Molecular Mechanisms of the Diabetogenic Effects of Arsenic: Inhibition of Insulin Signaling by Arsenite and Methylarsonous Acid

@article{Paul2007MolecularMO,
  title={Molecular Mechanisms of the Diabetogenic Effects of Arsenic: Inhibition of Insulin Signaling by Arsenite and Methylarsonous Acid},
  author={David S. Paul and Anne W. Harmon and Vicenta Devesa and David J. Thomas and Miroslav St{\'y}blo},
  journal={Environmental Health Perspectives},
  year={2007},
  volume={115},
  pages={734 - 742}
}
Background Increased prevalences of diabetes mellitus have been reported among individuals chronically exposed to inorganic arsenic (iAs). However, the mechanisms underlying the diabetogenic effects of iAs have not been characterized. We have previously shown that trivalent metabolites of iAs, arsenite (iAsIII) and methylarsonous acid (MAsIII) inhibit insulin-stimulated glucose uptake (ISGU) in 3T3-L1 adipocytes by suppressing the insulin-dependent phosphorylation of protein kinase B (PKB/Akt… 

Acute and long-term effects of arsenite in HepG2 cells: modulation of insulin signaling

Arsenite perturbs cellular signaling pathways involved in fuel metabolism: it impairs cellular responsiveness toward insulin, while at the same time stimulating insulin-like signaling to attenuate the expression of genes involved in glucose metabolism and the release of the hepatokine SelP, which is known to modulate peripheral insulin sensitivity.

Exposures to arsenite and methylarsonite produce insulin resistance and impair insulin-dependent glycogen metabolism in hepatocytes

Examination of glycogen metabolism in primary murine hepatocytes exposed in vitro to arsenite or its methylated metabolite, methylarsonite, revealed that both iAs3 + and MAs3+ inhibit insulin-dependent phosphorylation of protein kinase B/Akt, one of the mechanisms involved in the regulation of GS and GP by insulin.

Environmental arsenic as a disruptor of insulin signaling.

  • David S. PaulV. Devesa M. Stýblo
  • Biology
    Metal ions in biology and medicine : proceedings of the ... International Symposium on Metal Ions in Biology and Medicine held ... = Les ions metalliques en biologie et en medecine : ... Symposium international sur les ions metalliques ...
  • 2008
Because mice clear iAs and its metabolites more rapidly than humans, much higher exposure levels may be needed in mouse studies to produce the diabetogenic effects of iAs commonly found in human populations exposed to iAs from environmental sources.

Arsenic induces diabetic effects through beta-cell dysfunction and increased gluconeogenesis in mice

Comparing the influences of inorganic arsenic on normal and diabetic mice by systems toxicology approaches suggested that iAs exposure could cause pre-diabetic effects by altering the lipid metabolism, gluconeogenesis and insulin secretion in normal individual, and worsen diabetic effects in diabetes individual by these processes.

Association between Arsenic Suppression of Adipogenesis and Induction of CHOP10 via the Endoplasmic Reticulum Stress Response

Low-level iAs and MMA3+ trigger the ER stress response and up-regulate CHOP10, which inhibits C/EBPβ transcriptional activity, thus suppressing adipogenesis, and arsenic-induced dysfunctional adipogenesis may be associated with a reduced capacity of WAT to store lipids and with insulin resistance.

In vitro toxic interaction of arsenic and hyperglycemia in mitochondria: an important implication of increased vulnerability in pre-diabetics

The results suggest that pre-diabetics with non-clinical hyperglycemia, who are inevitably exposed to low concentrations of arsenic through food and water, may develop mitochondrial dysfunction that accelerates their progression to diabetes over time.

The role of arsenic in obesity and diabetes

The currently available evidence is insufficient to conclude that low‐moderate dose arsenic is associated with diabetes or obesity development, and more investigations are needed to determine biological mechanisms linking arsenic exposure to obesity and diabetes.
...

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