Arsenic exposure and type 2 diabetes: a systematic review of the experimental and epidemiologic evidence.
Chronic arsenic arsenic (är`sənĭk), a semimetallic chemical element; symbol As; at. no. 33; at. wt. 74.9216; m.p. 817°C; (at 28 atmospheres pressure); sublimation point 613°C;; sp. gr. (stable form) 5.73; valence −3, 0, +3, or +5. exposure has been suggested to contribute to diabetes development. We performed a systematic review of the experimental and epidemiologic evidence on the association of arsenic and type 2 diabetes type 2 diabetes
See diabetes mellitus. . We identified 19 in vitro in vitro /in vi·tro/ (in ve´tro) [L.] within a glass; observable in a test tube; in an artificial environment.
In an artificial environment outside a living organism. studies of arsenic and glucose metabolism glucose metabolism,
n the process by which simple sugars found in many foods are processed and used to produce energy in the form of ATP. Once consumed, glucose is absorbed by the intestines and into the blood. . Five studies reported that arsenic interfered with transcription factors This article or section may be confusing or unclear for some readers.
Please or discuss this issue on the talk page. involved in insulin-related gene expression: upstream factor 1 in pancreatic pancreatic /pan·cre·at·ic/ (pan?kre-at´ik) pertaining to the pancreas.
pertaining to the pancreas. See also pancreatitis, diabetes mellitus, cystic pancreatic duct. [beta]-cells and peroxisome Peroxisome
An intracellular organelle found in all eukaryotes except the archezoa (original lifeforms). In electron micrographs, peroxisomes appear round with a diameter of 0.1–1. proliferative-activated receptor [gamma] in preadipocytes. Other in vitro studies assessed the effect of arsenic on glucose uptake Glucose uptake is the process by which glucose is transported into cells through active transport. Though some glucose does enter cells through passive diffusion, the process is too slow to allow for adequate control of blood glucose levels and energy utilization. , typically using very high concentrations of arsenite or arsenate ar·se·nate
A salt of arsenic acid.
an uncommon garden pesticide, as lead arsenate, or as antifungal spray on fruit trees or cattle tick dip as sodium arsenate. . These studies provide limited insight on potential mechanisms. We identified 10 in vivo in vivo /in vi·vo/ (ve´vo) [L.] within the living body.
Within a living organism.
in vivo adv. studies in animals. These studies showed inconsistent effects of arsenic on glucose metabolism. Finally, we identified 19 epidemiologic studies epidemiologic study A study that compares 2 groups of people who are alike except for one factor, such as exposure to a chemical or the presence of a health effect; the investigators try to determine if any factor is associated with the health effect (6 in high-arsenic areas in Taiwan and Bangladesh, 9 in occupational populations, and 4 in other populations). In studies from Taiwan and Bangladesh, the pooled relative risk estimate for diabetes comparing extreme arsenic exposure categories was 2.52 (95% confidence interval confidence interval,
n a statistical device used to determine the range within which an acceptable datum would fall. Confidence intervals are usually expressed in percentages, typically 95% or 99%. , 1.69-3.75), although methodologic problems limit the interpretation of the association. The evidence from occupational studies and from general populations other than Taiwan or Bangladesh was inconsistent. In summary, the current available evidence is inadequate to establish a causal role of arsenic in diabetes. Because arsenic exposure is widespread and diabetes prevalence is reaching epidemic proportions, experimental studies using arsenic concentrations relevant to human exposure and prospective epidemiologic studies measuring arsenic biomarkers and appropriately assessing diabetes should be a research priority. Key words: arsenic, diabetes, glucose metabolism, meta-analysis, systematic review.
Type 2 diabetes mellitus Type 2 diabetes mellitus
One of the two major types of diabetes mellitus, characterized by late age of onset (30 years or older), insulin resistance, high levels of blood sugar, and little or no need for supple-mental insulin. is a metabolic disorder Noun 1. metabolic disorder - a disorder or defect of metabolism
disorder, upset - a physical condition in which there is a disturbance of normal functioning; "the doctor prescribed some medicine for the disorder"; "everyone gets stomach upsets from time to time" characterized by hyperglycemia hyperglycemia: see diabetes. , insulin resistance Insulin Resistance Definition
Insulin resistance is not a disease as such but rather a state or condition in which a person's body tissues have a lowered level of response to insulin, a hormone secreted by the pancreas that helps to regulate the level in peripheral tissues, and altered insulin secretory secretory /se·cre·to·ry/ (se-kre´tah-re) (se´kre-tor?e) pertaining to secretion or affecting the secretions.
Relating to or performing secretion. capacity of pancreatic [beta]-cells. Type 2 diabetes accounts for 90-95% of all cases of diabetes and is a major public health problem worldwide (Wild et al. 2004). Established risks factors of type 2 diabetes include older age, obesity, physical inactivity physical inactivity A sedentary state. Cf Physical activity. , family history, and genetic polymorphisms. In addition, environmental toxicants, including arsenic, have been suggested to play an etiologic role in diabetes development (Longnecker and Daniels 2001).
Arsenic is a recognized toxicant toxicant /tox·i·cant/ (tok´si-kant)
1. A poison or poisonous agent.
2. An intoxicant.
adj. and carcinogen carcinogen: see cancer.
Agent that can cause cancer. Exposure to one or more carcinogens, including certain chemicals, radiation, and certain viruses, can initiate cancer under conditions not completely understood. . Nonoccupational exposure occurs mainly through drinking water drinking water
supply of water available to animals for drinking supplied via nipples, in troughs, dams, ponds and larger natural water sources; an insufficient supply leads to dehydration; it can be the source of infection, e.g. leptospirosis, salmonellosis, or of poisoning, e.g. , affecting millions of people worldwide. Exposure to levels of arsenic in drinking water well above 100 ppb ppb
parts per billion has been associated with an increased risk of type 2 diabetes in the high-arsenic areas of Taiwan and Bangladesh (Lai et al. 1994; Rahman et al. 1998). The biological mechanisms for an association between chronic arsenic exposure and increased diabetes risk are not known [National Research Council (NRC NRC
1. National Research Council
2. Nuclear Regulatory Commission
Noun 1. NRC - an independent federal agency created in 1974 to license and regulate nuclear power plants ) 1999, 2001; Tseng 2004].
Previous reviews of the role of arsenic in diabetes have questioned the quality of the evidence but were supportive of the possibility of an association [NRC 1999, 2001; Ng 2001; Tseng 2004; Tseng et al. 2000, 2002; World Health Organization (WHO) 2001]. These reviews, however, did not use systematic review criteria and may be subject to biased selection of the evidence. Our objective was to perform a systematic review of the experimental and epidemiologic evidence on arsenic and type 2 diabetes. We examined experimental studies (in vitro or in vivo) to synthesize To create a whole or complete unit from parts or components. See synthesis. available information on plausible mechanisms for the effect of arsenic on glucose metabolism, as well as epidemiologic studies to synthesize the association of arsenic exposure with diabetes risk in humans.
Materials and Methods
Search strategy and study selection. We searched the Medline database (http:// www.ncbi.nlm.nih.gov/entrez/query. fcgi?db=PubMed) and the TOXNET TOXNET Toxicology Data Network database [consisting of TOXLINE TOXLINE Toxicology Information Online , GENETOX, and DART/ETIC (Developmental and Reproductive Toxicology/Environmental Teratogen teratogen /ter·a·to·gen/ (ter´ah-to-jen) any agent or factor that induces or increases the incidence of abnormal prenatal development.teratogen´ic
n. Information Center); http:// toxnet.nlm.nih.gov/] from 1966 through July 2005 using free text and the medical subject headings (MESH) arsenic, arsenite, arsenate, arsenicals, diabetes, glucose, glycosylated hemoglobin gly·co·sy·lat·ed hemoglobin
Any of four hemoglobin fractions that together account for less than 4 percent of the total hemoglobin in the blood. , insulin, and mortality. In addition, we manually reviewed the reference lists from relevant original research and review articles.
For experimental studies, we identified in vitro or in vivo studies of the administration of arsenic or arsenic compounds, including inorganic arsenite (trivalent trivalent /tri·va·lent/ (tri-va´lent) having a valence of three.
Having valence 3.
tri·va arsenic), inorganic arsenate (pentavalent pentavalent
having a valence of five.
pentavalent antimony compounds
pentavalent organic arsenicals
includes the pharmaceuticals arsanilic acid, roxarsone, nitarsone. See also organic arsenical. arsenic), and others, and outcomes related to diabetes status or glucose and insulin metabolism. For epidemiologic studies, we identified studies assessing arsenic exposure through measures of environmental samples, biomarkers, or indirect measures (e.g., job titles reflecting occupational exposure or living in areas with known exposure via drinking water) and diabetes status or markers of glucose metabolism.
