Exposures to arsenite and methylarsonite produce insulin resistance and impair insulin-dependent glycogen metabolism in hepatocytes

Abstract

Environmental exposure to inorganic arsenic (iAs) has been shown to disturb glucose homeostasis, leading to diabetes. Previous laboratory studies have suggested several mechanisms that may underlie the diabetogenic effects of iAs exposure, including (i) inhibition of insulin signaling (leading to insulin resistance) in glucose metabolizing peripheral tissues, (ii) inhibition of insulin secretion by pancreatic β cells, and (iii) dysregulation of the methylation or expression of genes involved in maintenance of glucose or insulin metabolism and function. Published studies have also shown that acute or chronic iAs exposures may result in depletion of hepatic glycogen stores. However, effects of iAs on pathways and mechanisms that regulate glycogen metabolism in the liver have never been studied. The present study examined glycogen metabolism in primary murine hepatocytes exposed in vitro to arsenite (iAs) or its methylated metabolite, methylarsonite (MAs). The results show that 4-h exposures to iAs and MAs at concentrations as low as 0.5 and 0.2 µM, respectively, decreased glycogen content in insulin-stimulated hepatocytes by inhibiting insulin-dependent activation of glycogen synthase (GS) and by inducing activity of glycogen phosphorylase (GP). Further investigation revealed that both iAs and MAs inhibit insulin-dependent phosphorylation of protein kinase B/Akt, one of the mechanisms involved in the regulation of GS and GP by insulin. Thus, inhibition of insulin signaling (i.e., insulin resistance) is likely responsible for the dysregulation of glycogen metabolism in hepatocytes exposed to iAs and MAs. This study provides novel information about the mechanisms by which iAs exposure impairs glucose homeostasis, pointing to hepatic metabolism of glycogen as one of the targets.

A State-of-the-Science Review of Arsenic’s Effects on Glucose Homeostasis in Experimental Models

“…Hepatic manifestations are also present upon exposure, with the up-regulation of PCK1 and other rate-limiting enzymes of gluconeogenesis (Liu et al 2014). Trivalent methylated arsenical metabolites MMA and DMA share similar effects to their parent compound, interfering with metabolic pathways involved in glucose homeostasis (Zhang et al 2017;Hou et al 2013;Douillet et al 2013).…”

“…Arsenite treatment for 4 h also inhibited insulin-stimulated AKT phosphorylation at serines 308 and 473, characteristic of AKT activity (Zhang et al 2017). In contrast, the activity of glycogen synthase kinase 3, a downstream effector of AKT, was not affected by exposure to arsenite (Zhang et al 2017).…”

“…A recent study reported a dose-dependent decrease in glycogen content in mouse primary hepatocytes treated with low-dose (0:5-2 lM) arsenite for 4 h (Zhang et al 2017). Exposure to arsenite resulted in a dose-dependent reduction in insulin-dependent activation of glycogen synthase (GS), the rate-controlling enzyme in glycogenesis, and activation of GP, the rate-controlling enzyme in glycogenolysis (Zhang et al 2017). Arsenite treatment for 4 h also inhibited insulin-stimulated AKT phosphorylation at serines 308 and 473, characteristic of AKT activity (Zhang et al 2017).…”

“…Exposure to arsenite resulted in a dose-dependent reduction in insulin-dependent activation of glycogen synthase (GS), the rate-controlling enzyme in glycogenesis, and activation of GP, the rate-controlling enzyme in glycogenolysis (Zhang et al 2017). Arsenite treatment for 4 h also inhibited insulin-stimulated AKT phosphorylation at serines 308 and 473, characteristic of AKT activity (Zhang et al 2017). In contrast, the activity of glycogen synthase kinase 3, a downstream effector of AKT, was not affected by exposure to arsenite (Zhang et al 2017).…”

“…Four hours of exposure to arsenite and MMA III + concentrations as low as 0:5-2 lM decreased glycogen levels in insulinstimulated primary murine hepatocytes by interfering with ratelimiting glycogenesis genes GS and GP and increasing glucose output (Zhang et al 2017). Both arsenite and MMA III + downregulated GS and up-regulated GP, in addition to inhibiting AKT phosphorylation, insulin's regulatory step for glycogen synthesis (Zhang et al 2017).…”