Evaluation of the Association Between Arsenic and Diabetes

A National Toxicology Program Workshop Review

Elizabeth A. Maull; Habibul Ahsan; Joshua Edwards; Matthew P. Longnecker; Ana Navas-Acien; Jingbo Pi; Ellen K. Silbergeld; Miroslav Styblo; Chin-Hsiao Tseng; Kristina A. Thayer; Dana Loomis

Disclosures

Environ Health Perspect. 2012;120(12):1658-1670. 

In This Article

Mechanisms

A number of in vitro studies implicate several pathways by which arsenic can influence pancreatic β-cell function and insulin sensitivity, including oxidative stress, glucose uptake and transport, gluconeogenesis, adipocyte differentiation, and Ca2+ signaling (reviewed by Díaz-Villaseñor et al. 2007; Druwe and Vaillancourt 2010; Tseng 2004; see also Figure 3). Several of these pathways are discussed in more detail below, but in general the studies fall into the following categories: a) studies that use high concentrations of arsenic (≥ 1 mM) to examine stress response in various cell types, although the concentrations used limit interpretation because they are not considered physiologically relevant, resulting in cytotoxicity; b) studies that test lower concentrations (< 100 μM) of arsenic and report inhibition of insulin signaling and insulin-dependent glucose uptake by adipocytes or myotubes (Paul et al. 2007b; Walton et al. 2004; Yen et al. 2010); and c) studies in insulinoma cell lines or isolated pancreatic islets that suggest that the mechanisms by which arsenic affects β-cells to inhibit insulin expression and/or secretion are concentration dependent (Díaz-Villaseñor et al. 2006, 2008; Fu et al. 2010; Pi et al. 2007). At relatively low concentrations (in the submicromolar range) certain adaptive cellular responses to arsenic-induced oxidative stress [i.e., induction of antioxidant enzymes and reduced reactive oxygen species (ROS)] may result in an impairment of glucose-stimulated insulin secretion (Fu et al. 2010; Pi et al. 2007). High concentrations result in irreversible damage (including oxidative damage) to β-cells followed by apoptosis or necrosis (Macfarlane et al. 1997, 1999; Ortsater et al. 2002).

Figure 3.

In vitro studies related to arsenic and diabetes. Abbreviations: Δ, cytotoxicity reported at specified concentration level; aP2, fatty acid-binding protein; As2O3, arsenic trioxide; AsIII, arsenite; AsV, arsenate; Ca, calcium; C/EBPα, CCAAT/enhancer binding protein (C/EBP alpha); DMAIII oxide, dimethylarsine oxide; DMAV, dimethylarsinate; HIF1a, hypoxia inducible factor, alpha; HO1, heme oxygenase 1; IUF1, insulin upstream factor 1 (also known as PDX1); KLF5, Kruppel-like factor 5; MAPKAP-K2, mitogen-activated protein kinase-activated protein kinase 2; MAsIII oxide, methylarsine oxide; MAsV, monosodium methylarsonate; Nrf2, transcription factor NF-E2–related factor 2; PDX1, pancreatic and duodenal homeobox 1 (also known as IUF1); PhAsO, oxophenylarsine; PPARγ, peroxisome proliferator-activated receptor γ; ROS, reactive oxygen species.
*p < 0.05; doses at which statistically significant effects were observed.

Influence of Inorganic Arsenic on Glucose-stimulated Insulin Secretion in Pancreatic β-cells

Chronic oxidative stress leading to oxidative damage has long been implicated in β-cell dysfunction in diabetes. Oxidative stress is also implicated in many aspects of arsenic toxicity, and a recent in vitro study suggests that transcription factor NF-E2–related factor 2 (Nrf2)-mediated antioxidant response may influence arsenite-induced impairment of glucose-stimulated insulin secretion in β-cells at low concentrations of arsenite (Fu et al. 2010). The transcription factor Nrf2 is a key cellular component that defends cells against toxicities of oxidants and electrophiles by regulating both constitutive and inducible expression of many antioxidant/detoxification enzymes (Fu et al. 2010; He and Ma 2010). Although antioxidants are generally considered protective for cells, this same Nrf2-driven induction of endogenous antioxidant enzymes meant to maintain intracellular redox homeostasis and limit oxidative damage may also have a negative impact on insulin secretion by diminishing the availability of ROS, such as hydrogen peroxide (H2O2). Reactive oxygen species' signals produced during glucose metabolism are becoming recognized as intracellular regulators of glucose-stimulated insulin secretion acting to increase insulin secretion (Leloup et al. 2009; Pi et al. 2007, 2010).

Thus, the Nrf2-mediated antioxidant response appears to play paradoxical roles in β-cell function by a) blunting glucose-triggered ROS signaling and thus resulting in reduced glucose-stimulated insulin secretion, and b) protecting β-cells from oxidative damage and subsequent apoptosis/necrosis (Fu et al. 2010). Chronic exposure to inorganic arsenic and the production of its methylated trivalent metabolites have been linked to oxidative stress; however, at the levels generally expected in low-to-moderate human exposures, they are not likely to reach cytotoxic concentrations sufficient to cause irreversible damage, although at these levels they may activate Nrf2. Therefore, premise a above is potentially more relevant to β-cell dysfunction in the context of low-level environmental arsenic exposure, whereas premise b might be associated with β-cell damage and failure induced by high doses of arsenic.