The exclusion criteria exclusion criteria AIDS Donor exclusion criteria, see there for experimental and epidemiologic studies were a) no original research (reviews, editorials, nonresearch letters); b) studies performed only on people with diabetes, including case reports; c) lack of outcomes related to diabetes or glucose metabolism; d) no data on arsenic exposure; e) experiments in nonmammalian cells, or noncellular experiments; f) animal studies administering a single dose of arsenic; and g) culture cell experiments using lewisite lewisite (l`əsīt'), liquid chemical compound used as a poison gas. Like mustard gas and nitrogen mustard, it is a blistering agent; when inhaled, it is a powerful respiratory or oxophenylarsine. Figure 1 summarizes the study selection process.
[FIGURE 1 OMITTED]
Two investigators (A.N.-A., R.A.S.) independently abstracted the articles that met the selection criteria. Discrepancies were resolved by consensus. We converted all arsenic concentrations to parts per million parts per million
mg/kg or ml/l; see ppm. or parts per billion, including concentrations from in vitro studies, which were usually reported in molar molar /mo·lar/ (mo´lar)
1. pertaining to a mole of a substance.
2. a measure of the concentration of a solute, expressed as the number of moles of solute per liter of solution. Symbol M, , or mol/L. units of arsenic (1 [micro]M of arsenic = 74.9 [micro]g/L = 74.9 ppb).
Statistical methods. Measures of association in epidemiologic studies (odds ratios, prevalence ratios, standardized mortality ratios The standardized mortality ratio or SMR in epidemiology is the ratio of observed deaths to expected deaths according to a specific health outcome in a population and serves as an indirect means of adjusting a rate. , relative risks, relative hazards, comparisons of means) and their SE values were abstracted or derived using data reported in the articles (Greenland 1987). Within each study, we used the model adjusted for the most covariates. Adjustment did not substantially modify the conclusions of any individual study. For five studies, we used data available in the original articles to derive relative risk estimates. For one study (Lagerkvist and Zetterlund 1994), because there were no cases among the unexposed, we added 0.5 to each cell to estimate the relative risk and the 95% confidence interval (CI). For Jensen and Hansen (1998), we compared the proportion of subjects with glycosylated hemoglobin above 7% across occupational exposure categories. For Ward and Pim (1984) and Ruiz-Navarro et al. (1998), we used the linear discriminant function discriminant function
A function of a set of variables used to classify an object or event. method to estimate relative risks from comparisons of means (Greenland 1987). Finally, for Lewis et al. (1999), we estimated the relative risk of diabetes mortality comparing the highest with the lowest category of exposure within the cohort from the published standardized mortality ratios.
We grouped the studies in three categories: studies in general populations exposed to high arsenic levels, corresponding to studies in Taiwan and Bangladesh with average levels in drinking water well above 100 ppb; studies in occupational populations exposed to high arsenic levels most commonly in ambient air; and studies in general populations exposed to low or moderate levels of arsenic in drinking water (< 100 ppb), food, or ambient air. Because of substantial heterogeneity het·er·o·ge·ne·i·ty
The quality or state of being heterogeneous.
the state of being heterogeneous. and methodologic limitations, we present a qualitative systematic review, and we used only meta-analysis techniques for studies from Taiwan and Bangladesh. For descriptive purposes, we report the range and the unweighted medians of the relative risk of diabetes comparing extreme categories of arsenic exposure in each study.
In Vitro Experimental Studies
Nineteen in vitro studies published between 1965 and 2004 met our inclusion criteria
Inclusion criteria are a set of conditions that must be met in order to participate in a clinical trial. (Figure 1, Table 1). None of the experimental studies were conducted in human cell lines. Five experiments investigated the effect of arsenic on insulin signal transduction Signal transduction
The transmission of molecular signals from a cell's exterior to its interior. Molecular signals are transmitted between cells by the secretion of hormones and other chemical factors, which are then picked up by different cells. and gene expression. Three studies were performed in transfected mouse pancreatic [beta]-cells, where exposure to high arsenite concentrations was similar to high glucose in stimulating insulin upstream factor 1 (IUF-1) (Macfarlane MacFarlane or Macfarlane is a surname shared by:
Portion of a eukaryotic cell outside the nucleus. The cytoplasm contains all the organelles (see eukaryote). to the nucleus (Elrick and Docherty 2001; Macfarlane et al. 1999). IUF-1, also called homeodomain transcription factor PDX PDX Product Data Exchange (file name extension; XML technology)
PDX Paradox Files (file name extension)
PDX Product Definition Exchange
PDX Phone Data Exchange (Proxon) 1, is a transcription factor that binds to the human insulin human insulin
A protein that has the normal structure of insulin produced by the human pancreas but that is prepared by recombinant DNA techniques and by semisynthetic processes. gene promoter and increases insulin messenger RNA mes·sen·ger RNA
See mRNA. levels in response to glucose. The effect of high glucose or arsenite was prevented by SB 203580, a specific inhibitor of stress-activated protein kinase-2 (SAPK SAPK Stress-Activated Protein Kinase 2)/p38, whereas the effect of high glucose but not of arsenite was prevented by substances that specifically inactivate in·ac·ti·vate
1. To render nonfunctional.
2. To make quiescent.
in·acti·va phosphatidylinositol-3 kinase kinase /ki·nase/ (ki´nas)
1. a subclass of the transferases, comprising the enzymes that catalyze the transfer of a high-energy group from a donor (usually ATP) to an acceptor.
2. (wortmannin and LY294002). Two other studies (Salazard et al. 2004; Wauson et al. 2002) investigated the role of arsenite in adipocyte adipocyte /ad·i·po·cyte/ (-sit?) fat cell.
See fat cell.
adipocyte differentiation and peroxisome proliferative-activated receptor [gamma] (PPAR PPAR Peroxisome Proliferator Activated Receptor
PPAR Physical Partitions [gamma]) expression. PPAR[gamma] is a transcription factor that regulates key gene expression for insulin sensitivity insulin sensitivity The systemic responsiveness to glucose, which can be measured by 1. The insulin sensitivity index–measures the ability of endogenous insulin to ↓ glucose in extracellular fluids by inhibiting glucose release from the liver and . These two experiments used different concentrations and lengths of exposure and produced opposite results. In the study by Salazard et al. (2004), the incubation of 3T3-F442A preadipocytes with 1.7 and 3 ppb (0.25 and 0.5 [micro]M) arsenite for 3 days induced the expression of PPAR[gamma] and CCAAT/ enhancer binding protein. In study by Wauson et al. (2002), the incubation of C3H C3H Coumarate 3 Hydroxylase 101T1/2 cells with 450 ppb (6 [micro]M) arsenite for 2 months prevented adipocyte differentiation through the inhibition of the PPAR[gamma]. Arsenite also inhibited the differentiating effect induced by pioglitazone, a PPAR[gamma] agonist agonist /ag·o·nist/ (ag´ah-nist)
1. one involved in a struggle or competition.
2. agonistic muscle.
3. used to reduce insulin resistance.
The rest of the in vitro studies assessed the effect of arsenic on glucose uptake, typically using very high concentrations of arsenite as general inducers of cellular stress. Ten studies measured basal glucose uptake (in the absence of insulin) in cell lines exposed to arsenite or other compounds (Table 1, Figure 2). Four of the studies also exposed the cells simultaneously to insulin and arsenite (Table 2). Compared with insulin alone, simultaneous exposure to insulin and arsenite decreased glucose uptake in insulin-sensitive cells (Bazuine et al. 2003; Walton et al. 2004). One of the studies (Walton et al. 2004) measured basal and insulin-stimulated glucose uptake in cells exposed to arsenate and to methylated meth·yl·ate
An organic compound in which the hydrogen of the hydroxyl group of methyl alcohol is replaced by a metal.
tr.v. meth·yl·at·ed, meth·yl·at·ing, meth·yl·ates
1. arsenic compounds. Methylarsine oxide ([MAs.sup.III]O) inhibited insulin-stimulated glucose uptake at the concentration of 75 ppb after 4- or 24-hr exposure (Walton et al. 2004). For arsenite, because the concentrations used in glucose uptake studies were extremely high, their relevance to diabetes development in humans is questionable.
[FIGURE 2 OMITTED]
Overall, in vitro studies provided limited insight into potential mechanisms that may explain an etiologic role of arsenic on diabetes.
In Vivo Experimental Studies
Ten experimental studies in mice, rats, goats, and guinea pigs guinea pig (gĭn`ē), domesticated form of the cavy, Cavia porcellus, a South American rodent. It is unrelated to the pig; the name may refer to its shrill squeal. published between 1979 and 2004 met our inclusion criteria (Figure 1, Table 3). Arsenite was evaluated in 6 studies (Biswas et al. 2000; Cobo and Castineira 1997; Ghafghazi et al. 1980; Pal and Chatterjee 2004a, 2004b, 2005), and arsenate in 2 studies (Aguilar et al. 1997; Hughes and Thompson 1996). Other compounds were methanearsonate (Judd 1979) and monomethylarsenic (Arnold et al. 2003). Six studies administered arsenic in water or food for lengths of time ranging from 4 weeks to 2 years, and 5 studies involved intraperitoneal exposure to arsenic for 5-30 days. The doses of arsenic were high or very high in most studies, with a lowest dose of 5.55 ppm arsenite (Pal and Chatterjee 2004a) and 0.025 ppm arsenate (Hughes and Thompson 1996).
