Ethnic differences in association of high body mass index with early onset of Type 1 diabetes – Arab ethnicity as case study

<div><p>Objective</p><p>The “accelerator hypothesis” predicts early onset of Type 1 diabetes (T1D) in heavier children. Studies testing direction of correlation between body mass index (BMI) and age at onset of T1D in different continental populations have reported differing results–inverse, direct, and neutral. Evaluating the correlation in diverse ethnic populations is required to generalize the accelerator hypothesis.</p><p>Methods</p><p>The study cohort comprised 474 Kuwaiti children of Arab ethnicity diagnosed with T1D at age 6 to 18 years during 2011–2013. Age- and sex-adjusted BMI z-scores were calculated by comparing the BMI measured at diagnosis with Kuwaiti pediatric population reference data recorded during comparable time-period. Multiple linear regression and Pearson correlation analyses were performed.</p><p>Results</p><p>BMI z-score was seen inversely associated with onset age (r,-0.28; p-value<0.001). Children with BMI z-score>0 (<i>i</i>.<i>e</i>. BMI >national average) showed a stronger correlation (r,-0.38; p-value<0.001) than those with BMI z-score<0 (r,-0.19; p-value<0.001); the former group showed significantly lower mean onset age than the latter group (9.6±2.4 <i>versus</i> 10.5±2.7; p-value<0.001). Observed inverse correlation was consistent with that seen in Anglo-saxon, central european, caucasian, and white children while inconsistent with that seen in Indian, New Zealander, and Australian children.</p><p>Conclusions</p><p>The accelerator hypothesis generalizes in Arab pediatric population from Kuwait.</p></div

Summary of findings from previous studies on association between age- and sex-adjusted BMI z-scores and age at onset of T1D in various populations.

<p>Summary of findings from previous studies on association between age- and sex-adjusted BMI z-scores and age at onset of T1D in various populations.</p

Multiple linear regression models for association between BMI z-score and age at onset of T1D in the cohort of 6 to 18 years stratified by BMI z-score >0 and <0.

<p>Multiple linear regression models for association between BMI z-score and age at onset of T1D in the cohort of 6 to 18 years stratified by BMI z-score >0 and <0.</p

Flowchart depicting the filtering steps used to derive the data sets on children and adolescents with age at onset of T1D during 2 to <6 years, and during 6 to18 years.

<p>Flowchart depicting the filtering steps used to derive the data sets on children and adolescents with age at onset of T1D during 2 to <6 years, and during 6 to18 years.</p

qRT-PCR expression of Flag parafibromin WT and mutant mRNAs.

<p>The assay, performed in presence and absence of cycloheximide (CHX 500 μM, final concentration) shows that the inhibition of the degradation process led to the total recovery of the mutant mRNAs.</p

Family trees for the three Cases.

<p>The arrow indicates the proband; “+” indicates the presence of the mutation; na = DNA not available. For Case III no relatives were recruited at the time of this report.</p

Immunoblot detection of CDC73.

<p>Total protein cell lysates from cell transfected with WT and mutants (R77P, delVV, delENIP) vectors were detected with Anti-Flag antibody showing that the mutant proteins are poorly expressed with respect to the WT: the same assay performed in presence of the proteasome inhibitor, MG132 (25 μM, final concentration), led to the partial recovery of the mutant proteins.</p

MTT test.

<p>Proliferation assay at different time points (24, 48 and 72 h). The WT vector limited the cell growth, while all the three mutant vectors caused cell overgrowth in presence of the endogenous parafibromin, suggesting a dominant interfering effect.</p

CHX Chase assay.

<p>The western blot performed in presence of MG132, after 48 h from transfection showed that the mutated proteins were degraded (a) up to the 80% with respect to the WT, with short half-lives around the 2,5 h (b).</p