Yingyun Gong1, Jidong Liu2, Yanfeng Xue2, Zhong Zhuang2, Sichong Qian2, Wenjun Zhou2, Xin Li2, Justin Qian2, Guolian Ding3, Zheng Sun4. 1. Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Department of Medicine-Endocrinology, Baylor College of Medicine, Houston, TX, United States of America. 2. Department of Medicine-Endocrinology, Baylor College of Medicine, Houston, TX, United States of America. 3. Department of Medicine-Endocrinology, Baylor College of Medicine, Houston, TX, United States of America; The International Peace Maternity and Child Health Hospital, Institute of Embryo-Fetal Original Adult Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: dingguolian@shsmu.edu.cn. 4. Department of Medicine-Endocrinology, Baylor College of Medicine, Houston, TX, United States of America; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States of America. Electronic address: zheng.sun@bcm.edu.
Abstract
BACKGROUND: Inorganic arsenic (iAs) is a widespread environmental toxin. In addition to being a human carcinogen, its effect on diabetes has started to gain recognition recently. Insulin is the key hormone regulating systemic glucose metabolism. The in vivo effect of iAs on insulin sensitivity has not been directly addressed. OBJECTIVES: Here we use mouse models to dissect the dose-dependent effects of iAs on glucose metabolism in vivo. METHODS: We performed hyperinsulinemic-euglycemic clamp, the gold standard analysis of systemic insulin sensitivity. We also performed dynamic metabolic testings and RNA-seq analysis. RESULTS: We found that a low-dose exposure (0.25 ppm iAs in drinking water) caused glucose intolerance in adult male C57BL/6 mice, likely by disrupting glucose-induced insulin secretion without affecting peripheral insulin sensitivity. However, a higher-dose exposure (2.5 ppm iAs) had diminished effects on glucose tolerance despite disrupted pancreatic insulin secretion. Insulin Clamp analysis showed that 2.5 ppm iAs actually enhanced systemic insulin sensitivity by simultaneously enhancing insulin-stimulated glucose uptake in skeletal muscles and improved insulin-mediated suppression of endogenous glucose production. RNA-seq analysis of skeletal muscles revealed that 2.5 ppm iAs regulated expression of many genes involved in the metabolism of fatty acids, pyruvate, and amino acids. CONCLUSION: These findings suggest that iAs has opposite glycemic effects on distinct metabolic tissues at different dose thresholds. Such non-monotonic dose-response effects of iAs on glucose tolerance shed light on the complex interactions between iAs and the systemic glucose metabolism, which could potentially help reconcile some of the conflicting results in human epidemiological studies.
BACKGROUND:Inorganic arsenic (iAs) is a widespread environmental toxin. In addition to being a human carcinogen, its effect on diabetes has started to gain recognition recently. Insulin is the key hormone regulating systemic glucose metabolism. The in vivo effect of iAs on insulin sensitivity has not been directly addressed. OBJECTIVES: Here we use mouse models to dissect the dose-dependent effects of iAs on glucose metabolism in vivo. METHODS: We performed hyperinsulinemic-euglycemic clamp, the gold standard analysis of systemic insulin sensitivity. We also performed dynamic metabolic testings and RNA-seq analysis. RESULTS: We found that a low-dose exposure (0.25 ppm iAs in drinking water) caused glucose intolerance in adult male C57BL/6 mice, likely by disrupting glucose-induced insulin secretion without affecting peripheral insulin sensitivity. However, a higher-dose exposure (2.5 ppm iAs) had diminished effects on glucose tolerance despite disrupted pancreatic insulin secretion. Insulin Clamp analysis showed that 2.5 ppm iAs actually enhanced systemic insulin sensitivity by simultaneously enhancing insulin-stimulated glucose uptake in skeletal muscles and improved insulin-mediated suppression of endogenous glucose production. RNA-seq analysis of skeletal muscles revealed that 2.5 ppm iAs regulated expression of many genes involved in the metabolism of fatty acids, pyruvate, and amino acids. CONCLUSION: These findings suggest that iAs has opposite glycemic effects on distinct metabolic tissues at different dose thresholds. Such non-monotonic dose-response effects of iAs on glucose tolerance shed light on the complex interactions between iAs and the systemic glucose metabolism, which could potentially help reconcile some of the conflicting results in human epidemiological studies.
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