Testing the Accelerator Hypothesis

Abstract

OBJECTIVE -The "accelerator hypothesis" predicts that fatness is associated with an earlier age at onset of type 1 diabetes. We tested the hypothesis using data from the SEARCH for Diabetes in Youth study.RESEARCH DESIGN AND METHODS -Subjects were 449 youth aged Ͻ20 years at diagnosis who had positive results for diabetes antibodies measured 3-12 months after diagnosis (mean 7.6 months). The relationships between age at diagnosis and fatness were examined using BMI as measured at the SEARCH visit and reported birth weight, both expressed as SD scores (SDSs).RESULTS -Univariately, BMI SDS was not related to age at diagnosis. In multiple linear regression, adjusted for potential confounders, a significant interaction was found between BMI SDS and fasting C-peptide (FCP) on onset age (P Ͻ 0.0001). This interaction remained unchanged after additionally controlling for number and titers of diabetes antibodies. An inverse association between BMI and age at diagnosis was present only among subjects with FCP levels below the median (Ͻ0.5 ng/ml) (regression coefficient Ϫ7.9, P ϭ 0.003). A decrease of 1 SDS in birth weight (639 g) was also associated with an ϳ5-month earlier age at diagnosis (P ϭ 0.008), independent of sex, race/ethnicity, current BMI, FCP, and number of diabetes antibodies.CONCLUSIONS -Increasing BMI is associated with younger age at diagnosis of type 1 diabetes only among those U.S. youth with reduced ␤-cell function. The intrauterine environment may also be an important determinant of age at onset of type 1 diabetes. Diabetes Care 29:290 -294, 2006T he "accelerator hypothesis" postulates that obesity-associated insulin resistance accelerates the disease process of type 1 diabetes. The marker is an earlier age at onset of type 1 diabetes associated with increased BMI (1).In contemporary societies, increasing childhood obesity may account for the increasing incidence and younger age at onset of type 1 diabetes (2) and for the difficulty in distinguishing between type 1 and type 2 diabetes (3,4). The accelerator hypothesis suggests that the increased incidence of type 1 diabetes may be caused by an accelerated progression rather than by an increase in the absolute lifetime risk (1). In support of accelerated progression, the incidence of type 1 diabetes rose in children (0 -14 years) but fell later in life (15-34 or 39 years) in Sweden (5,6) and Belgium (7). Obesity-induced insulin resistance may upregulate the ␤-cells, which become susceptible to an autoimmune attack (8). If this is correct, we can hypothesize that the association between BMI and onset age, if present, may be mediated through an intensified autoimmune response.Studies have linked in utero growth restriction with an increased risk for future chronic diseases, including obesity and insulin resistance. The association between birth weight and age at onset of type 1 diabetes has not been systematically studied.We aimed to test aspects of the accelerator hypothesis using data from the SEARCH for Diabetes in Youth (9). We hypothesized that hig...

To boldly go—or to go too boldly? The accelerator hypothesis revisited

“…The size of these studies allows us to conclude with some confidence that insulin sensitivity is not a major influence upon progression to diabetes in those with FPIR above the tenth centile of a control population; its influence only emerges in those with advanced insulin secretory failure or early metabolic abnormalities. Independently, and by a different route, analysis of a subset of participants in the SEARCH study led to a similar conclusion: increasing BMI is associated with decreasing age of diagnosis of type 1 diabetes only in those with evidence of reduced beta cell function [14]. We may conclude that decreasing insulin sensitivity can accelerate onset in those with advanced beta cell failure and/or metabolic decompensation, but has no causal role in the pathogenesis of type 1 diabetes.…”

A population-specific diabetogenic haplotype HLA-A2,Cw1,B56,DR4,DQ8 is associated with high birthweight in Finnish diabetic families

“…11 It is not clear whether high (X4000 g) or low (p2500 g) birthweight (BW) increases the risk of T1D or whether no association exists between BW and T1D. [12][13][14][15][16][17] Findings from recent epidemiological studies suggest an association between high BW and an increased risk of T1D, especially in children with a BW of 4000 g or more. 14,15 It has also been shown that infants born large for gestational age have an increased risk of T1D.…”

Double Diabetes: The Search for a Treatment Paradigm in Children and Adolescents

“…The accelerator hypothesis is controversial because studies designed to prove its validity have reached various conclusions [35,[60][61][62][63][64][65]. Reports from the United Kingdom indicated a relationship between younger age at diagnosis of T1D and higher body mass index (BMI) in Middlesbrough [35], and Plymouth [64],but not in Birmingham [61].…”