linear growth velocity and the autoimmune disease process, it is useful to note that statistical adjustment for HLA and family history did not materially affect these associations.
While a variety of biologic mechanisms may be responsible for greater demand on the beta cell to produce insulin, the mechanism by which increased beta cell stress may lead to IA and type 1 diabetes may be more straight-forward. Greater beta cell activity in response to high glucose concentrations has been linked with increased beta cell expression of the GAD antigen (46
). Also, more active beta cells have been shown to be more susceptible to cytokine damage (47
). Thus, increasing beta cell activity, due to any cause, may trigger or exacerbate an autoimmune disease process. We are limited in this exploration by our lack of measurements on IGF-1, growth hormone, insulin, insulin resistance and beta cell function in DAISY children.
Our finding that shorter height was a weak risk factor for IA development was unexpected in light of the previously described associations between greater height and type 1 diabetes development(19
). One possible explanation of this unexpected finding is that shorter children may have experienced fetal or early life growth restriction, and may be more likely to grow more rapidly than their peers. Therefore, shorter height may simply proxy greater height growth velocity in the analysis of healthy children for the development of IA. We note that shorter height was not associated with earlier type 1 diabetes development in autoimmune children, which suggests that the biologic mechanisms represented by shorter height may only be important at the earliest stages of the disease.
Childhood obesity and rapid weight gain, as measured by childhood BMI, weight growth velocity, and BMI growth velocity, were not associated with earlier IA development in healthy children, or more rapid progression to type 1 diabetes in autoimmune children. These findings run contrary to previous reports (18
) which suggested that increased height, weight, and/or BMI may be associated with type 1 diabetes or islet autoimmunity development. It is possible that the effects of obesity (weight or BMI) on the autoimmune disease process might be more evident in children without genetic risk for type 1 diabetes, and therefore may not be detectable in DAISY’s higher risk population. Also, the majority of these studies found associations with size or growth in very young ages, which was not the population of the current study. Our results suggest that the association with height velocity and type 1 diabetes is present at later ages in childhood. We are not able to make any inferences regarding the role of height growth velocity in the risk of islet autoimmunity and type 1 diabetes in children under the age of 2 years.
In conclusion, greater height growth velocity is either directly involved, or correlated with unmeasured factors involved, in the natural evolution from genetic susceptibility to autoimmunity and type 1 diabetes development in pre-pubertal children. Our results support further exploration of the biologic mechanisms underlying the association between rapid linear childhood growth rate, IA development, and progression to type 1 diabetes.