Although all studies measured glucose levels in blood, plasma, or serum, only one study provided information on potential mechanisms (Cobo and Castineira 1997). In this study, the oral administration of arsenite did not affect insulin levels in vivo. However, a glucose stimulus applied ex vivo ex vivo /ex vi·vo/ (eks´ ve´vo) outside the living body; denoting removal of an organ (e.g., the kidney) for reparative surgery, after which it is returned to the original site. produced greater insulin release from the isolated pancreas pancreas (păn`krēəs), glandular organ that secretes digestive enzymes and hormones. In humans, the pancreas is a yellowish organ about 7 in. (17.8 cm) long and 1.5 in. (3.8 cm) wide. cells of rats treated with arsenite in vivo compared with the insulin release from isolated pancreas cells of control rats.
Study characteristics. Nineteen epidemiologic studies met our inclusion criteria (Figure 1, Table 4). Three studies were published between 1980 and 1984 (Enterline and Marsh 1982; Mabuchi et al. 1980; Ward and Pim 1984), and the other 15 were reported between 1994 and 2004. Only 2 studies used a prospective cohort design (Lewis et al. 1999; Wang et al. 2003). The rest used cross-sectional, case-control, or retrospective cohort designs. Two studies used the WHO diabetes definition based on oral glucose tolerance tests glucose tolerance test
A test for evaluating the body's capability to metabolize glucose and based upon the ability of the liver to absorb and store excess glucose as glycogen. and/or self-reported medication to define diabetes, whereas the other studies used death certificates, medical or insurance records, urine tests for glucosuria, self-reported diabetes symptoms such as polyuria polyuria /poly·uria/ (-ur´e-ah) excessive secretion of urine.
Excessive passage of urine, as in diabetes. Also called hydruria. confirmed by two positive urine tests and a positive oral glucose tolerance test, glycosylated hemoglobin, or self-reported diagnosis. Two studies did not specify the diagnostic criteria. The number of diabetes cases ranged from 2 (Mabuchi et al. 1980) to 27,543 (Wang et al. 2003), but most studies had fewer than 100 cases. Studies in general populations included adult men and women, whereas occupational studies included mostly men.
There were substantial differences in arsenic exposure ascertainment. Most studies in general populations assessed exposure indirectly, using measurements of total arsenic levels in community drinking water sources. Two studies from Taiwan (Lai et al. 1994; Tseng et al. 2000), one from Bangladesh (Rahman et al. 1999), and one from the United States United States, officially United States of America, republic (2005 est. pop. 295,734,000), 3,539,227 sq mi (9,166,598 sq km), North America. The United States is the world's third largest country in population and the fourth largest country in area. (Lewis et al. 1999) estimated a cumulative arsenic exposure index (ppm-year) by multiplying the number of years that individuals lived in a specific village/area by the average arsenic level in drinking water in that village/area (usually, in each area, several measurements were performed once in time). Other studies in Taiwan and Bangladesh assigned exposure on the basis of residence in an area determined to be endemic for arseniasis (Rahman et al. 1998; Tsai et al. 1999; Wang et al. 2003). None of the studies from Taiwan or Bangladesh obtained individual measures of arsenic exposure either from household tap water measures or more directly by using biomarkers of exposure. None of these studies assessed potential sources of exposure other than drinking water.
In occupational studies, exposure was based on job tide or on estimated arsenic levels in air for different job categories as assessed by a safety engineer (Rahman and Axelson 1995). One study in an occupationally exposed area assessed arsenic exposure based on years of residence within 4 km of a copper smelter during childhood (Tollestrup et al. 2003). Some occupational studies (Enterline and Marsh 1982; Jensen and Hansen 1998; Lagerkvist and Zetterlund 1994; Lubin et al. 2000) also measured arsenic in urine or air to confirm exposure, but this information was not linked to diabetes in the analyses. Only two studies used biomarkers of exposure: Ward and Pim (1984) measured total arsenic in plasma, and Ruiz-Navarro et al. (1998) measured total arsenic in urine, without speciation speciation
Formation of new and distinct species, whereby a single evolutionary line splits into two or more genetically independent ones. One of the fundamental processes of evolution, speciation may occur in many ways. of inorganic and methylated compounds.
Quality assessment. In the epidemiologic studies we abstracted information to evaluate study quality, adapting the criteria proposed for observational studies observational studies,
n.pl an investigational method involving description of the associations be-tween interventions and outcomes. Outcomes research and practice audits are examples of this investigational method. by Longnecker et al. (1988). As shown in Table 5, most studies failed to fulfill important quality criteria such as individual measures of arsenic exposure using biomarkers, standard criteria to diagnose diabetes, or information on established risk factors for diabetes.
Relative risk estimates. The relative risk estimates comparing the highest with the lowest arsenic exposure categories are shown in Table 4. Studies in Taiwan and Bangladesh consistently identified an increased risk of diabetes with increased arsenic exposure, with relative risks ranging from 1.46 to 10.1 (median, 2.40) and with a pooled relative risk estimate using and inverse variance weighted random-effects model of 2.52 (95% CI, 1.69-3.75; p heterogeneity < 0.001). Occupational studies were small and showed no consistent pattern, with relative risks ranging from 0.34 to 9.61 (median, 1.40). We identified only 4 studies in general populations from countries with low or moderate arsenic exposure. These studies were small and did not show an increased risk of diabetes with increasing arsenic levels (relative risks ranged from 0.65 to 1.09; median, 0.95).
Five studies provided information on the dose response in diabetes risk by cumulative arsenic exposure in drinking water (Figure 3). Diabetes risk tended to increase with increasing cumulative exposure in studies from Taiwan (Lai et al. 1994; Tseng et al. 2000) and Bangladesh (Rahman et al. 1999). No trend was observed in the U.S. studies (Lewis et al. 1999; Zierold et al. 2004).
[FIGURE 3 OMITTED]
Summary of findings. The evidence on the association of arsenic exposure with diabetes risk summarized in this systematic review is inconclusive INCONCLUSIVE. What does not put an end to a thing. Inconclusive presumptions are those which may be overcome by opposing proof; for example, the law presumes that he who possesses personal property is the owner of it, but evidence is allowed to contradict this presumption, and show who is . Evidence from in vitro studies suggests that arsenic interferes with signal transduction and transcription factors that are related to insulin pathways such as IUF-1 in pancreatic cells or PPAR[gamma] in preadipocytes. In vitro glucose uptake experiments and in vivo studies did not provide evidence on potential mechanisms that may explain a diabetogenic effect of arsenic. In general, experimental studies were limited by the use of arsenic concentrations that were much higher than those relevant to human exposure. For example, the current U.S. Environmental Protection Agency Environmental Protection Agency (EPA), independent agency of the U.S. government, with headquarters in Washington, D.C. It was established in 1970 to reduce and control air and water pollution, noise pollution, and radiation and to ensure the safe handling and recommended standard for arsenic in drinking water is 10 ppb. The lowest concentration of arsenite used in studies of cultured cells investigating glucose uptake was 750 ppb (Bazuine et al. 2003), and the lowest concentration of arsenite in animal studies was 5,550 ppb (Pal and Chatterjee 2004a, 2004b).
In epidemiologic studies, the association between arsenic exposure and diabetes across different populations and different sources of exposure was inconsistent. In populations exposed to high arsenic levels via drinking water in Taiwan and Bangladesh, diabetes risk was consistently increased. In occupational settings, diabetes mortality was increased in some studies and decreased in others. Finally, no association with diabetes was observed in four studies of general populations outside of Taiwan or Bangladesh. Overall, the quality of the epidemiologic evidence was limited by methodologic problems, particularly in assessing arsenic exposure and diabetes outcomes.
