Arsenic and diabetes mellitus: a putative role for the immune system

Figures & data

Figure 1. The process of development of DM. T1DM is characterized as a hypoinsulinemic and hyperglycemic state resulting from the autoimmune destruction of the islet beta-cells. T2DM is a hyperinsulinemic state initially to compensate insulin resistance in muscle, liver, and adipose tissues due to inflammatory responses or altered insulin receptor signaling; but over time insulin levels are reduced due to dysfunction of islet beta-cells, i.e. hypoinsulinemia. Hyperglycemic state remains in T2DM.

Figure 2. Main sources of exposure to arsenic for people. People can be exposed to arsenic through contaminated drinking-water and food, occupational exposures, and smoking tobacco.

Table 1. Effects of arsenic on the immune system.

Model	Arsenic exposure	Immune response to arsenic exposure	Major findings induced by arsenic exposure	References
Innate immune system
In humans:
A large population in West Bengal, India	Arsenic exposure through drinking water	Immunosuppressive	Increased the prevalence of cough, shortness of breath, and chest sounds (crepitations and/or rhonchi) in the lungs	Mazumder et al. (2000)
People in West Bengal, India	Arsenic exposure via ground water: urine arsenic averaged 642 µg/L	Immunosuppressive	Monocyte-derived macrophages cell rounding and reduced adhesion, nitric oxide anion production, and phagocytic capacity	Banerjee et al. (2009)
Pregnant women and their children in rural Bangladesh	Arsenic exposure via tubewell water	Immunosuppressive	Arsenic exposure was negatively correlated with child immunity (IL-7, lactoferrin and child thymic index), and positively associated with acute respiratory infections	Raqib et al. (2009)
Health Effects of Arsenic Longitudinal Study cohort in rural Bangladesh	Arsenic exposure via household water (0.6–326 µg/L)	Immunosuppressive	Early-life arsenic exposure disrupted the innate host defense pathway in children (plasma LL-37 levels, decreased MDM-mediated Spn killing and SBA responses, and PBMC formation of cytokines)	Parvez et al. (2019)
In rodent models:
Mouse model of bacteremic S. aureus infection	sodium arsenite (i.p. injection) at 0.5 mg/kg/d for 15 days	Immunosuppressive	Increased bacterial load in blood, decreased adhesion properties and phagocytic activity of splenic macrophages and delayed bacterial clearance by spleen	Bishayi and Sengupta (2003)
Pregnant mice	100 µg/L sodium arsenic via drinking water from gestation day 8 until birth.	Proinflammatory	Increased genes expression in the lung related to mucus production and innate immunity in their offspring	Ramsey, Bosco, et al. (2013)
Mouse model	drinking water exposures to sodium arsenite (100 µg/L or 500 µg/L) for 45–60 days	Immunosuppressive	Reduction of small intestinal CD4+ IELs (TCR$\text{α}\text{β}2$+, CD8$\text{α}\text{α}2$+) and mature macrophages of innate immune cell subsets	Medina et al. (2020)
In vitro models:
Murine keratinocyte cell line (HEL30)	sodium arsenate (0.5–100 µm)	Proinflammatory	cytokine (IL1$\text{α}2$) overproduction which promotes skin hyperkeratosis and cancer	Corsini et al. (1999)
HAPI microglia cells	arsenic trioxide (0.5–20 nm)	Proinflammatory	Upregulation of IL-6 in a dose- and time-dependent manner	Chen et al. (2016)
