2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) reverses hyperglycemia in a type II diabetes mellitus rat model by a mechanism unrelated to PPARγ

Abstract

It has been asserted that exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increases the risk for diabetes mellitus in humans, observable as hyperglycemia resulting from insulin resistance. There is no animal model for the induction of diabetes by TCDD. On the contrary, TCDD has been shown to increase insulin sensitivity in rats. Therefore, a diabetic rat model was used to study the effects of TCDD on preexisting diabetes. Type II diabetes was induced in male rats by a high-fat diet and streptozotocin. After manifestation of the disease, these rats received loading dose rates (LDRs) of 3.2, 6.4, and 12.8 microg/kg of TCDD p.o., followed by weekly maintenance dose rates. Rats fed a high-fat diet and not dosed with streptozotocin nor with TCDD served as nondiabetic controls. By day 2, serum-glucose levels in diabetic rats treated with the high LDR of 12.8 microg/kg TCDD were already significantly reduced. By day 8, serum-glucose levels had decreased to control levels and were maintained for the duration of the study (32 days). Thus, TCDD effectively counteracted hyperglycemia in this diabetic rat model. In healthy animals, TCDD induced PPAR gamma transcription and activity in a different dose range than that observed for the hypoglycemic effect.

Evaluation of the Association between Persistent Organic Pollutants (POPs) and Diabetes in Epidemiological Studies: A National Toxicology Program Workshop Review

“…In contrast, in different animal models, TCDD has been shown to cause hypoglycemia (Fried et al 2010; Gorski and Rozman 1987; Viluksela et al 1998, 1999), to have no effect on glucose levels (Unkila et al 1995), or to cause both hyperglycemia and hypoglycemia at different time points during or after dosing (Ebner et al 1988; Potter et al 1983). Although epidemiology studies tend to show a positive relationship between TCDD body burdens and insulin levels (Cranmer et al 2000; Michalek et al 1999), TCDD typically causes hypoinsulinemia and increased insulin sensitivity in animals (Ebner et al 1988; Fried et al 2010; Gorski et al 1988; Gorski and Rozman 1987; Potter et al 1983; Stahl et al 1992; Weber et al 1987). Thus, in animal models, exposure to TCDD mimics the feature of reduced insulin secretion observed in the clinical progression of prediabetes to overt diabetes.…”

The Paradox of Progress: Environmental Disruption of Metabolism and the Diabetes Epidemic

“…While these data are consistent with epidemiological observations linking TCDD exposure to diabetes, other studies have shown that TCDD has hypoglycemic effects. In a rat model of diabetes incorporating high-fat diet coupled with streptozotocin treatment, TCDD treatment reduced plasma glucose levels (36). However, this study may reflect an alternative metabolic disruption of quasi-starvation mediated through TCDD suppression of gluconeogenesis via inhibition of PEPCK (37).…”

TCDD modulation of gut microbiome correlated with liver and immune toxicity in streptozotocin (STZ)-induced hyperglycemic mice

“…However, positive associations between diabetes and TCDD exposure have not been reproduced in laboratory animal models. In fact, TCDD has been shown to reverse hyperglycemia in a type 2 diabetes mellitus (T2D) rat model (Fried et al, 2010) and suppress type 1 diabetes mellitus (T1D) in non-obese diabetic (NOD) mice (Kerkvliet et al, 2009). Despite the appearing anti-diabetic effects, TCDD has been shown to promote a host of adverse metabolic diseases, including non-alcoholic fatty liver disease (NAFLD), a wasting-like syndrome, and cancer in lab animals.…”