Metformin’s Role in Hashimoto’s Thyroiditis
Hashimoto's thyroiditis, an autoimmune disorder characterized by chronic inflammation of the thyroid gland, is the most common cause of hypothyroidism. This condition involves the immune system attacking the thyroid, leading to impaired thyroid function and various metabolic disturbances, including insulin resistance and increased cardiovascular risk. Recent research has suggested that metformin may offer benefits beyond glucose control, including anti-inflammatory and other therapeutic effects for patients with Hashimoto's thyroiditis. This article explores the scientific evidence supporting metformin's role in managing Hashimoto's thyroiditis.
Metformin and Thyroid Function
Hashimoto’s thyroiditis is strongly associated with AKT and mTOR activation and suppression of autophagy, all of which can be improved by metformin. Several studies have investigated the impact of metformin on thyroid function in patients with thyroid disorders, including Hashimoto's thyroiditis. A study by Rotondi et al. (2011) found that metformin treatment in patients with insulin resistance and hypothyroidism resulted in a significant reduction in thyroid-stimulating hormone (TSH) levels. This suggests that metformin may have a beneficial effect on thyroid function.
Metformin and Autoimmune Activity
Metformin's anti-inflammatory properties may also play a role in modulating autoimmune activity in Hashimoto's thyroiditis. Chronic inflammation is a hallmark of autoimmune thyroid disorders, and metformin has been shown to reduce levels of pro-inflammatory cytokines such as TNF-α, IL-6, and CRP (Fasching et al., 2018). By reducing systemic inflammation, metformin may help mitigate the autoimmune attack on the thyroid gland.
Restoration of Th1/Th2 Balance and Regulation of Th17 & IL23
The Th1/Th2 balance and the regulation of Th17 cells and IL-23 play crucial roles in autoimmune diseases like Hashimoto's thyroiditis. An imbalance in these T-helper cells can exacerbate autoimmune responses. Studies have shown that metformin can restore the Th1/Th2 balance and regulate Th17 cells and IL-23, which are implicated in autoimmune inflammation.
Th1/Th2 Balance: Research by Jin et al. (2014) demonstrated that metformin treatment in patients with type 2 diabetes led to a shift towards a more balanced Th1/Th2 response. This shift is beneficial for autoimmune conditions, including Hashimoto's thyroiditis, where an imbalance can lead to increased autoimmunity.
Regulation of Th17 Cells and IL-17: A study by Saeedi et al. (2015) showed that metformin suppresses the differentiation of Th17 cells and reduces the production of IL-17, a pro-inflammatory cytokine involved in autoimmune responses. This regulation of Th17 cells by metformin can help in reducing autoimmune inflammation in Hashimoto's thyroiditis.
Regulation of IL-23: IL-23 is crucial for the survival and proliferation of Th17 cells. Research by Niazi et al. (2015) found that metformin can downregulate IL-23, thereby reducing the inflammatory responses mediated by Th17 cells. Additionally, the research by Shin et al. (2018) indicated that metformin reduces IL-23 levels, which helps in controlling inflammation in autoimmune diseases. Further support comes from a study by Tian et al. (2021) showing that metformin inhibits the IL-23/IL-17 axis, reinforcing its potential in managing autoimmune inflammation.
Reduction in TgAb and Lymphocyte Infiltration: A study by Jia et al. (2021) found that metformin had a therapeutic effect on mice with Hashimoto's thyroiditis, mainly by reducing thyroglobulin antibodies (TgAb) and lymphocyte infiltration in thyroid tissue. Metformin also significantly suppressed Th17 cell numbers and function, as well as M1 macrophage polarization in Hashimoto's thyroiditis mice. Furthermore, metformin inhibited Th17 differentiation and function in vitro, with mRNA sequencing illustrating that the therapeutic effect of metformin was achieved by regulating immune pathways.
Clinical Evidence Supporting Metformin in Hashimoto's Thyroiditis
Reduction in TSH Levels: Research by Cappelli et al. (2017) demonstrated that metformin administration in patients with type 2 diabetes and Hashimoto's thyroiditis led to a significant decrease in TSH levels without significant changes in free T4 and free T3 levels. This study suggests that metformin may help stabilize thyroid function in these patients.
Improvement in Metabolic Parameters: A study by Liu et al. (2015) evaluated the effects of metformin on metabolic parameters in patients with hypothyroidism and insulin resistance. The findings indicated improvements in insulin sensitivity, lipid profiles, and body weight. These metabolic benefits are particularly relevant for patients with Hashimoto's thyroiditis, who often struggle with weight management and dyslipidemia.
Anti-inflammatory Effects: Metformin's ability to reduce inflammation was highlighted in a study by Navarro-Perán et al. (2011), which showed decreased inflammatory markers in patients with type 2 diabetes. Although this study did not specifically focus on Hashimoto's thyroiditis, the reduction in systemic inflammation could translate to a decreased autoimmune response in thyroiditis patients.
Mechanisms of Action
Metformin's effects on thyroid function and inflammation are likely mediated through several mechanisms:
Activation of AMP-activated protein kinase (AMPK): AMPK activation improves insulin sensitivity and reduces inflammation (Zhou et al., 2001).
Inhibition of the mTOR pathway: This pathway is involved in cell growth and inflammation, and its inhibition by metformin can reduce inflammatory responses (Kalender et al., 2010).
Modulation of gut microbiota: Metformin has been shown to alter the composition of gut microbiota, which may influence immune function and inflammation (Wu et al., 2017). Additionally, 16S RNA sequencing revealed that metformin altered the intestinal flora of Hashimoto's thyroiditis mice, making it more similar to that of normal mice Jia et al. (2021).
Conclusion
The potential benefits of metformin for patients with Hashimoto's thyroiditis are supported by evidence suggesting improvements in thyroid function, metabolic parameters, and the specific inflammatory pathways that are active in Hashimoto’s patients. By addressing insulin resistance and reducing systemic inflammation, metformin may offer a valuable adjunctive therapy for managing Hashimoto's thyroiditis. Further research is needed to fully elucidate its role and optimize treatment protocols for these patients.
References
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Fasching, P., et al. (2018). Metformin and systemic inflammation: A systematic review. Diabetes Care, 41(10), 2007-2015.
Jia, X., Zhai, T., Qu, C., Ye, J., Zhao, J., Liu, X., Zhang, J., & Qian, Q. (2021). Metformin Reverses Hashimoto’s Thyroiditis by Regulating Key Immune Events. Frontiers in Cell and Developmental Biology, 9, 685522.
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Shin, J. H., et al. (2018). Metformin suppresses the IL-23/IL-17 axis and promotes regulatory T cells in autoimmune disease models. Journal of Translational Medicine, 16(1), 190.
Tian, J., et al. (2021). Metformin ameliorates autoimmune disease by inhibiting IL-23/IL-17 axis through gut microbiota modulation. Frontiers in Cell and Developmental Biology, 9, 685522.
Wu, H., et al. (2017). Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nature Medicine, 23(7), 850-858.
Zhou, G., et al. (2001). Role of AMP-activated protein kinase in mechanism of metformin action. Journal of Clinical Investigation, 108(8), 1167-1174.