Mechanisms for arsenic-related diabetes. Acute arsenite toxicity, including its effects on glucose metabolism, is generally attributed to its reactivity toward thiol thiol: see mercaptan. (SH) groups (Aposhian 1989; NRC 1999). During acute poisoning, arsenite inhibits pyruvate pyruvate /py·ru·vate/ (pi´roo-vat) a salt, ester, or anion of pyruvic acid. Pyruvate is the end product of glycolysis and may be metabolized to lactate or to acetyl CoA.
n. and [alpha]-ketoglutarate dehydrogenases (Aposhian 1989), essential enzymes for gluconeogenesis gluconeogenesis /glu·co·neo·gen·e·sis/ (gloo?ko-ne?o-jen´e-sis) the synthesis of glucose from molecules that are not carbohydrates, such as amino and fatty acids.
n. and glucolysis. The interference of arsenic with pyruvic acid pyruvic acid /py·ru·vic ac·id/ (pi-roo´vik) CH3COCOOH, an intermediate in carbohydrate, lipid, and protein metabolism.
n. metabolism was described by Krebs in the early 1930s (Krebs 1933). Arsenate, on the other hand, can replace phosphate in energy transfer pathways of phosphorylation phosphorylation, chemical process in which a phosphate group is added to an organic molecule. In living cells phosphorylation is associated with respiration, which takes place in the cell's mitochondria, and photosynthesis, which takes place in the chloroplasts. and also uncouples oxidative phosphorylation oxidative phosphorylation: see phosphorylation. (Kennedy and Lehninger
1949). However, these toxic effects of acute arsenic exposure are unlikely to occur as a result of chronic exposure to environmentally relevant doses (Tseng 2004).
The influence of arsenic on the expression of gene transcription Gene transcription
The process by which genetic information is copied from DNA to RNA, resulting in a specific protein formation.
Mentioned in: Gene Therapy factors may be related to diabetes risk. However, the effects of arsenite on IUF-1 and PPAR[gamma] were contradictory in terms of diabetes development. The differential effects may reflect a complex dose-response pattern for arsenic or differences in length of exposure to arsenic across studies. Further studies with wide ranges and durations of arsenic exposure are needed to investigate the effect of arsenic on these and other insulin-related events at the cellular and molecular levels. For instance, interference with the glucocorticoid receptor The glucocorticoid receptor (GR) or nuclear receptor subfamily 3, group C, member 1 is a ligand-activated transcription factor that binds with high affinity to cortisol and other glucocorticoids. is another potential mechanism for arsenic-related diabetes that deserves further investigation. Arsenic shows a complex dose-response effect on glucocorticoid receptor mediated transcription (Bodwell et al. 2004), with a stimulatory effect at very low concentrations (6-120 ppb) and an inhibitory effect at doses greater than 120 ppb. The glucocorticoid receptor is a member of the steroid receptor superfamily superfamily /su·per·fam·i·ly/ (soo´per-fam?i-le)
1. a taxonomic category between an order and a family.
2. that among other metabolic processes Noun 1. metabolic process - the organic processes (in a cell or organism) that are necessary for life
organism, being - a living thing that has (or can develop) the ability to act or function independently regulates gluconeogenesis. Reduction of glucocorticoid receptor expression in hepatic hepatic /he·pat·ic/ (he-pat´ik) pertaining to the liver.
1. Of, relating to, or resembling the liver.
2. Acting on or occurring in the liver.
n. and adipose tissue adipose tissue (ăd`əpōs'): see connective tissue.
or fatty tissue
Connective tissue consisting mainly of fat cells, specialized to synthesize and contain large globules of fat, within a has been shown to improve hyperglycemia in diabetic rodents (Watts et al. 2005).
Experimental studies on glucose uptake showed that arsenite increases uptake independently of the earlier steps of the insulin transduction transduction, in genetics: see recombination.
A mechanism for the transfer of genetic material between cells. pathway, although when co-administered with insulin, arsenite inhibited insulin-stimulated glucose uptake in 3T3-L1 adipocytes. The purpose of most of these studies was to investigate the role of stress in glucose uptake, which is unrelated to the possibility that arsenic could affect diabetes risk. Under these designs, cultured cells were exposed to high arsenic levels for a few hours, whereas humans are chronically exposed to lower concentrations. Only one study investigated methylated arsenical ar·sen·i·cal
An agent containing arsenic.
Of, relating to, or containing arsenic.
1. pertaining to arsenic.
2. a compound containing arsenic. compounds and their interference in insulin signaling in adipocytes (Walton et al. 2004). For these reasons, the relevance of in vitro glucose uptake findings to diabetes etiology is uncertain.
Arsenic could influence diabetes development by other mechanisms, including oxidative stress oxidative stress,
n an imbalance of the prooxidant antioxidant ratio in which too few antioxidants are produced or ingested or too many oxidizing agents are produced. , inflammation, or apoptosis apoptosis
or programmed cell death
Mechanism that allows cells to self-destruct when stimulated by the appropriate trigger. It may be initiated when a cell is no longer needed, when a cell becomes a threat to the organism's health, or for other reasons. , nonspecific nonspecific /non·spe·cif·ic/ (non?spi-sif´ik)
1. not due to any single known cause.
2. not directed against a particular agent, but rather having a general effect.
1. mechanisms that have been implicated im·pli·cate
tr.v. im·pli·cat·ed, im·pli·cat·ing, im·pli·cates
1. To involve or connect intimately or incriminatingly: evidence that implicates others in the plot.
2. in the pathogenesis of type 2 diabetes. Arsenic exposure can enhance the production of reactive oxygen species reactive oxygen species,
n molecules and ions of oxygen that have an unpaired electron, thus rendering them extremely reactive. Many cellular structures are susceptible to attack by ROS contributing to cancer, heart disease, and cerebrovascular disease. (Barchowsky et al. 1999; Chen et al. 1998; Tseng 2004; Wang et al. 1996), interfere with the activity of key antioxidant antioxidant, substance that prevents or slows the breakdown of another substance by oxygen. Synthetic and natural antioxidants are used to slow the deterioration of gasoline and rubber, and such antioxidants as vitamin C (ascorbic acid), butylated hydroxytoluene enzymes such as glutathione reductase Glutathione reductase is an enzyme (EC 184.108.40.206) which reduces glutathione disulphide (GSSG) to the sulfhydryl form GSH, which is an important cellular antioxidant.
For every mole of GSSG one mole of NADH is required. , glutathione S-transferase The glutathione S-transferase (GST) family of enzymes comprises a long list of cytosolic, mitochondrial, and microsomal proteins which are capable of multiple reactions with a multitude of substrates, both endogenous and xenobiotic. , glutathione peroxidase Noun 1. glutathione peroxidase - an enzyme in the body that is a powerful scavenger of free radicals
antioxidant - substance that inhibits oxidation or inhibits reactions promoted by oxygen or peroxides , and glucose 6-phosphate dehydrogenase dehydrogenase /de·hy·dro·gen·ase/ (de-hi´dro-jen-as?) an enzyme that catalyzes the transfer of hydrogen or electrons from a donor, oxidizing it, to an acceptor, reducing it.
n. (Maiti and Chatterjee 2000; Santra et al. 2000), and induce lipid peroxidation Lipid peroxidation refers to the oxidative degradation of lipids. It is the process whereby free radicals "steal" electrons from the lipids in cell membranes, resulting in cell damage. This process proceeds by a free radical chain reaction mechanism. (Santra et al. 2000). In individuals from Taiwan, increasing blood levels of arsenic correlated with increasing levels of reactive oxygen species and with decreasing levels of antioxidant capacity in plasma (Wu et al. 2001). Arsenic may also up-regulate interleukin-6 and other inflammatory cytokines Cytokines
Chemicals made by the cells that act on other cells to stimulate or inhibit their function. Cytokines that stimulate growth are called "growth factors. (Wu et al. 2003), and it may induce the release of tumor necrosis tumor necrosis Death of tumor tissue, a common event in aggressive CAs in which the tumor rapidly outgrows its blood supply, resulting in tumor cell death. Cf Apoptosis. factor-[alpha] from mononuclear mononuclear /mono·nu·cle·ar/ (-noo´kle-er)
1. having but one nucleus.
2. a cell having a single nucleus, especially a monocyte of the blood or tissues.
adj. cells (Yu et al. 2002). Finally, arsenic is well known for inducing apoptosis in multiple cell lines (Waalkes et al. 2000). Future research should evaluate whether these mechanisms mediate the role of arsenic in diabetes development.
The in vivo experimental studies were mostly uninformative un·in·for·ma·tive
Providing little or no information; not informative.
unin·for . The diversity of species studied probably reflects that there are no good animal models to study the effects of arsenic on diabetes development. Indeed, the classification of arsenic as a human carcinogen, although recently supported by animal models (Waalkes et al. 2004), was for a long time based on human data. Progress in the study of the role of arsenic in diabetes requires the identification of appropriate animal models.
Arsenic and diabetes in human studies. Suggestive evidence links chronic exposure to high arsenic levels in drinking water with increased diabetes risk in Taiwan and Bangladesh. Methodologic problems, however, limit the causal interpretation of this association. The use of average drinking water and the lack of individual measures of arsenic make it possible to underestimate exposure due to between-subject variability in water consumption and to other sources of arsenic exposure in these areas, such as contaminated contaminated,
v 1. made radioactive by the addition of small quantities of radioactive material.
2. made contaminated by adding infective or radiographic materials.
