Xenobiotic mediated diabetogenesis: Developmental exposure to dichlorvos or atrazine leads to type 1 or type 2 diabetes in Drosophila

Free Radic Biol Med. 2019 Sep;141:461-474. doi: 10.1016/j.freeradbiomed.2019.07.013. Epub 2019 Jul 15.

Abstract

The increased incidence of diabetes to the magnitude of a global epidemic is attributed to non-traditional risk factors, including exposure to environmental chemicals. However, the contribution of xenobiotic exposure during the development of an organism to the etiology of diabetes is not fully addressed. Developing stages are more susceptible to chemical insult, but knowledge on the consequence of the same to the onset of diabetes is residual. In this context, by using Drosophila melanogaster having conserved Insulin/Insulin growth factor-like signaling (IIS) as well as glucose homeostasis as a model, we evaluated the potential of developmental exposure to dichlorvos (DDVP, an organophosphorus pesticide) or atrazine (herbicide) to cause diabetes in exposed organisms. Flies exposed to DDVP during their development display insulin deficiency or type 1 diabetes (T1D) while those exposed to atrazine show insulin resistance or type 2 diabetes (T2D), suggesting that exposure to these xenobiotics during organismal development can result in diabetes and that different mechanisms underlie pesticide mediated diabetes. We show that oxidative stress-mediated c-Jun N-terminal kinase (JNK) signaling activation underlies insulin resistance in flies exposed to atrazine during their development while DDVP-mediated T1D involves activation of caspase-mediated cell death pathway. Mitigation of oxidative stress through over-expression of SOD2 in atrazine (20μg/ml) exposed flies, revealed significantly decreased oxidative stress levels and reduced phosphorylation of JNK. Moreover, glucose and Akt phosphorylation levels in SOD2 over-expression flies exposed to atrazine were comparable to those in controls, suggesting restoration in insulin sensitivity. Therefore, exposure to xenobiotics during development is a common risk factor for the development of type 1 or type 2 diabetes. Accordingly, the present study cautions against the use of such diabetogenic pesticides. Also, mitigation of oxidative stress or anti-oxidant supplementation could be a potential therapy for xenobiotic mediated type 2 diabetes.

Keywords: Apoptosis; Glucose homeostasis; Insulin signaling; JNK; Oxidative stress; SOD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Atrazine / toxicity
  • Diabetes Mellitus, Type 1 / chemically induced
  • Diabetes Mellitus, Type 1 / genetics*
  • Diabetes Mellitus, Type 1 / metabolism
  • Diabetes Mellitus, Type 1 / pathology
  • Diabetes Mellitus, Type 2 / chemically induced
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • Dichlorvos / toxicity
  • Disease Models, Animal
  • Drosophila melanogaster / drug effects
  • Drosophila melanogaster / genetics
  • Gene Expression / drug effects
  • Homeostasis / drug effects
  • Humans
  • Insulin / genetics
  • Insulin Resistance / genetics*
  • JNK Mitogen-Activated Protein Kinases
  • Oxidation-Reduction / drug effects
  • Oxidative Stress / drug effects*
  • Oxidative Stress / genetics
  • Signal Transduction / drug effects
  • Superoxide Dismutase / genetics
  • Xenobiotics / toxicity

Substances

  • Insulin
  • Xenobiotics
  • Dichlorvos
  • Superoxide Dismutase
  • superoxide dismutase 2
  • JNK Mitogen-Activated Protein Kinases
  • Atrazine