Thyroid Diseases, Metformin and the AMP Kinase Pathway

Abstract

Introduction Thyroid hormone and adenosine monophosphate-activated protein kinase (AMPK) are 2 major determinants of energy balance. Thyroid hormone is known to be a key factor that stimulates energy use in energy balance. It is involved in almost every stage of energy use. The uptake of energy substances into the cell, their conversion to adenosine triphosphate (ATP) in the mitochondria, and the use of ATP in all cellular processes where energy is required are under the stimulating control of tri-iodothyronine and partially 3,5-diiodo-L-thyronine. A deficiency in thyroid hormone production results in ineffective utilization of energy substrates in the cell, despite their sufficient level. A well-known example of this condiAn increase in the adenosine monophosphate (AMP)/adenosine triphosphate ratio activates AMP-activated protein kinase (AMPK), leading to inhibition of the mammalian target of rapamycin signaling pathway that is associated with autophagy, mitochondriogenesis, glucose uptake, mRNA stabilization, and cell cycle regulation. Metformin activates AMPK and inhibits mitochondrial oxidative phosphorylation. Currently, there is an increasing interest in investigating the effects of metformin on thyroid diseases. Recent data show an association between metformin treatment and lower incidence of thyroid cancer, better survival of patients with thyroid cancer, and lower thyroid volume and nodule size. Insulin-like growth factor receptor and AKT pathways are the AMPK-independent mechanisms through which metformin acts on thyroid diseases. Although metformin has a promising role in adjuvant therapy for thyroid cancers, welldesigned prospective trials are required before reaching a final decision.