Chronic Exposure to Aroclor 1254 Disrupts Glucose Homeostasis in Male Mice via Inhibition of the Insulin Receptor Signal Pathway

Abstract

Epidemiological studies demonstrate that polychlorinated biphenyls (PCBs) induce diabetes and insulin resistance. However, the development of diabetes caused by PCBs and its underlying mechanisms are still unclear. In the present study, male C57BL/6 mice were orally administered with Aroclor 1254 (0.5, 5, 50, and 500 μg/kg) once every 3 days for 60 days. The body weight and the fasting blood glucose levels were significantly elevated; the levels of serum insulin, resistin, tumor necrosis factor α (TNFα), and interleukin-6 (IL-6) increased, while glucagon levels decreased in the animals treated with Aroclor 1254. Pancreatic β-cell mass significantly increased, while α-cell mass was reduced. Aroclor 1254 inhibited the expression of the insulin receptor signaling cascade, including insulin receptor, insulin receptor substrate, phosphatidylinositol 3-kinase-Akt, and protein kinase B and glucose transporter 4, both in the skeletal muscle and the liver. The results suggested that chronic exposure to Aroclor 1254 disrupted glucose homeostasis and induced hyperinsulinemia. The significant elevation of serum resistin, TNFα and IL-6 indicated that obesity caused by Aroclor 1254 is associated with insulin resistance. The elevation of blood glucose levels could have been mainly as a result of insulin receptor signals pathway suppression in skeletal muscle and liver, and a decrease in pancreatic α-cells, accompanied by a reduction of serum glucagon levels, may play an important role in the development of type 2 diabetes.

Tributyltin in male mice disrupts glucose homeostasis as well as recovery after exposure: mechanism analysis

“…In liver, it induces fatty acid oxidation, decreases lipid synthesis, decreases the uptake of free fatty acid, and represses gluconeogenesis by enzyme downregulation (Kershaw and Flier 2004;Meier and Gressner 2004). However, in the present study, adiponectin levels were increased in mice exposed to TBT for 45 days, which was consistent with previous studies showing an elevation of serum adiponectin levels in mice exposed to PCBs (Wahlang et al 2013;Zhang et al 2015). This might be due to an adaptation to the obesity, since adiponectin levels increase as fat mass decreases (Stern et al 2016).…”

“…Protein extraction and polyacrylamide gel electrophoresis (SDS-PAGE) was performed based on our previous methods (Zhang et al 2015). The membrane with transferred proteins was incubated overnight at 4 °C with antibody against IRα (1:500), IRβ (1:500), IRS1 (1:1000), p-IRS1 (1:1000), p-IR (1:1000), PI3K (1:1000), Akt (1:500), p-Akt (1:500), and Glut4 (1:500).…”

A compromised liver alters polychlorinated biphenyl-mediated toxicity

“…However, Aroclor1260 exposure significantly increased insulin sensitivity in the MCD-fed mice which was counterintuitive since this group displayed no improvement in plasma glucose levels and displayed decreased gluconeogenic gene expression. This group also exhibited decreased pancreatic insulin secretion and could be attributed to pancreatic cell dysfunction that occurred with PCB exposure (Jensen et al 2014; Zhang et al 2015). However more studies concerning toxicant exposure and pancreatic function are needed to further comprehend the mechanisms associated with this phenomenon.…”

Mitochondria as target of endocrine-disrupting chemicals: implications for type 2 diabetes

“…At higher doses (20 and 200 mg/kg/day), BPA also impaired insulin signaling and decreased hepatic glucose oxidation and glycogen content (Jayashree et al 2013). Analogously, the exposure to some PCBs, such as aroclor (0.5, 5, 50 and 500 μg/kg/day), PCB-118 (37.5 mg/kg), PCB-138 (37.5 mg/kg) or PCB-126 (10 μg/kg/day), has been associated to increased body weight gain, IR, hyperinsulinemia and changes in pancreatic α-(decrease) and β-cell (increase) mass (Ruzzin et al 2009, Zhang et al 2015a, Kim et al 2016, Loiola et al 2016. Importantly, complex interactions between diet and PCBs have been reported in the development of metabolic disorders.…”