In recent years, the number of individuals with insulin resistance and DM-2 has increased. Recently, high iodine levels (> 221ug / L excess) have been founded in patients with DM-2 [17], also high glucose levels and blood pressure were associated with DM-2 without alterations in their thyroid profile (Liu J et al., 2019). In addition to, the relationship between urinary iodine concentrations (UIC) and metabolic diseases, for example, ranges from 300 to 799 UIC are associated with metabolic syndrome, impaired glucose tolerance occurrence and prediabetes occurrence [19]. This evidence suggest that iodine participate in glucose regulation. In this regard, we evaluated for the first time the direct effect of iodine as lugol solution on glucose transport in mature 3T3-L1 adipocytes and insulin secretion in pancreatic cells. Our results showed that low doses of iodine as lugol solutions increases the glucose analog 2-NBDG transport in adipocytes and induce the secretion of insulin. These results agree with the increase in glucose transport in adipose tissue from individuals who have been administered thiazolidinedione (TZDs) a group of drugs that act as PPAR-γ ligands [24, 25] and have a similar mechanism of action to the lugol [26]. In our study we found that higher lugol doses induces proliferation inhibition, caspase-3 activation and oxidative stress in fibroblast, adipocytes and pancreatic cells. In agreement, in MCF-7 cell lines, the formation of iodolactones that act as a PPAR-γ ligand that bind to specific DNA sequences [9–11] can activate the expression of genes associated to lipid and glucose metabolism or apoptosis [13]. This result supports our recent finding that lugol induces a lipolytic effect dependent on PPAR-γ expression in 3T3-L1 adipocytes [12]. The glucose internalization in adipose tissue requires the mobilization of vesicles containing GLUT4 from cytoplasm to the cell membrane [27]. Although in this study we did not evaluate the mobilization of GLUT4, our results suggest that glucose transport dependent on GLUT4 expression. This could be related with PPAR-γ activation (which is very abundant in adipose tissue), because this transcription factor has been shown to directly regulate the expression of GLUT4 and c-Cbl proteins [28, 29]. This is supported by our previous study in mature adipocytes 3T3-L1 which showed that iodine-lugol solutions treatment increase PPAR-γ expression [12]. In addition, the region − 66/+163 pb of the GLUT4 promoter has Response Elements to PPAR (PPRE) which can regulate its expression [30].
On the other hand, exposure with lugol for 30 min and 6h did not significantly affect total protein expression of insulin receptor in adipocytes. These results lead us to hypothesize that exist an increase in the activation of β subunit of the receptors, because some reports have shown that hypoglycemic drugs increase phosphorylation of insulin receptors and not its total expression [31, 32]. Furthermore, no responsive elements for PPAR-γ have been identified in promotor regions of the insulin receptors [33].
TZD have shown effects on insulin sensibility at Akt level in several models of obesity and diabetes, demonstrating the importance of this kinase in glucose metabolism [24]. According to our results, exposure with lugol for 30 min and 6h did not produce changes in the total expression of Akt protein, although we show the activation of serine residues-473 from Akt (p < 0.05 vs control). In this regard, some authors have demonstrated an increase in the activation of phosphorylated form of Akt in diabetic patients treated with rosiglitazone [29, 33]. Moreover, different investigations have demonstrated the effects of TZDs in improving the activity of Akt and PI3K protein kinases is due to direct or indirect activation of PPAR-γ and its effect on gene expression [34]. For example, in muscle cells from individuals with T2D and obesity troglitazone increases the expression of PPAR-γ at mRNA and protein level, as well as increases in the activity of glycogen synthase [35]. Because serine-473 phosphorylation of Akt can be considered as an indirect downstream marker of PI3K protein activity [24]. This suggest that iodine lugol solution will also improve the activity of this protein, an assumption that is supported by the fact that TZD can activate the p110 catalytic subunit of PI3K [34]. Another explanation may involve the phosphorylation of AS160 protein on multiple sites by Akt, then AS160 phosphorylated is required for the translocation of GLUT4 to the plasma membrane [36]. In addition, the gene TBC1D4 that encoded to AS160 protein a Rab-GTPase-activating protein is regulated by ER-alpha and iodine treatment can activate these receptors [37], this suggest that AS160 could be participating in the translocation of GLUT4 to the membrane, although this hypothesis should be studied.
In conclusion, iodine as lugol regulates the glucose metabolism, and low doses of iodine lugol solutions stimulated glucose uptake through Akt phosphorylation at S473 and GLUT4 expression in mature adipocytes and induces insulin secretion in Beta-TC-6 cells. Higher iodine concentrations inducing loss of cell viability, caspase-3 activation and oxidative stress. The present study provides an approach to the effect of lugol on glucose metabolism, it is necessary more research to corroborate the results and establish a detailed mechanism of action in animal models. Further studies are required to determine the iodine excess effects on pancreas tissue.