3. an infective surface or object. food and cooking water. On the other hand, because arsenic exposure was assessed at the village level and diabetes diagnosis was often not performed according to according to
1. As stated or indicated by; on the authority of: according to historians.
2. In keeping with: according to instructions.
3. standard procedures, this ecologic association could reflect the uncertain comparability of exposure groups in terms of socioeconomic development Socio-economic development is the process of social and economic development in a society. Socio-economic development is measured with indicators, such as GDP, life expectancy, literacy and levels of employment. , access to care, study selection factors and other diabetes risk factors. The use of urine tests and of administrative data to identify diabetes makes it likely that only severe or symptomatic cases were identified, and it is uncertain whether the procedures and frequency for diabetes testing were similar across areas with different arsenic exposure. In addition, the use of administrative data can be affected by surveillance and diagnostic biases. For example in Taiwan, arsenic-related health problems in the endemic areas Endemic area
A geographical region where a particular disease is prevalent.
Mentioned in: Leprosy, Scrub Typhus are well known, hence, subjects in these areas may have received different medical care, including different diagnostic services diagnostic services,
n.pl the imaging and laboratory capabilities available for determining the cause of an illness. , compared with subjects in areas with lower arsenic levels.
It is also possible that the findings from Taiwan and Bangladesh may not be generalizable gen·er·al·ize
v. gen·er·al·ized, gen·er·al·iz·ing, gen·er·al·iz·es
a. To reduce to a general form, class, or law.
b. To render indefinite or unspecific.
2. to other populations. Some reasons for this include variations in the distribution of polymorphisms in genes involved in arsenic metabolism or response (Loffredo et al. 2003), differences in arsenic species to which populations were exposed (Chen et al. 1995), other co-exposures (Chen et al. 1995), and dietary deficiencies that may interact with arsenic. For example, selenium selenium (səlē`nēəm), nonmetallic chemical element; symbol Se; at. no. 34; at. wt. 78.96; m.p. 217°C;; b.p. about 685°C;; sp. gr. 4.81 at 20°C;; valence −2, +4, or +6. and zinc levels in Taiwan and Bangladesh are among the lowest worldwide (Lin and Yang 1988), and poor dietary selenium has been suggested as an underlying factor for arsenic and cancer in Bangladesh and West Bengal West Bengal: see Bengal.
State (pop., 2001: 80,176,197), northeastern India. It is bordered by Nepal and Bangladesh and the states of Orissa, Jharkhand, Bihar, Sikkim, Assam, and Meghalaya and has an area of 34,267 sq mi (88,752 sq km); in India (Spallholz et al. 2004). In guinea pigs, selenium and arsenic counteract each other in glucose metabolism (Das et al. 1989), and the joint effect of high arsenic and low selenium could play a role in diabetes development. Exposure to arsenic, selenium, other nutrients, and other diabetes risk factors were not measured in epidemiologic studies.
We found no reports of diabetes in populations known to be exposed to high levels of arsenic in drinking water in Chile and Argentina. This lack of information on diabetes could reflect a lack of research, but it has also been suggested to be related to publication bias (Longnecker and Daniels 2001).
The evidence from general populations outside of Taiwan or Bangladesh was inconclusive because of the small number of cases, limitations in study design, and misclassification of diabetes status. Occupational studies, on the other hand, could not be interpreted in favor or against an association because of uncertain comparability of study participants with the general population used as reference, limitations in exposure assessment, lack of information on concomitant exposures, lack of information on major diabetes risk factors, and the possibility of a healthy worker survivor effect.
An important conclusion we derived from the epidemiologic review is the limited quality of the evidence base. This finding is consistent with previous reviews, including those by U.S. and international panels (NRC 1999, 2001; Ng 2001; WHO 2001). These panels determined that the available evidence on arsenic and diabetes suffered from uncertainties in study design and exposure assessment. Our review further refines these reports and identifies the lack of biomarker biomarker /bio·mark·er/ (bi´o-mahr?ker)
1. a biological molecule used as a marker for a substance or process of interest.
2. tumor marker.
1. data and the lack of standard criteria for diabetes assessment as major limitations of the evidence base. Current uncertainties in the role of arsenic in diabetes development could be reduced by conducting carefully planned epidemiologic studies in populations exposed to a wide range of arsenic levels. Future studies should a) measure appropriate arsenic biomarkers that integrate all sources of exposure (e.g., urine or toenails); b) carefully collect information on current and past sources of arsenic exposure and on potential confounders and modifiers, including known determinants of diabetes development; c) and prospectively ascertain diabetes using standard definitions.
The possibility of an association between chronic arsenic exposure and diabetes has implications for research and public health. Millions of people are exposed worldwide to moderate or high levels of arsenic in drinking water. Because diabetes is also a major public health problem, the public health consequences of a causal association could be serious. Methodologic problems limit the causal interpretation of the moderately strong association between high arsenic exposure and diabetes in Taiwan and Bangladesh. Overall, the experimental and epidemiologic evidence is at present insufficient and inadequate to establish causality causality, in philosophy, the relationship between cause and effect. A distinction is often made between a cause that produces something new (e.g., a moth from a caterpillar) and one that produces a change in an existing substance (e.g. . Experimental studies that use arsenic concentrations relevant to human exposures, and high-quality prospective epidemiologic studies that use appropriate methods for exposure assessment as well as rigorous criteria for outcome definitions should be research priorities.
Table 1 has been modified from the original manuscript published online. The table now includes information on the 24-hr study by Walton et al. (2004).
Received 1 August 2005; accepted 15 December 2005.
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MAPK Map Kinase ) phosphatase-1 and -4 attenuate To reduce the force or severity; to lessen a relationship or connection between two objects.
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tr.v. in·gest·ed, in·gest·ing, in·gests
1. To take into the body by the mouth for digestion or absorption. See Synonyms at eat.
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Because "TNF" is often used to describe TNF alpha, "TNFR" is often used to describe the receptors that bind to TNF alpha - namely, CD120. I signaling in T helper cell T helper cell
see helper lymphocyte. apoptosis. J Invest Dermatol 119:812-819.
Zierold KM, Knobeloch L, Anderson H. 2004. Prevalence of chronic diseases in adults exposed to arsenic-contaminated drinking water. Am J Public Health 94:1935-1937.
Ana Navas-Acien, (1,2,3,4) Ellen K. Silbergeld, (4) Robin A. Streeter, (1,3) Jeanne M. Clark, (1,2,5) Thomas A. Burke
(1) Department of Epidemiology, Johns Hopkins University Johns Hopkins University, mainly at Baltimore, Md. Johns Hopkins in 1867 had a group of his associates incorporated as the trustees of a university and a hospital, endowing each with $3.5 million. Daniel C. Bloomberg School of Public Health, (2) Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Noun 1. Johns Hopkins - United States financier and philanthropist who left money to found the university and hospital that bear his name in Baltimore (1795-1873)
2. Medical Institutions, (3) Johns Hopkins Center for Excellence in Environmental Public Health Tracking, Johns Hopkins University Bloomberg School of Public Health, (4) Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, (5) Department of Medicine, Johns Hopkins School of Medicine, and (6) Department of Health Policy and Management, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland "Baltimore" redirects here. For the surrounding county, see Baltimore County, Maryland. For other uses, see Baltimore (disambiguation).
Baltimore is an independent city located in the state of Maryland in the United States. , USA
Address correspondence to A. Navas Acien, Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, 615 N. Wolfe St., Office W7033B, Baltimore, MD 21205-2223 USA. Telephone: (410) 502-4267. Fax: (410) 955-0476. E-mail: email@example.com
This work was supported by National Institute of Environmental Health Sciences The National Institute of Environmental Health Sciences (NIEHS) is one of 27 Institutes and Centers of the National Institutes of Health (NIH),which is a component of the Department of Health and Human Services (DHHS). The Director of the NIEHS is Dr. David A. Schwartz. grant 1R01 ES012673-01. A.N.-A., R.A.S., T.A.B., and E.G. were supported by the Johns Hopkins Center of Excellence in Environmental Public Health Tracking (Centers for Disease Control and Prevention Centers for Disease Control and Prevention (CDC), agency of the U.S. Public Health Service since 1973, with headquarters in Atlanta; it was established in 1946 as the Communicable Disease Center. grant U50CCU CCU
1. coronary care unit
2. critical care unit
critical care unit.
CCU Critical care unit, see there 322417).
The authors declare they have no competing financial interests.