Macrophages derived from THP-1 cells	sodium arsenite (50 nM–500 nM)	Immunosuppressive	Suppression of pro-inflammatory cytokines (IL-1$\text{β}2$ and TNF-$\text{α}2$), nitric oxide, and phagocytosis	Xu et al. (2018)
Adaptive immune system
In humans:
Humans in Taiwan, China	Long-term exposure to arsenic through arsenic-tainted well water	Proinflammatory	Increased gene expression of inflammatory molecules (IL1B, IL6, CCL2/MCP1, MMP1 etc.) in circulating lymphocytes of people with intermediate (4.64–9.00 µg/L), and high (9.60–46.5 µg/L) levels of blood arsenic	Wu et al. (2003)
Cross-sectional study of children in a high arsenic polluted region in Mexico	Mean concentration in urine arsenic of 186.7 µg/L	Immunosuppressive	Reduced CD4 subpopulation proportion, CD4/CD8 ratio and IL-2 secretion	Soto-Pena et al. (2006)
Cross-sectional study in a high arsenic polluted region in India	Arsenic exposure via drinking water at the average level of 189.65 µg/L	Immunosuppressive	Decreased T-cell proliferation and secretion of cytokines (TNF-$\text{α}2$, IFN$\text{γ}2$, IL2, IL10, IL5 and IL4)	Biswas et al. (2008)
Copper smelter workers in Chile	Chronic arsenic exposure	Immunosuppressive	Lymphocyte oxidative damage with a positive correlation between urinary arsenic levels and oxidative stress markers	Escobar et al. (2010)
Male workers from nonferrous plants in the northeastern part of China	The subjects are separated into two groups: group 1 with urine total arsenic < 50 µg/g; group 2 with urine total arsenic ≥ 50 µg/g	Proinflammatory	Elevated concentrations of IL-8, TNF-$\text{α}2$, and TGF-$\text{α}2$ in urine in the high urinary arsenic workers (≥ 50 µg/g) compared with the low urinary arsenic workers (< 50 µg/g)	Liu, Sun, et al. (2014)
In rodent models:
Mice	Following a two-week inhalation exposure to arsenic trioxide at concentrations of 50 µg/m^3 and 1 mg/m^3	Immunosuppressive	T-dependent humoral immune response is highly susceptible to arsenic trioxide suppression	Burchiel et al. (2009)
Male ApoE-/- mice	Early post-natal exposure (3-week-old mice exposed to 49 mg/L arsenic as NaAsO2 in drinking water for 7–33 weeks) or adult exposure to 49 mg/L arsenic for 24 weeks	Proinflammatory	Increased oxidative stress, inflammation, and atherosclerotic lesion formation	Srivastava et al. (2009)
SKH-1 mice	via drinking water at 0, 50, 100 and 200 mg/L for 1 month	Proinflammatory	Enhanced ROS production, cutaneous inflammation-related p38/MAPKAPK-2 MAPK signaling, alterations in Th-1/Th-2/Th-17 cytokines/chemokines and their receptors	Li et al. (2011)
Rats	sodium arsenite (100 mg/L) through drinking water for 90 days	Proinflammatory	Increased production of pre-inflammatory mediators (IL-1$\text{β}2$, IL-6, MCP-1, VCAM, sICAM) and serum C-alterations	Kesavan et al. (2014)
In vitro models:
Isolated human peripheral blood mononuclear cells (PBMC)	sodium arsenite at 1 µM	Immunosuppressive	Reduced IL2 secretion, T cell proliferation and activity as well as immune and stress genes expression	Martin-Chouly et al. (2011)
Human bronchial epithelial (HBE) cells	sodium arsenite at 1.0 µM for 0, 10, 20, or 30 cell generations	Proinflammatory	Increased IL-6 secretion, activated STAT3 and miR-21 expression	Luo et al. (2013)
Human keratinocytes (HaCaT) cell line	Sodium arsenite at 1.0 µM for 30 cell passages	Proinflammatory	Increased IL-6 secretion, activated STAT3 and miR-21 expression	Lu et al. (2015)

