Retracted: Receptor for advanced glycation end products reveals a mechanism regulating thyroid hormone secretion through the SIRT1/Nrf2 pathway

Abstract

Advanced glycation end products (AGEs) play a causative role in the complications involved with diabetes mellitus (DM). Nowadays, DM with hypothyroidism (DM-hypothyroidism) is indicative of an ascended tendency in the combined morbidity. In this study, we examine the role of the receptor (RAGE) played for AGEs in thyroid hormone (TH) secretion via the silent information regulator 1 (SIRT1)/nuclear factor erythroid-derived factor 2-related factor 2 (Nrf2) pathway. Blood samples were collected from patients with type 2 DM (T2DM)-hypothyroidism and from patients with T2DM, followed by detection of serum AGEs level. The underlying regulatory mechanisms of RAGE were analyzed in association with the treatment of high glucose, siRNA against RAGE, AGE, SIRT1, or Nrf2 vector in normal immortalized thyroid Nthy-ori 3-1 cells. Serum of patients with T2DMhypothyroidism indicated promoted levels of AGEs vs those with just T2DM. Both AGEs and high glucose triggered cellular damage, increased oxidative stress, as well as displayed a decreased survival rate along with TH secretion in the Nthy-ori 3-1 cells. Moreover, AGEs and high glucose also led to RAGE upregulation, both SIRT1 and NRF2 downregulation, and the decreased expression of TH secretion-related proteins in Nthy-ori 3-1 cells. Notably, these alternations induced by the AGEs can be reserved by silencing RAGE or upregulating either SIRT1 or Nrf2, indicating a mechanism of regulating TH secretion through the SIRT1/Nrf2 pathway. Collectively, our data proposed that AGEs and high glucose exerted a potent effect on cellular damage and TH deficiency in Nthy-ori 3-1 cells through the RAGE upregulation as well as SIRT1/Nrf2 pathway inactivation. This mechanism may underlie the occurrence of DM-hypothyroidism. K E Y W O R D Shypothyroidism, Nthy-ori 3-1 cells, nuclear factor erythroid-derived factor 2-related factor 2, receptor for advanced glycation end products, silent information regulator 1, type 2 diabetes mellitus J Cell Biochem. 2019;120:4582-4598. wileyonlinelibrary.com/journal/jcb 4582 |

Lower free thyroid hormone levels are associated with high blood glucose and insulin resistance; these normalize with metabolic improvement of type 2 diabetes

“…Increased risks for metabolic syndrome were associated with a decrease in serum FT4, especially in nonobese adults 25 . Chen et al proposed that advanced glycation end products (AGEs) and high glucose levels exerted a potent effect on cellular damage and thyroid hormone deficiency through AGE upregulation as well as silent mating type information regulation 2 homolog‐1 (SIRT1)/nuclear factor‐E2‐related factor 2 (Nrf2) pathway inactivation 26 . In obese children, hyperthyrotropinemia could already be detected in the prepubertal age, and the increased oxidative stress might represent one of the key regulators of TSH levels 27 .…”

The Regulatory Effect of SIRT1 on Extracellular Microenvironment Remodeling

“…In clinical work, Diabetes mellitus is often found to be coexisted with hypothyroidism [53]. This might be partially related to the upregulation of advanced glycation end products (AGEs), high glucose induce advanced glycation end products receptor (RAGE) and the inactivation of SIRT1/nuclear factor erythroid 2-related factor (NRF2) pathway [54][55][56] (Fig. 2B).…”

Genome‑wide profiling of DNA methylation and gene expression unravel the epigenetic landscape in diabetes-related hypothyroidism

“…Wnt signaling pathway was found under control of DNA methylation in our study and was reported to be linked to inflammation, which suggested that DNA methylation of specific genes of Wnt signaling pathway might participated in diabetes-related hypothyroidism [ 28 , 29 ]. Chen et al confirmed that high concentration of glucose inhibited proliferation of Nthy-ori3-1 cells and arrested more thyroid cells in G0/G phase [ 30 ]. This finding suggested that the reduction of thyroid cells might be partly responsible for low thyroid hormone levels.…”