Characterization of the Impaired Glucose Homeostasis Produced in C57BL/6 Mice by Chronic Exposure to Arsenic and High-Fat Diet

Paul, David S.; Walton, Felecia S.; Saunders, R. Jesse; Stýblo, Miroslav

doi:10.1289/ehp.1003324

Cited by 119 publications

(115 citation statements)

References 14 publications

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“…It is also possible that the observed hyperglycemia is linked to the development of NAFLD, and therefore, additional studies are needed to investigate the effects of fetal arsenic exposure on insulin levels. Nevertheless, the observation that glucose levels increased over time in the IU arsenic-exposed mice is consistent with the epidemiological studies associating type 2 diabetes mellitus with arsenic exposure [29,31], as well as with molecular mechanism and animal studies demonstrating that arsenic may impair insulin response and sensitivity [27,28,43,44].…”

Section: Discussionsupporting

confidence: 87%

Fetal exposure to arsenic results in hyperglycemia, hypercholesterolemia, and nonalcoholic fatty liver disease in adult mice

Sanchez-Soria¹,

Broka²,

Quach³

et al. 2014

J Toxicol Health

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Background: Exposure to arsenic is a major concern in the United States and worldwide, since this metalloid has been associated with a number of ailments, including cardiovascular and metabolic diseases. Environmental exposures to toxicants throughout fetal development have been shown to play a critical role as triggers of adult disease. Methods: This study aimed to evaluate the contribution of fetal arsenic exposure to the onset of metabolic syndrome. Swiss Webster mice were exposed to either 100 ppb sodium arsenite or sodium chloride via the dam's drinking water from embryonic day 6 until birth. Weight and metabolic end-points were evaluated throughout the 36 week study. Retroorbital bleeds and blood plasma analyses were done to evaluate glucose, lipids, triglycerides and liver enzymes. Livers were evaluated histologically to assess extent and progression of nonalcoholic fatty liver disease. Cardiovascular outcomes such as blood pressure and ventricular hypertrophy were evaluated using non-invasive tail-cuff method and echocardiography respectively.Results: Blood plasma analysis demonstrated that in-utero (IU) arsenic-exposed mice exhibited a significant increase in plasma glucose levels between weaning age and 4 months of age, which remained elevated after 8 months. Similarly, IU arsenic-exposed mice showed a consistent elevation in LDL and total cholesterol at weaning age, 4 months and 8 months of age. Mouse weight was not statistically different between groups, and no significant cardiovascular changes were seen. Further histological analysis of liver samples demonstrated the development of nonalcoholic fatty liver disease in IU arsenic-exposed mice, as evidenced by major morphological changes and an increase in steatosis concomitant with hepatocellular ballooning. Conclusions: Taken together, the results found in this study suggest that IU arsenic exposure is a possible contributor to metabolic syndrome onset in mice, having important implications in the evaluation of fetal exposures on the development of adult disease.

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Section: Discussionsupporting

confidence: 87%

Fetal exposure to arsenic results in hyperglycemia, hypercholesterolemia, and nonalcoholic fatty liver disease in adult mice

Sanchez-Soria¹,

Broka²,

Quach³

et al. 2014

J Toxicol Health

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“…PTAE treated HFD fed as well as HFD + STZ diabetic mice showed significantly lower blood glucose at all time points and lower AUC when compared to obese control and diabetic control which is shown in Table 4 41,42 . It may be due to the presence of hypoglycemic effect of flavonoids, phenols and saponins present in PTAE which we have reported in our previous study.…”