Figure 3. Mechanisms of arsenic-induced effects on immunity in T1DM. Arsenic can promote the development of T1DM through direct pancreatic beta-cell destruction, gut microbiome alterations inducing abnormal autoimmune or inflammatory responses.

Figure 4. Mechanisms of arsenic interference of immunity in T2DM. Arsenic-induced T2DM is mainly through insulin resistance due to impairing the insulin signaling cascade, affecting oxidative stress and antioxidant pathways and inducing chronic inflammation; pancreatic beta-cell damage and dysfunction due to ROS production and enzymatic impairment; stimulation of liver gluconeogenesis due to Pck1 expression, among which the immune system is implicated to be involved in these processes.

Table 2. Molecular mechanisms of arsenic-induced immune dysfunction in T1DM.

Model	Arsenic exposure	Major findings	References
In humans:
Humans in a highly arsenic-contaminated district in West Bengal, India	Arsenic content in water at 202.68 ± 188.12 µg/L; in urine at 612.90 ± 336.91 µg/L	Secretion of inflammatory cytokines IL-6 and IL-8, and serum ANA levels (an autoimmunity marker)	Das et al. (2012)
Humans in five sites of US (South Carolina, Ohio, Colorado, California, and Washington)	Mean total Arsenic level at 83.1 ng/L in plasma	Low iAs% versus high monomethylated arsenic [MMA]% and dimethylated arsenic [DMA]% is associated with a higher odds of T1DM	Grau-Perez et al. (2017)
Children in Bangladeshi aged 4–6 years old	Mean drinking water arsenic concentration for the high and low exposed groups at 218.8 and 1.7 µg/L respectively	Alteration of the gut microbiome composition in early childhood	Dong et al. (2017)
In vivo rodent models:
Mice	Oral exposure to 10 mg/L arsenite for 4 weeks	Changes in composition of gut microbiota	Lu et al. (2014)
C57/BL6J mice	As2O3 at 1, 2 and 4 mg/L via drinking water for 12 weeks	Islet $\text{β}2$-cell destruction: impaired $\text{β}2$-cell function through endoplasmic reticulum stress-autophagy pathway	Wu et al. (2018)
C57BL/6 mice	sodium arsenite at 50 mg/L in drinking water for 6 months	Disruption in structure of intestinal tissues, the intestinal microbiome and metabolome	Li, Yang, et al. (2021)
In vitro models:
Murine pancreatic islets	48-hour exposures to low subtoxic concentrations of iAsIII, MAsIII or DMAsIII.	Islet $\text{β}2$-cell destruction: Inhibition of glucose stimulated insulin secretion	Douillet et al. (2013)
INS-1 cells	sodium arsenite at 0.25-1 µM for 96 h	Apoptosis of pancreatic beta-cells through inhibiting TrxR activity	Yao et al. (2015)

Table 3. Molecular mechanisms of arsenic-induced immune dysfunction in T2DM.

