The role of long-term exposure to Bisphenol A on insulin resistance in patients with type 2 diabetes

In humans with and without DM, exposure to BPA could interfere with insulin signaling pathways and cause insulin resistance.

The burden of diabetes type 2 (T2D) has emerged as one of the leading causes of death worldwide is a significant healthcare concern worldwide. In addition to known risk factors for T2D such as physical inactivity and obesity, recent epidemiologic data have suggested an association between exposure to chemical contaminants found in processed foods, such as Bisphenol A (BPA), T2D, and obesity. BPA is a well-known endocrine disruptor with estrogenic effects 100- to 10000-fold less potent than 17b-estradiol. It is a widely used chemical in industrial manufacturing of several polycarbonate consumer products such as plastic food and beverage containers and epoxy resin applications. Studies on animal models have shown an association between perinatal BPA exposure and increased offspring body weight at 6 months of age. Although limited evidence supports glucose intolerance and exposure to BPA after birth, a single low dose of BPA injection ((10 mg/kg) and 4 or 8 days of injected 100 mg/kg BPA) has been shown to induce insulin resistance in adult male mice. In addition, several epidemiologic studies in human specimens have established an association between exposure to BPA and T2D and suggested that BPA may impair the expression of components of insulin-induced glucose uptake pathway and GLUT4, leading to insulin resistance develops in skeletal muscle and adipocytes as one possible mechanism by which BPA induces glucose intolerance.

A recent cross-sectional study investigating the association between exposure to BPA in the Pakistani population and risk factors of diabetes mellitus (DM) examined data from 400 participants, most of whom had DM (61.75%). Participants’ urine and blood samples and sociodemographic data were collected. Urinary BPA levels diabetes risk factors were determined using the Pearson correlation coefficient. Obese participants (BMI > 27) from semi-urban and industrial areas showed a significantly higher BPA level (p < 0.05). The study hypothesized that exposure to bisphenol-A could significantly provoke predefined inflammatory mediators such as C-reactive protein (CRP) and interleukine-6 (IL-6) among participants with DM, which could interfere with insulin pathways resulting in increased insulin resistance. BPA levels were significantly higher (p < 0.05) in obese people (BMI > 27) living in semi-urban and industrial areas. BPA was detectable in 75% of study participants. Urinary BPA level was found to be higher in diabetic participants than non-diabetics. Elevated levels of HbA1 correlated with urinary BPA level (r = 0.6028), HOMA-IR (r = 0.5356), CRP (r = 0.6946), BUN (r = 0.6077), AST (r = 0.5151), FFA (r = 0.5759), TGs (r = 0.5608), and MDA (r = 0.6908). This data provides evidence that supports the role of BPA exposure as a risk factor for T2DM. Hepatic mitochondria are sensitive to BPA, and prolonged exposure can elevate hepatic levels of malondialdehyde, adipocytokines such as IL6 and TNF-alpha. Increased levels of these inflammatory mediators, adiponectin, and leptin have been shown to induce insulin resistance by disrupting insulin signaling pathways responsible for insulin signaling. 

Levels of malondialdehyde (MDA), an oxidative stress biomarker, exhibited a significant positive correlation with urinary BPA exposure in participants with and without DM. The study concluded that exposure to BPA can impose a significant negative correlation with the levels of antioxidant enzymes, including superoxide dismutase (SOD) and Glutathione (GSH), among those in the diabetic group compared to non-diabetic participants who showed a nonsignificant correlation. The study concluded that prolonged exposures to BPA impair insulin signaling by increasing levels of inflammatory cytokines known to induce metabolic pathways that ultimately lead to decreased insulin signaling and provoke insulin resistance.

Practice Pearls:

• Bisphenol A is a well-known endocrine disruptor with an estrogenic effect used in industrial manufacturing and is linked to insulin resistance in both animals and humans.
• Exposure to BPA could disrupt several antioxidant enzymes and provoke inflammatory mediators such as C-reactive protein (CRP) and interleukine-6 (IL-6).
• Because a strong positive relationship between urinary BPA concentrations (mg/dL) and T2DM detailed has been shown, more research is required to explain the complex dose-response relationship between BPA exposure and risk of T2DM.

Akash, Muhammad Sajid, and Kanwal Rehman. “Exposure of Endocrine Disrupting Chemical Is

a Risk Factor for the Pathogenesis and Development of Metabolic Disorders.” Metabolism, vol.

116, 2021, p. 154498., https://doi.org/10.1016/j.metabol.2020.154498. 

Moon, Min Kyong et al. “Long-term oral exposure to bisphenol A induces glucose intolerance and insulin resistance.” The Journal of endocrinology vol. 226,1 (2015): 35-42. doi:10.1530/JOE-14-0714

Alonso-Magdalena P, Morimoto S, Ripoll C, Fuentes E & Nadal A 2006 The estrogenic effect of bisphenol A disrupts pancreatic b-cell function
in vivo and induces insulin resistance. Environmental Health Perspectives 114 106–112. (doi:10.1289/ehp.8451)

Elmoataz Elmamoun, PharmD Candidate, 2022, South College School of Pharmacy