Autophagy upregulation as a possible mechanism of arsenic induced diabetes

Abstract

The key features of type 2 diabetes mellitus (T2DM) caused by high fat diet (HFD) in combination with arsenic (As) exposure (pronounced glucose intolerance despite a significant decrease in insulin resistance) are different from those expected for T2DM. Autophagy has been considered as a possible link between insulin resistance and obesity. Therefore in this study, we utilized autophagy gene expression profiling via real-time RT-PCR array analysis in livers of NMRI mice exposed to an environmentally relevant and minimally cytotoxic concentration of arsenite (50 ppm) in drinking water while being fed with a HFD for 20 weeks. Out of 84 genes associated with autophagy under study, 21 genes were related to autophagy machinery components of which 13 genes were downregulated when HDF diet was applied. In this study, for the first time, it was shown that the exposure to arsenic in the livers of mice chronically fed with HFD along with increased oxidative stress resulted in the restoration of autophagy [upregulation of genes involved in the early phase of phagophore formation, phagophore expansion and autophagosome-lysosome linkage stages]. Considering the role of arsenic in the induction of autophagy; it can be argued that reduced insulin resistance in HFD − As induced diabetes may be mediated by autophagy upregulation.

Crosstalk between autophagy and apoptosis induced by camphor in Schizosaccharomyces pombe

“…Our results showed that low-dose camphor (0.4 mg/mL) caused a strong autophagy activation (see Figures 1A and 1B), which is similar to low-dose arsenic exposure, known to induce autophagy in human cancer cell lines, i.e. BEAS-2B cells (Zhang et al, 2012) and U-373-MG cells (Kanzawa et al, 2003), or in mouse liver (Zeinvand-Lorestani et al, 2018). When camphor and arsenic doses increased to higher levels (two-to fivefold), cells in both experimental groups showed a significant decrease in the number of GFP-Atg8 dots, although cell viability decreased to its lowest levels and a strong cell death signal was activated, as shown in Figures 2 and 3.…”

Arsenite exposure suppresses adipogenesis, mitochondrial biogenesis and thermogenesis via autophagy inhibition in brown adipose tissue

“…from Dr. Zhang’s group treated As (III) concentrations ranging 0.5 to 5 µM [37.5 to 375 ppb] in NIH 3T3 fibroblasts upto 48 hrs and observed that arsenic inhibits SNARE complex formation by enhancing O-GlcNAcylation of SNAP29 and drives autophagy dysfunction 73 . However, in another arsenic research group suggested that arsenic at 50 ppm (equivalent of 50,000 ppb or 667 µM) in drinking water administration in NMRI mice under 20 weeks of HFD actually increased both macroautophagy and Chaperon-mediated autophagy (CMA) in liver tissues 74 . Since the macroautophagy response is more rapid and the CMA is activated when macroautophagy is inhibited or defective under prolonged nutritional stress 75–77 , the upregulation of gene expression levels of both macroautophagy and CMA genes would be a compensation effect of serious macroautophagy or CMA defect and possible non-apoptotic cell death in liver.…”

Fatigue, Sleep, and Autoimmune and Related Disorders

“…Neurons in the brainstem project toward many areas of the brain that can modulate fatigue including the amygdala, cortex, central nucleus of the amygdala, nucleus accumbens, paraventricular nucleus, and lateral hypothalamic areas of the hypothalamus, cerebellum, and other areas of the brainstem (314, 315). The NTS projects to areas of the brain that modulate the respiratory response (315), which could serve to alter oxygen and nutrient supply to affect fatigue. The NTS has projections to the other areas of the brain stem including the dorsal raphe nucleus and locus coeruleus.…”