Vis sammendrag
Background: Diabetes affects millions of people worldwide with a continued increase in incidence occurring
within the pediatric population. The potential contribution of persistent organic pollutants (POPs) to diabetes in
youth remains poorly known, especially regarding type 1 diabetes (T1D), generally the most prevalent form of
diabetes in youth.
Objectives: We investigated the associations between POPs and T1D in youth and studied the impacts of POPs on
pancreatic β-cell function and viability in vitro.
Methods: We used data and plasma samples from the SEARCH for Diabetes in Youth Case Control Study
(SEARCH-CC). Participants were categorized as Controls, T1D with normal insulin sensitivity (T1D/IS), and T1D
with insulin resistance (T1D/IR). We assessed plasma concentrations of polychlorinated biphenyls (PCBs) and
organochlorine pesticides and estimated the odds of T1D through multivariable logistic regression. In addition,
we performed in vitro experiments with the INS-1E pancreatic β-cells. Cells were treated with PCB-153 or p,p’-
DDE at environmentally relevant doses. We measured insulin production and secretion and assessed the mRNA
expression of key regulators involved in insulin synthesis (Ins1, Ins2, Pdx1, Mafa, Pcsk1/3, and Pcsk2), glucose
sensing (Slc2a2 and Gck), and insulin secretion (Abcc8, Kcnj11, Cacna1d, Cacna1b, Stx1a, Snap25, and Sytl4).
Finally, we assessed the effects of PCB-153 and p,p’-DDE on β-cell viability.
Results: Among 442 youths, 112 were controls, 182 were classified with T1D/IS and 148 with T1D/IR. The odds
ratios (OR) of T1D/IS versus controls were statistically significant for p,p’-DDE (OR 2.0, 95% confidence interval
(CI) 1.0, 3.8 and 2.4, 95% CI 1.2, 5.0 for 2nd and 3rd tertiles, respectively), trans-nonachlor (OR 2.5, 95% CI 1.3,
5.0 and OR 2.3, 95% CI 1.1, 5.1 for 2nd and 3rd tertiles, respectively), and PCB-153 (OR 2.3, 95% CI 1.1, 4.6 for
3rd tertile). However, these associations were not observed in participants with T1D/IR. At an experimental
level, treatment with p,p’-DDE or PCB-153, at concentrations ranging from 1 × 10-15 M to 5 × 10-6 M, impaired
the ability of pancreatic β-cells to produce and secrete insulin in response to glucose. These failures were par-
alleled by impaired Ins1 and Ins2 mRNA expression. In addition, among different targeted genes, PCB-153
significantly reduced Slc2a2 and Gck mRNA expression whereas p,p’-DDE mainly affected Abcc8 and Kcnj11.
While treatment with PCB-153 or p,p’-DDE for 2 days did not affect β-cell viability, longer treatment progres-
sively killed the β-cells
