High T3 Induces β-Cell Insulin Resistance via Endoplasmic Reticulum Stress

Abstract

Hyperthyroidism can cause glucose metabolism disorders and insulin resistance. Insulin resistance in muscle and adipose tissues has been extensively studied, whereas investigations on β-cell insulin resistance are limited. This study preliminarily explored the effects of high T3 levels on β-cell line (MIN6) insulin resistance, as well as the roles of endoplasmic reticulum stress (ERS). In this study, we treated β-cell line with T3, with or without an inhibitor of phosphotyrosine phosphatases (PTPs, sodium vanadate) or ERS inhibitor (4-PBA). The results indicated that high levels of T3 significantly inhibited insulin secretion in β-cell line. In addition, we observed an upregulation of p-IRS-1ser307 and downregulation of Akt. These results can be corrected by sodium vanadate. Moreover, high T3 levels upregulate the ERS-related proteins PERK, IRE1, ATF6, and GRP78, as well as ERS-related apoptosis CHOP and caspase-12. Similarly, this change can be corrected by 4-PBA. These results suggest that high T3 levels can induce insulin resistance in β-cell line by activating ERS and the apoptotic pathway.

Metabolic Syndrome and Psoriasis: Mechanisms and Future Directions

“…Treatment with the ER stress inhibitor (tauroursodeoxycholate) can improve metabolic parameters in MetS rat and mitigate the MetS-induced cardiovascular complications (101). Reducing ER stress can alleviate IR (102)(103)(104)(105). Specifically, the interfered transport of newly synthesized insulin proreceptors from ER to the plasma membrane can inhibit the proteolytic maturation of insulin proreceptors.…”

Selenium and Selenoproteins at the Intersection of Type 2 Diabetes and Thyroid Pathophysiology

“…In thyrotoxicosis, T3 levels were positively correlated with IR, with the glucagon-to-ghrelin ratio identified as a significant determinant in this relationship [112]. Although high levels of T3 may cause IR in muscle and adipose tissue, only recently, a study documented that high T3 levels are further capable of inducing IR in β-cells by activating endoplasmic reticulum stress (ERS) (increased expression of ERS-related proteins PERK, IRE1, ATF6 and GRP78) and the apoptotic pathway (upregulation of the ERS apoptosis markers CHOP and caspase-12) [113]. An increased degradation of insulin has also been described in hyperthyroidism, which also determined an increased rate of gluconeogenesis and glycogenolysis, increased glucose uptake in peripheral tissues (especially in skeletal muscle), and the production of proinflammatory cytokines (e.g., interleukin 6 and tumor necrosis factor alpha) from adipose tissue [114].…”