Model	Arsenic exposure	Major findings	References
Arsenic-induced insulin resistance and inhibition of glucose uptake:
3T3-L1 adipocytes	arsenite (up to 50 µM) and methylarsonous acid (up to 2 µM) for 4h	Inhibited ISGU by suppressing PKB/Akt phosphorylation	Walton et al. (2004)
3T3-L1 adipocytes	arsenite (up to 100 mM) and methylarsonous acid (up to 300 µM) for 4h	inhibited ISGU by inhibition of PDK-1/PKB/Akt-mediated transduction	Paul et al. (2007)
Mice	arsenite (up to 50 mg/L) or methylarsonous acid (up to 5 mg/L) in drinking water for 8 weeks	Impaired glucose tolerance by iAs^III	Paul et al. (2008)
3T3-L1 adipocytes	iAs^3+ up to 2 µM for 7 days	Suppressed glucose uptake by stimulating ROS accumulation and activation of NFE2L2 pathway, increased inflammatory response genes and decreased GLUT4 expression	Xue et al. (2011)
Mice	NaAsO2 orally 3 mg/kg body weight for 12 weeks	Cyto-degenerative effect and ROS accumulation in pancreatic beta-cells and hepatocytes; over-expression of TNF-$\text{α}2$ and IL6; impaired insulin signaling by reducing GLUT4, IRS1, IRS2, PI3 K, AKT and PPAR$\text{γ}2$	Chakraborty et al. (2012)
Mice	sodium arsenite at 5, 10 and 20 mg/kg, intra-gastrically	Activation of NFE2L2-mediated cellular antioxidant system in spleen, thymus, and PBMCs	Duan et al. (2015)
Mice 3T3L1 preadipocytes and C2C12 myotubes	arsenic at 0.5-2 µM for 8 weeks	Decreased insulin-stimulated glucose uptake and GLUT4 expression via oxidative stress-regulated mitochondrial Sirt3-FOXO3a signaling	Padmaja Divya et al. (2015)
Arsenic-induced beta-cell dysfunction:
Pancreatic beta-cells obtained from young adult male Wistar rats	sodium arsenite at 0.5, 1, 2, 5 and 10 µM for 72 and 144 h	Impaired pancreatic beta-cell insulin synthesis and secretion	Diaz-Villasenor et al. (2006)
Male Wistar rats	sodium arsenite orally at 1.7 mg/kg (12 h) for 90 days	Induced oxidative stress, pancreas damage, and insulin resistance	Izquierdo-Vega et al. (2006)
Hamster pancreatic HIT-T15 beta-cell; ICR mice	In HIT-T15 beta-cells, at 1–10 µM for 24 h; in mice, As2O3 at 10 mg/L in drinking water for 12 weeks	In HIT-T15 cells, induced oxidative stress. In mice, induced sub-acute peri-pancreatitis and islet damage	Yen et al. (2007)
RINm5F rat pancreatic beta-cell	Sodium arsenite (up to 5 µM) for 72 h	Impaired insulin secretion by decreasing the oscillations of [Ca^2±]i and calpain-10 partial proteolysis of SNAP-25	Diaz-Villasenor, Burns, et al. (2008)
INS-1(832/13) cells	Arsenite at 0.05–0.5 µM for 96 h	Activation of NFE2L2 and oxidative stress response, dampened ROS signaling, decreased GSIS and disturbed beta-cell function	Fu et al. (2010)
Pancreatic beta-cell-derived RIN-m5F cells and male ICR mice	As2O3 at 10 µm in RIN-m5F cells; at 5 mg/L in drinking water in mice for 6 weeks	Decreased insulin secretion and cell viability, increased beta-cell apoptosis	Lu et al. (2011)
Normal and male C57BKS/Leprdb (db/db) mice	sodium arsenite at 3 mg/L for 16 weeks	Increased gluconeogenesis, pancreatic beta-cell dysfunction, and oxidative damages in pancreas in both normal and diabetic mice	Liu, Guo, et al. (2014)
INS-1 cells	sodium arsenite at 0.25–1µM for 96 h	Apoptosis through inhibiting TrxR activity in pancreatic beta-cells	Yao et al. (2015)
INS-1 cells	sodium arsenite at 10 µm for 72 h	Increased ROS, reduced mitochondrial membrane potential, disrupted lysosomal membrane integrity, and induced pancreatic beta-cell apoptosis	Pan et al. (2016)
Arsenic-associated stimulation of gluconeogenesis:
Chick embryo in vivo and rat hepatoma H411E cells in culture	sodium arsenite at 100 µM/kg in vivo and 0.33 µM in cells	Increased both basal and hormone-induced Pck1 gene expression in chick embryo and H411E cells	Hamilton et al. (1998)
Mice	As2O3 at 0.05 or 0.5 mg/L via drinking water for 2–6 weeks	Increased hepatic gluconeogenesis by up-regulating Pck1 gene expression	Huang et al. (2015)
Arsenic induced inflammatory cytokines:
Humans in Taiwan, China	Subjects with low (0–4.32 µg/L), intermediate (4.64–9.00 µg/L), and high (9.60–46.5 µg/L) levels of blood arsenic	Elevated gene expressions of IL1B, IL6 chemokine C-C motif ligand 2/monocyte chemotactic protein-1 (CCL2/MCP1), chemokine C-X-C motif ligand 1/growth-related oncogene alpha, chemokine C-X-C motif ligand 2/growth-related oncongene beta, CD14, and matrix MMP1	Wu et al. (2003)
Pregnant women from a longitudinal, mother–child cohort in Matlab, Bangladesh	The median Urine arsenic concentrations at GW8 and GW30 were at 66 and 60 µg/L respectively	Enhanced placental inflammatory responses (IL1$\text{β}2$, TNF-$\text{α}2$, and IFN$\text{γ}2$), reduced placental T cells, and altered cord blood cytokines (IL1$\text{β}2$, IL8, IFN$\text{γ}2$, TNF-$\text{α}2$)	Ahmed et al. (2011)
Pregnant women in the New Hampshire area in US	High level (> 5 µg/L in water, and > 5 µg/L in urine) and low level (< 0.5 µg/L in water, and < 5 µg/L in urine)	Maternal urinary arsenic concentrations are related to impaired function of T-cell in cord blood; in placental samples, higher in utero urinary arsenic concentrations are positively associated with IL1$\text{β}2$ expression	Nadeau et al. (2014)

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Data availability statement

No data were generated for this review manuscript.