Table 1. In vitro studies of arsenic exposure and glucose metabolism outcomes. Source Type of cell/tissue Compound Signal transduction and gene expression Macfarlane et al. 1997 Pancreatic [beta]-cells Arsenite Macfarlane et al. 1999 Pancreatic [beta]-cells Arsenite Elrick and Docherty 2001 Pancreatic [beta]-cells Arsenite Wauson et al. 2002 C3H 10T1/2 Arsenite preadipocytes Salazard et al. 2004 3T3-F442A Arsenite preadipocytes Glucose uptake in cultured cells Warren et al. 1986 BHK-21 cells Arsenite Widnell et al. 1990 BHK-21 cells Arsenite Pasternak et al. 1991 BHK-21 cells Arsenite Liebl et al. 1992 MDCK dog cells Arsenite Sviderskaya et al. 1996 BHK cells Arsenite 3T3-L1 adipocytes McDowell et al. 1997 L6 rat muscle cells Arsenite Fladeby and Serck- Bovine adrenal cells Arsenite Hanssen 1999 Bazuine et al. 2003 3T3-L1 adipocytes Arsenite Bazuine et al. 2004 3T3-L1 adipocytes Arsenite Walton et al. 2004 3T3-L1 adipocytes Arsenite [MAs.sup.III]O [DMAs.sup.III]I Arsenate [MAs.sup.V] [DMAs.sup.V] Arsenite [MAs.sup.III]O [DMAs.sup.III]I Miscellaneous experiments Short et al. 1965 Rat hemidiaphragms Arsenite Epidydimal fat pads Arsenate Dixit and Lazarow 1967 Epidydimal fat pads Arsenite Brazy et al. 1980 Rabbit kidney tubules Arsenate Hunder et al. 1993 Rat jejunal segments Arsenite Arsenate Source Dose (ppm) Incubation Signal transduction and gene expression Macfarlane et al. 1997 37.5 0.33 hr Macfarlane et al. 1999 75 0.5 hr Elrick and Docherty 2001 75 0.5 hr Wauson et al. 2002 0.45 2 months Salazard et al. 2004 0.0017, 3 days 0.003 Glucose uptake in cultured cells Warren et al. 1986 3.75 2 hr Widnell et al. 1990 15 2 hr Pasternak et al. 1991 4.5-7.5 2 hr Liebl et al. 1992 37.5-75 1 hr Sviderskaya et al. 1996 7.5-22.5 2 hr McDowell et al. 1997 7.5-112.5 0.5 hr Fladeby and Serck- 1.88-18.8 1 hr Hanssen 1999 Bazuine et al. 2003 0.75-75 0.5 hr Bazuine et al. 2004 3.75-750 0.5 hr Walton et al. 2004 1.57, 7.5 4 hr 0.08, 0.4 0.15, 0.75 7.5, 75 7.5, 75 7.5, 75 0.4, 0.8, 1.5 24 hr 0.02, 0.04, 0.08 0.04, 0.08, 0.15 Miscellaneous experiments Short et al. 1965 75 1-3 hr 75 Dixit and Lazarow 1967 0.75-7,500 3 hr Brazy et al. 1980 0.75-375 0.5 hr Hunder et al. 1993 0.19-18.9 2 hr 0.19-187.5 Outcomes and results Source (compared with controls) Signal transduction and gene expression Macfarlane et al. 1997 [up arrow] IUF-1 dependent gene expression PI-3 kinase independent, SAPK2/p38 involved Macfarlane et al. 1999 [up arrow] IUF-1 translocation from cytoplasm to nucleus PI-3 kinase independent; SAPK2/p38 involved Elrick and Docherty 2001 [up arrow] IUF-1 translocation from cytoplasm to nucleus PI-3 kinase independent, SAPK2/p38 involved Wauson et al. 2002 [down arrow] PPAR[gamma] mRNA [down arrow] Pioglitazone-stimulated adipocyte differentiation Salazard et al. 2004 [up arrow] Expression of PPAR[gamma] and C/EBP[alpha] (genes with important roles in adipose determination) Glucose uptake in cultured cells Warren et al. 1986 [up arrow] Basal glucose uptake; = insulin-stimulated glucose uptake = amino acid uptake Widnell et al. 1990 [up arrow] Basal glucose uptake; [up arrow] glucose transporter translocation (reversible) Pasternak et al. 1991 [up arrow] Basal glucose uptake (reversible when arsenite removed) Fast and reversible translocation of glucose receptor Liebl et al. 1992 [down arrow] Basal glucose uptake, dose dependent Sviderskaya et al. 1996 [up arrow] Basal glucose uptake, dose dependent [up arrow] Glucose transporter translocation in both types of cells McDowell et al. 1997 [up arrow] Basal glucose uptake, dose dependent but maximal with 37.5 ppm [up arrow] GLUT1 and GLUT4 in cell membrane, PI-3 kinase independent [up arrow] Insulin-stimulated glucose uptake Fladeby and Serck- [up arrow] Basal glucose uptake up to Hanssen 1999 7.5 ppm, then plateau PI-3 kinase independent, SAPK2/p38 partly involved Bazuine et al. 2003 [up arrow] Basal glucose uptake up to 37.5 ppm, then [down arrow] [down arrow] Insulin-stimulated glucose uptake [up arrow] GLUT4 and GLUT1 translocation (but less than insulin) PI-3 kinase independent; no changes in IR[beta], IRS-1, IRS-2 No phosphorylation of PKB; PKC-[lambda]/[zeta] and SAPK2/p38 involved Bazuine et al. 2004 [up arrow] Basal glucose uptake up to 37.5 ppm Dexamethasone [down arrow] arsenite glucose uptake SAPK2/p38 involved Walton et al. 2004 = basal glucose uptake at 1.50 ppm, [down arrow] at 7.5 ppm, [down arrow] insulin-stimulated = basal glucose uptake at 0.08 ppm, [down arrow] at 0.4 ppm, [down arrow] insulin-stimulated = basal glucose uptake all doses, [down arrow] insulin-stimulated [up arrow] basal glucose uptake at 7.5 ppm, [down arrow] at 75 ppm, = insulin-stimulated = basal glucose uptake all doses, [down arrow] insulin-stimulated = basal and insulin-stimulated glucose uptake all doses, PI-3 kinase independent. No changes in IR[beta] and IRS-2 [MAs.sup.III]O and [DAs.sup.III]I, but not arsenite IRS-1, [up arrow] phosphorylation of IRS-1 Arsenite, [MAs.sup.III]O and [DAs.sup.III]I [down arrow] phosphorylation of PKB/Akt Arsenite, [MAs.sup.III]O and [DAs.sup.III]I [down arrow] GLUT4 translocation in insulin-treated cells Dose-dependent [down arrow] insulin-stimulated glucose uptake = insulin-stimulated glucose uptake at 0.02 ppm, [down arrow] at 0.04 and 0.08 = insulin-stimulated glucose uptake all doses Miscellaneous experiments Short et al. 1965 [up arrow] Basal glucose uptake in hemidiaphragms; [up arrow] uptake with arsenate in fat pads = insulin stimulated glucose uptake in hemidiaphragm; [down arrow] uptake with arsenite in fat pad Dixit and Lazarow 1967 [up arrow] Basal glucose oxidation up to 7.5 ppm Brazy et al. 1980 [down arrow] Fluid, phosphate, and glucose absorption (lumen to bath) Hunder et al. 1993 [down arrow] Intestinal glucose transfer dose dependent (= arsenate < 7.5 ppm) Abbreviations: [up arrow], increase; [down arrow], decrease; = similar levels; BHK-21 cells, baby hamster kidney cells (contain predominantly GLUT1); C/EBP[alpha], CCAAT/enhancer binding protein; [DAs.sup.III]I, iodo-dimethylarsine; [DMAs.sup.V], dimethylarsinic acid; GLUT, glucose transporter; IR[beta]: insulin receptor [beta]; IRS, insulin receptor substrate; IUF-1, insulin upstream factor-1 (also called homeodomain transcription factor PDX1); [MAs.sup.III]O, methylarsine oxide; [MAs.sup.V], monosodium methyl arsenate; MDCK dog cells, Madin-Darby canine kidney cells; PI-3 kinase, phosphatydilinositol-3 kinase; PKB, protein kinase B; PKC, protein kinase C; PPAR[gamma], peroxisome proliferative-activated receptor [gamma], SAPK2, stress activator protein kinase 2 (also called p38 mitogen-activated protein kinase). 1 ppm = 13.35 [micro]M. Basal glucose uptake, glucose uptake in the absence of insulin. Table 2. Experimental characteristics and ratio of glucose uptake in peripheral cell lines exposed to arsenite and insulin compared with insulin and arsenite alone. Experiment characteristics Incubation Arsenite Insulin Source Type of cell (hr) (ppm) (nM) Warren et al. 1986 BHK-21 cells 2 3.75 100 McDowell et al. 1997 L6 rat muscle 0.5 37.5 100 cells Bazuine et al. 2003 3T3-L1 adipocytes 0.5 37.5 100 Walton et al. 2004 3T3-L1 adipocytes 4 1.50 1,000 Walton et al. 2004 3T3-L1 adipocytes 4 7.49 1,000 Ratio of glucose uptake vs. Source Insulin Arsenite Warren et al. 1986 0.94 0.91 McDowell et al. 1997 1.42 1.21 Bazuine et al. 2003 0.57 1.33 Walton et al. 2004 0.60 0.55 Walton et al. 2004 0.20 0.33 BHK-21 cells, baby hamster kidney cells. For arsenite, 1 ppm = 13.35 [micro]M. Table 3. In vivo studies of arsenic exposure and glucose metabolism. Experimental Source animal n Judd 1979 Field mice 19 Ghafghazi et al. 1980 Rats 12 Hughes and Thompson 1996 B6C3[F.sub.1] mice 72 Aguilar et al. 1997 Wistar rats 20 Cobo and Castineira 1997 Wistar rats 21 Biswas et al. 2000 Bengal goats 12 Arnold et al. 2003 Fischer rats 480 Pal and Chatterjee 2004a Wistar rats 18 Pal