Dataset Information

Experimental BPA Exposure and Glucose-Stimulated Insulin Response in Adult Men and Women.

ABSTRACT:

Context

Human cross-sectional and animal studies have shown an association of the chemical bisphenol A (BPA) with insulin resistance, type 2 diabetes, and other metabolic diseases, but no human experimental study has investigated whether BPA alters insulin/C-peptide secretion.

Design

Men and postmenopausal women (without diabetes) were orally administered either the vehicle or a BPA dose of 50 µg/kg body weight, which has been predicted by US regulators (Food and Drug Administration, Environmental Protection Agency) to be the maximum, safe daily oral BPA dose over the lifetime. Insulin response was assessed in two cross-over experiments using an oral glucose tolerance test (OGTT; experiment 1) and a hyperglycemic (HG) clamp (experiment 2). Main outcomes were the percentage change of BPA session measures relative to those of the control session.

Results

Serum bioactive BPA after experimental exposure was at levels detected in human biomonitoring studies. In the OGTT, a strong positive correlation was found between hemoglobin A1c(HbA1c) and the percentage change in the insulinogenic index (Spearman = 0.92), an indicator of early-phase insulin response, and the equivalent C-peptide index (Pearson = 0.97). In the HG clamp study, focusing on the later-phase insulin response to a stable level of glucose, several measures of insulin and C-peptide appeared suppressed during the BPA session relative to the control session; the change in insulin maximum concentration (Cmax) was negatively correlated with HbA1c and the Cmax of bioactive serum BPA.

Conclusions

This exploratory study suggests that BPA exposure to a dose considered safe by US regulators may alter glucose-stimulated insulin response in humans.

SUBMITTER: Stahlhut RW

PROVIDER: S-EPMC6169468 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Publications

Experimental BPA Exposure and Glucose-Stimulated Insulin Response in Adult Men and Women.

Stahlhut Richard W RW Myers John Peterson JP Taylor Julia A JA Nadal Angel A Dyer Jonathan A JA Vom Saal Frederick S FS

Journal of the Endocrine Society 20180912 10

<h4>Context</h4>Human cross-sectional and animal studies have shown an association of the chemical bisphenol A (BPA) with insulin resistance, type 2 diabetes, and other metabolic diseases, but no human experimental study has investigated whether BPA alters insulin/C-peptide secretion.<h4>Design</h4>Men and postmenopausal women (without diabetes) were orally administered either the vehicle or a BPA dose of 50 µg/kg body weight, which has been predicted by US regulators (Food and Drug Administrati ...[more]

PMID: 30302422

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Project description:BackgroundThe variant rs11085226 (G) within the gene encoding polypyrimidine tract binding protein 1 (PTBP1) was reported to associate with reduced insulin release determined by an oral glucose tolerance test (OGTT) as well as an intravenous glucose tolerance test (IVGTT). The aim of the present study was to validate the association of the rs11085226 G-allele of PTBP1 with previously investigated OGTT- and IVGTT-derived diabetes-related metabolic quantitative phenotypes, to conduct exploratory analyses of additional measures of beta-cell function, and to further investigate a potential association with type 2 diabetes.MethodsPTBP1 rs11085226 was genotyped in 20,911 individuals of Danish Caucasian ethnicity ascertained from 9 study samples. Case control analysis was performed on 5,634 type 2 diabetic patients and 11,319 individuals having a normal fasting glucose level as well as 4,641 glucose tolerant controls, respectively. Quantitative trait analyses were performed in up to 13,605 individuals subjected to an OGTT or blood samples obtained after an overnight fast, as well as in 596 individuals subjected to an IVGTT.ResultsAnalyses of fasting and OGTT-derived quantitative traits did not show any significant associations with the PTBP1 rs11085226 variant. Meta-analysis of IVGTT-derived quantitative traits showed a nominally significant association between the variant and reduced beta-cell responsiveness to glucose (β = -0.1 mmol · kg(-1) · min(-1); 95% CI: -0.200.20 - -0.024; P = 0.01) assuming a dominant model of inheritance, but failed to replicate a previously reported association with area under the curve (AUC) for insulin. Case control analysis did not show an association of the PTBP1 rs11085226 variant with type 2 diabetes.ConclusionsDespite failure to replicate the previously reported associations of PTBP1 rs11085226 with OGTT- and IVGTT-derived measures of beta-cell function, we did find a nominally significant association with reduced beta-cell responsiveness to glucose during an IVGTT, a trait not previously investigated, leaving the potential influence of this variant in PTBP1 on glucose stimulated insulin release open for further investigation. However, the present study does not support the hypothesis that the variant confers risk of type 2 diabetes.

Project description:Insulin receptor (Insr) protein can be found at higher levels in pancreatic b-cells than in most other cell types, but the consequences of b-cell insulin resistance remain enigmatic. Ins1cre allele was used to delete Insr specifically in b-cells of both female and male mice which were compared to Ins1cre-containing littermate controls at multiple ages and on multiple diets. RNA-seq of recombined b-cells revealed significant differences in multiple pathways previously implicated in insulin secretion and cellular fate, including rewired Ras and NFkB signaling. Male, but not female, bInsrKO mice had reduced oxygen consumption rate, while action potential and calcium oscillation frequencies were increased in Insr knockout b-cells from female, but not male mice. Female bInsrKO and bInsrHET mice exhibited elevated insulin release in perifusion experiments, during hyperglycemic clamps, and following i.p. glucose challenge. Deletion of Insr did not reduce b-cell mass up to 9 months of age, nor did it impair hyperglycemia-induced proliferation. Based on our data, we adapted a mathematical model to include b-cell insulin resistance, which predicted that b-cell Insr knockout would improve glucose tolerance depending on the degree of whole-body insulin resistance. Indeed, glucose tolerance was significantly improved in female bInsrKO and bInsrHET mice when compared to controls at 9, 21 and 39 weeks. We did not observe improved glucose tolerance in adult male mice or in high fat diet-fed mice, corroborating the prediction that global insulin resistance obscures the effects of b-cell specific insulin resistance. We further validated our in vivo findings using the Ins1-CreERT transgenic line and found improved glucose tolerance 4 weeks after tamoxifen-mediated Insr deletion. Collectively, our data show that loss of b-cell Insr alone is sufficient to drive glucose-induced hyperinsulinemia, thereby improving glucose homeostasis in otherwise insulin sensitive dietary and age contexts.

Dataset Information

Experimental BPA Exposure and Glucose-Stimulated Insulin Response in Adult Men and Women.

Context

Design

Results

Conclusions

Publications

Experimental BPA Exposure and Glucose-Stimulated Insulin Response in Adult Men and Women.

Similar Datasets

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