The potential biological mechanisms of arsenic-induced diabetes mellitus
- PMID: 15163543
- DOI: 10.1016/j.taap.2004.02.009
The potential biological mechanisms of arsenic-induced diabetes mellitus
Abstract
Although epidemiologic studies carried out in Taiwan, Bangladesh, and Sweden have demonstrated a diabetogenic effect of arsenic, the mechanisms remain unclear and require further investigation. This paper reviewed the potential biological mechanisms of arsenic-induced diabetes mellitus based on the current knowledge of the biochemical properties of arsenic. Arsenate can substitute phosphate in the formation of adenosine triphosphate (ATP) and other phosphate intermediates involved in glucose metabolism, which could theoretically slow down the normal metabolism of glucose, interrupt the production of energy, and interfere with the ATP-dependent insulin secretion. However, the concentration of arsenate required for such reaction is high and not physiologically relevant, and these effects may only happen in acute intoxication and may not be effective in subjects chronically exposed to low-dose arsenic. On the other hand, arsenite has high affinity for sulfhydryl groups and thus can form covalent bonds with the disulfide bridges in the molecules of insulin, insulin receptors, glucose transporters (GLUTs), and enzymes involved in glucose metabolism (e.g., pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase). As a result, the normal functions of these molecules can be hampered. However, a direct effect on these molecules caused by arsenite at physiologically relevant concentrations seems unlikely. Recent evidence has shown that treatment of arsenite at lower and physiologically relevant concentrations can stimulate glucose transport, in contrary to an inhibitory effect exerted by phenylarsine oxide (PAO) or by higher doses of arsenite. Induction of oxidative stress and interferences in signal transduction or gene expression by arsenic or by its methylated metabolites are the most possible causes to arsenic-induced diabetes mellitus through mechanisms of induction of insulin resistance and beta cell dysfunction. Recent studies have shown that, in subjects with chronic arsenic exposure, oxidative stress is increased and the expression of tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) is upregulated. Both of these two cytokines have been well known for their effect on the induction of insulin resistance. Arsenite at physiologically relevant concentration also shows inhibitory effect on the expression of peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear hormone receptor important for activating insulin action. Oxidative stress has been suggested as a major pathogenic link to both insulin resistance and beta cell dysfunction through mechanisms involving activation of nuclear factor-kappaB (NF-kappaB), which is also activated by low levels of arsenic. Although without supportive data, superoxide production induced by arsenic exposure can theoretically impair insulin secretion by interaction with uncoupling protein 2 (UCP2), and oxidative stress can also cause amyloid formation in the pancreas, which could progressively destroy the insulin-secreting beta cells. Individual susceptibility with respect to genetics, nutritional status, health status, detoxification capability, interactions with other trace elements, and the existence of other well-recognized risk factors of diabetes mellitus can influence the toxicity of arsenic on organs involved in glucose metabolism and determine the progression of insulin resistance and impaired insulin secretion to a status of persistent hyperglycemia or diabetes mellitus. In conclusions, insulin resistance and beta cell dysfunction can be induced by chronic arsenic exposure. These defects may be responsible for arsenic-induced diabetes mellitus, but investigations are required to test this hypothesis.
Similar articles
-
Arsenic-induced alteration in the expression of genes related to type 2 diabetes mellitus.Toxicol Appl Pharmacol. 2007 Dec 1;225(2):123-33. doi: 10.1016/j.taap.2007.08.019. Epub 2007 Aug 31. Toxicol Appl Pharmacol. 2007. PMID: 17936320 Review.
-
[Amylin as an additional possible pathogenic factor in NIDDM and the insulin resistance syndrome].Vnitr Lek. 1996 Aug;42(8):557-60. Vnitr Lek. 1996. PMID: 8967027 Review. Slovak.
-
Interleukin-1 beta induced transient diabetes mellitus in rats. A model of the initial events in the pathogenesis of insulin-dependent diabetes mellitus?Dan Med Bull. 1998 Apr;45(2):157-80. Dan Med Bull. 1998. PMID: 9587701 Review.
-
Diabetes and mitochondrial function: role of hyperglycemia and oxidative stress.Toxicol Appl Pharmacol. 2006 Apr 15;212(2):167-78. doi: 10.1016/j.taap.2006.01.003. Epub 2006 Feb 20. Toxicol Appl Pharmacol. 2006. PMID: 16490224 Review.
-
Recent advances in the relationship between obesity, inflammation, and insulin resistance.Eur Cytokine Netw. 2006 Mar;17(1):4-12. Eur Cytokine Netw. 2006. PMID: 16613757 Review.
Cited by
-
Invited Perspective: Humanized Mice for Arsenic Metabolism-A Better Model for Investigating Arsenic-Induced Diseases?Environ Health Perspect. 2023 Dec;131(12):121308. doi: 10.1289/EHP13932. Epub 2023 Dec 27. Environ Health Perspect. 2023. PMID: 38150314 Free PMC article. No abstract available.
-
Associations between metals and metabolomic profiles related to diabetes among adults in a rural region.Environ Res. 2024 Feb 15;243:117776. doi: 10.1016/j.envres.2023.117776. Epub 2023 Dec 2. Environ Res. 2024. PMID: 38043890
-
Association Between Arsenic Toxicity, AS3MT Gene Polymorphism and Onset of Type 2 Diabetes.Biol Trace Elem Res. 2024 Apr;202(4):1550-1558. doi: 10.1007/s12011-023-03919-2. Epub 2023 Oct 27. Biol Trace Elem Res. 2024. PMID: 37889428
-
Metabolomics Analysis and Biochemical Profiling of Arsenic-Induced Metabolic Impairment and Disease Susceptibility.Biomolecules. 2023 Sep 20;13(9):1424. doi: 10.3390/biom13091424. Biomolecules. 2023. PMID: 37759824 Free PMC article.
-
Trichoderma and Nanotechnology in Sustainable Agriculture: A Review.Front Fungal Biol. 2021 Dec 1;2:764675. doi: 10.3389/ffunb.2021.764675. eCollection 2021. Front Fungal Biol. 2021. PMID: 37744133 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Medical
Research Materials