Abnormal Glucose Metabolism and Insulin Resistance Are Induced via the IRE1 α/XBP-1 Pathway in Subclinical Hypothyroidism

In this study, we firstly re-analyzed the data of a mature database (NHANES, 1999 ~ 2002) and found that both fasting plasma glucose levels and the proportion of hyperglycemic subjects in SCH patients were higher than those in euthyroid controls. And SCH was associated with a 2.29-time increased risk for diabetes. Then, we established an SCH mouse model and applied OGTT and ITT. SCH mice exhibited impaired glucose and insulin tolerance. Increased HOMA-IR index and decreased ISI index, indicating insulin resistance (IR), were also observed in the SCH state. Hepatic ERp29 and Bip, as well as IRE1α and XBP-1s induced significantly in SCH mice, suggesting the activation of endoplasmic reticulum (ER) stress, especially the IRE1α/XBP-1s pathway. Interestingly, when we rectified ER stress by using 4-phenyl butyric acid, abnormal glucose metabolism and IR status in SCH mice apparently improved. Our findings suggested that ER stress, predominately the IRE1α/XBP-1s pathway, may play a pivotal role in abnormal glucose metabolism and IR induced by SCH, which may provide potential strategies for the prevention and treatment of diabetes.
Source: Frontiers in Endocrinology - Category: Endocrinology Source Type: research