Influence of Trivalent Arsenicals on Glucose Uptake in Adipocytes and Skeletal Muscle Cells

Type 2 diabetes is characterized by disruptions in whole-body glucose homeostasis due to insulin resistance and impaired glucose utilization by peripheral tissues, including skeletal muscle and adipose tissue. Results of tissue culture studies suggest that arsenite and/or its methylated trivalent metabolites cause insulin resistance in adipocytes by inhibiting insulin signaling and insulin-activated glucose uptake. Arsenite can also interfere with the formation of insulin-sensitive adipocytes and myotubes by inhibiting adipogenic and myogenic differentiation (Salazard et al. 2004; Trouba et al. 2000; Walton et al. 2004; Yen et al. 2010).

Arsenite and its metabolites interact with a number of elements involved in insulin signaling, including insulin receptor substrate (IRS), phosphatidylinositol-3 kinase (PI3K), AKT, phosphoinositide-dependent kinase (PDK), and protein kinase C (PKC). AKT belongs to a class of enzymes important in regulating glucose metabolism, cell proliferation, apoptosis, transcription, and cell migration (Paul et al. 2007a; Walton et al. 2004). Insulin stimulates glucose uptake by binding to the insulin receptor and activating the IRS-1, IRS-2, PI3K, PDK, AKT, and/or PKC-ζ/PKC-λ signaling pathway(s) (Choi and Kim 2010; Standaert et al. 1999). Activation of PKC-ζ and PKC-λ stimulates Ras-related protein (RAB4A) activity, the association of RAB4A with kinesin-like protein KIF3B, and the interaction of KIF3B with microtubules. This process is essential for recruitment of glucose transporter type 4 (GLUT4) to the cytoplasmatic membrane and for insulin-dependent glucose uptake (Imamura et al. 2003; Lee et al. 2010). Subcytotoxic concentrations in the micromolar range of arsenite and its methylated trivalent metabolites, MMAIII and DMAIII, inhibit insulin-stimulated glucose uptake in cultured adipocytes by interfering with the phosphorylation of AKT-dependent mobilization of GLUT4. Arsenite and MMAIII inhibit PDK-catalyzed phosphorylation of AKT in the insulin signaling cascade; DMAIII inhibits GLUT4 translocation by interfering with the signaling step(s) downstream from AKT (Paul et al. 2007a; Walton et al. 2004). The adaptive antioxidant response associated with prolonged exposure to relatively low concentrations of arsenite in the 1–2 μM range have also been associated with suppression of insulin-stimulated AKT phosphorylation and glucose uptake in 3T3-L1 adipocytes causing an insulin resistant phenotype (Xue et al. 2011).

Insulin resistance is a hallmark of diabetes and the role of adipocytes in mediating insulin resistance is an active area of research. A number of studies have assessed the impact of arsenic on adipocytes. Arsenite inhibits and reverses differentiation of adipocytes by disrupting the expression of the genes involved in adipogenesis (Wauson et al. 2002). Expression of both peroxisome proliferator-activated receptor-γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα) is required for phenotypic differentiation of adipocytes, and arsenite inhibits expression of both of these transcription factors. Arsenite disrupts the interaction between PPARγ and its coactivator retinoid X receptor alpha (RXRα). Arsenic trioxide also inhibits AKT binding to PPARγ (Wang et al. 2005). Inhibition of these transcription factors reduces expression of PPARγ and C/EBPα target genes: adipocyte fatty acid binding protein (A-FABP), which is involved in preadipocyte differentiation, and p21, a protein whose expression is tightly regulated during adipogenesis (Wang et al. 2005; Wauson et al. 2002). Inhibition of p21 leads to activation of preadipocyte proliferation, thereby inhibiting adipocyte differentiation (Wang et al. 2005).

Myogenesis is associated with the development of the insulin-responsive glucose transport system and there are indications that arsenite may have similar effects on myogenic differentiation; however, this has not been studied to the same extent as its effects on adipocytes. Pathways mediating muscle differentiation include insulin-dependent activation of AKT/mTOR/p70 S6 kinase1/MEF2C/MYOD/MYOG signaling (Conejo et al. 2002; Xu and Wu 2000). Low concentrations (e.g, 20 nM) of arsenite have been shown to delay the differentiation of muscle cells from myoblasts to myotubes by repressing the transcription factor myogenin (Steffens et al. 2010). Arsenite also significantly decreases the phosphorylation of AKT and its downstream targets, mTOR and p70 S6 kinase1 proteins, during myogenic differentiation (Yen et al. 2010). Inhibition of AKT by arsenite was also demonstrated in muscle cells (Yen et al. 2010), and may lead to a reduction in glucose uptake in this tissue (Díaz-Villaseñor et al. 2007).

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