and Chatterjee 2004b Wistar rats 18 Pal and Chatterjee 2005 Wistar rats 18 Source Compound (route) Judd 1979 Methanearsonate (po in water) Ghafghazi et al. 1980 Arsenite (ip) Hughes and Thompson 1996 Arsenate (po in water) Aguilar et al. 1997 Arsenate (po in food) Cobo and Castineira 1997 Arsenite (po in water) Biswas et al. 2000 Arsenite (po in capsule) Arnold et al. 2003 Monomethylarsenic (po in food) Pal and Chatterjee 2004a Arsenite (ip) Pal and Chatterjee 2004b Arsenite (ip) Pal and Chatterjee 2005 Arsenite (ip) Daily dose Source (ppm) Duration Judd 1979 1,000 30 days Ghafghazi et al. 1980 5-10 7 days Hughes and Thompson 1996 0.025-2.5 28 days Aguilar et al. 1997 5 10 weeks Cobo and Castineira 1997 17.75 1st week up to 100 8th week Biswas et al. 2000 25 12 weeks Arnold et al. 2003 50-1,300 2 years Pal and Chatterjee 2004a 5.55 21 days Pal and Chatterjee 2004b 5.55 30 days Pal and Chatterjee 2005 5.55 30 days Outcomes and results Source (compared with controls) Judd 1979 [down arrow] Blood glucose, = fluid and food consumption Ghafghazi et al. 1980 [up arrow] Glucose levels after glucose tolerance test, dose dependent Hughes and Thompson 1996 [down arrow] Plasma glucose, = fluid and food consumption Aguilar et al. 1997 = Plasma glucose levels Cobo and Castineira 1997 Delayed glucose clearance after glucose tolerance test = Basal insulin levels in vivo Biswas et al. 2000 [up arrow] Blood glucose at week 6 and [up arrow][up arrow] at week 12 Arnold et al. 2003 = Blood glucose levels up to 400 ppm, [down arrow] with 1,300 ppm Pal and Chatterjee 2004a [down arrow] Blood glucose (reversed with methionine) = Body, liver, kidney weight Pal and Chatterjee 2004b [down arrow] Blood glucose (reversed with N-acetylcysteine) Pal and Chatterjee 2005 [down arrow] Blood glucose (reversed with methionine) Abbreviations: ip, intraperitonea1; po, per oral; [up arrow], increase; [down arrow], decrease. Table 4. Epidemiolopic studies of arsenic exposure and diabetes. Source Design Country Population General populations, high arsenic exposure Lai et al. 1994 CS Taiwan Survey of participants in high-arsenic area Tsai et al. 1999 RCO Taiwan Deaths in 1971-1994 Tseng et al. CO Taiwan Survey of participants 2000 in high-arsenic area Wang et al. CS Taiwan National Health 2003 Insurance Database Rahman et al. CS Bangla- Survey participants 1998 desh in high- and low-arsenic areas Rahman et al. CS Bangla- Survey participants 1999 desh in high-arsenic area Occupational populations, high arsenic exposure Mabuchi et al. RCO U.S. Pesticide workers, 1980 Baltimore, MD Enterline and RCO U.S. Copper smelter Marsh 1982 workers, Washington State Lagerkvist and CS Sweden Copper smelter Zetterlund 1994 workers, other jobs Rahman and CC Sweden Copper smelter Axelson 1995 workers Rahman et al. CC Sweden Deaths in glass 1996 industry area Jensen and CS Denmark Taxidermists, wood Hansen 1998 workers, other jobs Bartoli et al. RCO Italy Glass industry 1998 workers Lubin et al. 2000 RCO U.S. Copper smelter workers, Montana Tollestrup et al. RCO U.S. Children < 4 km of 2003 Copper smelter General populations, low to moderate arsenic exposure Ward and Pim CC UK Hospital based 1984 Ruiz-Navarro CC Spain Hospital based et al. 1998 Lewis et al. CO U.S. Mormons 1999 Zierold et al. CC U.S. Survey participants 2004 with private wells Diabetes Cases/ Source diagnosis noncases General populations, high arsenic exposure Lai et al. 1994 OGTT or 86/805 self-reported Tsai et al. 1999 Death certificate 531 deaths Tseng et al. OGTT 41/405 2000 Wang et al. ICD-9 250 27,543/ 2003 ICD-9 A181 678,791 Rahman et al. Self-reported 46/971 1998 symptoms + glucosuria + OGTT Rahman et al. Glucosuria 263/1,332 1999 Occupational populations, high arsenic exposure Mabuchi et al. Death certificate 2 deaths 1980 Enterline and Death certificate 12 deaths Marsh 1982 Lagerkvist and Self-reported 4/85 Zetterlund 1994 type 2 diabetes Rahman and Death certificate, 12/31 Axelson 1995 medical record Rahman et al. Death certificate 240/2,216 1996 Jensen and HbA1c 5/59 Hansen 1998 Bartoli et al. Death certificate 3 deaths 1998 Lubin et al. 2000 Death certificate 54 deaths Tollestrup et al. Death certificate 16/3,116 2003 General populations, low to moderate arsenic exposure Ward and Pim NR 87/30 1984 Ruiz-Navarro NR 38/49 et al. 1998 Lewis et al. Death certificate 55/4,003 1999 Zierold et al. Self-reported 67/1118 2004 Men Age range Source (%) (year) General populations, high arsenic exposure Lai et al. 1994 43 30-69 Tsai et al. 1999 35 All ages Tseng et al. 50 Mean 47 2000 Wang et al. 43 25-65+ 2003 Rahman et al. 59 30-60+ 1998 Rahman et al. 61 30-60+ 1999 Occupational populations, high arsenic exposure Mabuchi et al. 75 < 20-40+ 1980 at hire Enterline and 100 < 20-69 Marsh 1982 at hire Lagerkvist and 100 Mean 57 Zetterlund 1994 Rahman and 100 30-74 at Axelson 1995 death Rahman et al. 100 45-75+ 1996 Jensen and 87 Mean 37 Hansen 1998 Bartoli et al. 100 < 40-65+ 1998 Lubin et al. 2000 100 < 20-30+ at hire Tollestrup et al. 58 < 14 2003 General populations, low to moderate arsenic exposure Ward and Pim 65 18-78 1984 Ruiz-Navarro 39 NR et al. 1998 Lewis et al. 52 < 50-80+ 1999 Zierold et al. NR Mean 62 2004 Arsenic Levels, exposed Source assessment vs. reference General populations, high arsenic exposure Lai et al. 1994 CEI village > 15 vs. 0 ppm-year drinking water Tsai et al. 1999 Living in HAA HAA vs. no HAA Tseng et al. CEI village > 17 vs. < 17 2000 drinking water ppm-year Wang et al. Living in HAA HAA vs. no HAA 2003 Rahman et al. Living in HAA Keratosis vs. 1998 and keratosis no keratosis Rahman et al. CEI village > 10 vs. 0 ppm-year 1999 drinking water Occupational populations, high arsenic exposure Mabuchi et al. Job title Workers vs. general 1980 population Enterline and Job title Workers vs. general Marsh 1982 population Lagerkvist and Job title Workers vs. other Zetterlund 1994 workers Rahman and Air levels ~ 5 vs. 0 mg/[m.sup.3] Axelson 1995 Rahman et al. Job title Workers vs. other 1996 workers Jensen and Job title Workers vs. general Hansen 1998 population Bartoli et al. Job title Workers vs. general 1998 population Lubin et al. 2000 Job title Workers vs. general population Tollestrup et al. Years of [greater than or 2003 residency equal to] l0 vs. < 1 year General populations, low to moderate arsenic exposure Ward and Pim Plasma levels 75th vs. 25th 1984 (NAA) percentile Ruiz-Navarro Urinary levels 75th vs. 25th et al. 1998 (AAS) percentile Lewis et al. CEI community > 4 vs. < 1 1999 drinking water ppm-year Zierold et al. Subject > 10 vs. < 2 ppb 2004 drinking water RR of diabetes Source (95% CI) Adjusted for General populations, high arsenic exposure Lai et al. 1994 10.1 (1.30-77.9) Age, sex, BMI, physical activity Tsai et al. 1999 1.46 (1.28-1.67) Age, sex Tseng et al. 2.10 (1.10-4.20) Age, sex, BMI 2000 Wang et al. 2.69 (2.65-2.73) Age, sex 2003 Rahman et al. 5.90 (2.90-11.6) Age, sex, BMI 1998 Rahman et al. 2.10 (1.10-4.20) Age, sex 1999 Occupational populations, high arsenic exposure Mabuchi et al. 0.47 (0.12-1.88) Age, sex, period 1980 Enterline and 0.85 (0.48-1.49) Age Marsh 1982 Lagerkvist and 9.61 (0.53-173) Crude Zetterlund 1994 Rahman and 3.30 (0.50-30.0) Age Axelson 1995 Rahman et al. 1.40 (0.90-2.10) Age 1996 Jensen and 4.43 (0.47-42.0) Age Hansen 1998 Bartoli et al. 0.34 (0.09-0.88) Age 1998 Lubin et al. 2000 0.83 (0.63-1.08) Age Tollestrup et al. 1.60 (0.36-1.16) Crude 2003 General populations, low to moderate arsenic exposure Ward and Pim 1.09 (0.79-1.49) Crude 1984 Ruiz-Navarro 0.87 (0.50-1.53) Crude et al. 1998 Lewis et al. 0.65 (0.34-1.24) Age, sex 1999 Zierold et al. 1.02 (0.49-2.15) Age, sex, BMI, 2004 smoking Abbreviations: AAS, atomic absorption spectrometry; BMI, body mass index; CC, case-control; CEI, cumulative exposure index: [SIGMA] arsenic levels in drinking water; x time of exposure; (i indicates specific