Section: Discussionmentioning

confidence: 94%

Untitled

2016

IJPSR

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Objective: This study was aimed to evaluate the role of GLP-1, GIP in the hypoglycemic activity of Phlogacanthus thyrsiflorus Nees. Materials and Methods: We have evaluated the influence of Phlogacanthus thyrsiflorus Nees, a traditionally used antidiabetic medicinal plant on some metabolic parameters, glucose homeostasis, insulin production, glucagon like peptide 1 (GLP1) and gastric Inhibitory Polypeptide (GIP) in high fat diet fed (HFD) obese mice and High fat diet + streptozotocin (HFD + STZ) induced diabetic mice. Oral glucose tolerance test (OGTT) was done to study the glucose homeostasis in both HFD fed obese mice and HFD + STZ induced diabetic mice. Effect of P. thyrsiflorus on pancreatic beta cells was assessed using histological studies. Results: Phlogacanthus thyrsiflorus aqueous extract (PTAE) treatment lowered the blood glucose levels in HFD fed obese mice and HFD + STZ induced diabetic mice significantly. PTAE treatment reduced the weight gain in HFD fed obese mice and prevented the constant weight loss in HFD+STZ induced diabetic mice. PTAE treatment decreased the food intake significantly in HFD fed obese mice. PTAE treatment improved the glucose tolerance and the lipid profile in HFD fed obese mice. PTAE treatment decreased the insulin level in HFD fed obese mice and increased the insulin level in HFD + STZ induced diabetic mice. PTAE treatment increased the GLP -1 level and decreased the GIP level significantly in both HFD fed obese mice and HFD + STZ induced diabetic mice. Histological studies of pancreas showed that P.thyrsiflorus helps normalizing the pancreatic histoarchitecture. Conclusion: This study states that the hyperglycaemic activity of the P.thyrsiflorus is due to the modulation of the enteroinsular axis in the Hypoglycemic mice. However the study also revealed the doubtful role of GIP as incretins and its role in diabetes treatment.

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“…Both Type 1 and 2 DM are characterized by hyperglycemia. Interestingly, it has been demonstrated that laboratory animals exposed to inorganic arsenic develop phenotypes consistent with DM, namely increased fasting blood glucose, impaired glucose tolerance and/or insulin resistance (Supplementary Box 1) [19][20][21][22][23][24][25]. Additionally, prenatal exposure to inorganic arsenic predisposes offspring to the development of DM in laboratory studies [26,27].…”

Section: Mechanisms Of Arsenic-associated Dmmentioning

confidence: 99%

“…The fourth mechanism is the induction of gluconeogenesis. While these processes are also involved in Type 2 DM [25], the ability of arsenic to dysregulate these processes supports that it is a diabetogen (Box 1).…”

Section: Mechanisms Of Arsenic-associated Dmmentioning

confidence: 99%

“…However, it has also been shown that arsenic exposure is inversely related to fasting plasma insulin and to the measure of insulin resistance (HOMA-IR) [44]. Similarly, mice that were exposed to arsenic and fed a highfat diet displayed impaired glucose tolerance and a dose-dependent decrease in HOMA-IR, likely due to lower fasting insulin and higher fasting blood glucose than in mice fed a low-fat diet [25]. Insulin response to glucose challenge was also impaired in these mice.…”

Section: Mechanisms Of Arsenic-associated Dmmentioning

confidence: 99%

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Genetic and epigenetic mechanisms underlying arsenic-associated diabetes mellitus: a perspective of the current evidence

2017

Self Cite

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Chronic exposure to arsenic has been associated with the development of diabetes mellitus (DM), a disease characterized by hyperglycemia resulting from dysregulation of glucose homeostasis. This review summarizes four major mechanisms by which arsenic induces diabetes, namely inhibition of insulin-dependent glucose uptake, pancreatic β-cell damage, pancreatic β-cell dysfunction and stimulation of liver gluconeogenesis that are supported by both in vivo and in vitro studies. Additionally, the role of polymorphic variants associated with arsenic toxicity and disease susceptibility, as well as epigenetic modifications associated with arsenic exposure, are considered in the context of arsenic-associated DM. Taken together, in vitro, in vivo and human genetic/ epigenetic studies support that arsenic has the potential to induce DM phenotypes and impair key pathways involved in the regulation of glucose homeostasis.

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Characterization of the Impaired Glucose Homeostasis Produced in C57BL/6 Mice by Chronic Exposure to Arsenic and High-Fat Diet

Cited by 119 publications

References 14 publications

Fetal exposure to arsenic results in hyperglycemia, hypercholesterolemia, and nonalcoholic fatty liver disease in adult mice

Fetal exposure to arsenic results in hyperglycemia, hypercholesterolemia, and nonalcoholic fatty liver disease in adult mice

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Genetic and epigenetic mechanisms underlying arsenic-associated diabetes mellitus: a perspective of the current evidence

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