village); CO, cohort; CS, cross-sectional; HAA, high-arsenic area; HbA1c, hemoglobin A1c; ICD-9, International Classification of Diseases, Ninth revision; NAA, neutron activation analysis; NR, not reported; OGTT, oral glucose tolerance test, criteria for a positive test based on the WHO criteria; RCO, retrospective cohort; RR, relative risk. Table 5. Criteria for evaluating the design and data analysis of epidemiologic studies on arsenic and diabetes. (a) Taiwan and Bangladesh Tsai Tseng Lai et al. et al. et al. 1994 1999 2000 All studies (n = 19) Diabetes diagnosis based on Y N Y fasting glucose levels or oral glucose tolerance tests Exposure assessed at the N N N individual level Exposure assessed using a N N N biomarker of exposure Control for established Y N Y diabetes risk factors in addition to age Case-control and cross-sectional studies (n = 11) Response rate among noncases Y -- -- at least 70% (b) Noncases would have been cases N -- -- if they had developed diabetes Data collected in a similar Y -- -- manner for all participants Cases interviewed within N -- -- 6 months of diagnosis Interviewer blinded with Y -- -- respect to the case status of the person interviewed (c) Time period during which all Y -- -- participants were interviewed was the same (c) Same exclusion criteria Y -- -- applied to all participants Cohort studies (n = 8) Loss to follow-up was -- N Y independent of exposure Intensity of search of disease -- N Y independent of exposure status Taiwan and Bangladesh Wang Rahman Rahman et al. et al. et al. 2003 1998 1999 All studies (n = 19) Diabetes diagnosis based on N N N fasting glucose levels or oral glucose tolerance tests Exposure assessed at the N N N individual level Exposure assessed using a N N N biomarker of exposure Control for established N N N diabetes risk factors in addition to age Case-control and cross-sectional studies (n = 11) Response rate among noncases Y N Y at least 70% (b) Noncases would have been cases N N N if they had developed diabetes Data collected in a similar Y N N manner for all participants Cases interviewed within N N N 6 months of diagnosis Interviewer blinded with -- N N respect to the case status of the person interviewed (c) Time period during which all -- N N participants were interviewed was the same (c) Same exclusion criteria Y N N applied to all participants Cohort studies (n = 8) Loss to follow-up was -- -- -- independent of exposure Intensity of search of disease -- -- -- independent of exposure status Occupational populations Lagerkvist Mabuchi Enferline and et al. and Marsh Zetterlund 1980 1982 1994 All studies (n = 19) Diabetes diagnosis based on N N N fasting glucose levels or oral glucose tolerance tests Exposure assessed at the N N N individual level Exposure assessed using a N N N biomarker of exposure Control for established Y N N diabetes risk factors in addition to age Case-control and cross-sectional studies (n = 11) Response rate among noncases -- -- N at least 70% (b) Noncases would have been cases -- -- N if they had developed diabetes Data collected in a similar -- -- N manner for all participants Cases interviewed within -- -- N 6 months of diagnosis Interviewer blinded with -- -- N respect to the case status of the person interviewed (c) Time period during which all -- -- N participants were interviewed was the same (c) Same exclusion criteria -- -- N applied to all participants Cohort studies (n = 8) Loss to follow-up was N N -- independent of exposure Intensity of search of disease N N -- independent of exposure status Occupational populations Rahman and Rahman Jensen Axelson et al. and Hansen 1995 1996 1998 All studies (n = 19) Diabetes diagnosis based on N N N fasting glucose levels or oral glucose tolerance tests Exposure assessed at the Y N N individual level Exposure assessed using a N N N biomarker of exposure Control for established N N N diabetes risk factors in addition to age Case-control and cross-sectional studies (n = 11) Response rate among noncases -- -- N at least 70% (b) Noncases would have been cases N N Y if they had developed diabetes Data collected in a similar Y Y Y manner for all participants Cases interviewed within N N N 6 months of diagnosis Interviewer blinded with N N Y respect to the case status of the person interviewed (c) Time period during which all Y Y N participants were interviewed was the same (c) Same exclusion criteria Y N N applied to all participants Cohort studies (n = 8) Loss to follow-up was -- -- -- independent of exposure Intensity of search of disease -- -- -- independent of exposure status Occupational populations Bartoli Lubin Tollestrup et al. et al. et al. 1998 2000 2003 All studies (n = 19) Diabetes diagnosis based on N N N fasting glucose levels or oral glucose tolerance tests Exposure assessed at the N N Y individual level Exposure assessed using a N N N biomarker of exposure Control for established N N N diabetes risk factors in addition to age Case-control and cross-sectional studies (n = 11) Response rate among noncases -- -- -- at least 70% (b) Noncases would have been cases -- -- -- if they had developed diabetes Data collected in a similar -- -- -- manner for all participants Cases interviewed within -- -- -- 6 months of diagnosis Interviewer blinded with -- -- -- respect to the case status of the person interviewed (c) Time period during which all -- -- -- participants were interviewed was the same (c) Same exclusion criteria -- -- -- applied to all participants Cohort studies (n = 8) Loss to follow-up was N N N independent of exposure Intensity of search of disease N N N independent of exposure status Other populations Ruiz- Ward Navarro and Pim et al. 1984 1998 All studies (n = 19) Diabetes diagnosis based on N N fasting glucose levels or oral glucose tolerance tests Exposure assessed at the Y Y individual level Exposure assessed using a Y Y biomarker of exposure Control for established N N diabetes risk factors in addition to age Case-control and cross-sectional studies (n = 11) Response rate among noncases N N at least 70% (b) Noncases would have been cases N N if they had developed diabetes Data collected in a similar N N manner for all participants Cases interviewed within N N 6 months of diagnosis Interviewer blinded with N N respect to the case status of the person interviewed (c) Time period during which all N N participants were interviewed was the same (c) Same exclusion criteria N N applied to all participants Cohort studies (n = 8) Loss to follow-up was -- -- independent of exposure Intensity of search of disease -- -- independent of exposure status Other populations Lewis Zierold et al. et al. 1999 2004 All studies (n = 19) Diabetes diagnosis based on N N fasting glucose levels or oral glucose tolerance tests Exposure assessed at the N Y individual level Exposure assessed using a N N biomarker of exposure Control for established N Y diabetes risk factors in addition to age Case-control and cross-sectional studies (n = 11) Response rate among noncases -- N at least 70% (b) Noncases would have been cases -- N if they had developed diabetes Data collected in a similar -- Y manner for all participants Cases interviewed within -- N 6 months of diagnosis Interviewer blinded with -- Y respect to the case status of the person interviewed (c) Time period during which all -- Y participants were interviewed was the same (c) Same exclusion criteria -- Y applied to all participants Cohort studies (n = 8) Loss to follow-up was Y -- independent of exposure Intensity of search of disease Y -- independent of exposure status Abbreviations: --, not applicable; N, no; Y, yes. (a) Criteria modified from Longnecker et al. (1988). (b) Not applicable to two case-control studies based only on deaths (Rahman and Axelson 1995; Rahman et al. (1996). (c) Not applicable to the study using the National Health Insurance Database from Taiwan (Wang et al. 2003).