Impaired Glucose Metabolism, Anti-Diabetes Medications, and Risk of Thyroid Cancer

Abstract

The prevalence of obesity is progressively increasing along with the potential high risk for insulin resistance and development of type 2 diabetes mellitus. Obesity is associated with increased risk of many malignancies, and hyperinsulinemia has been proposed to be a link between obesity and cancer development. The incidence of thyroid cancer is also increasing, making this cancer the most common endocrine malignancy. There is some evidence of associations between obesity, insulin resistance and/or diabetes with thyroid proliferative disorders, including thyroid cancer. However, the etiology of such an association has not been fully elucidated. The goal of the present work is to review the current knowledge on crosstalk between thyroid and glucose metabolic pathways and the effects of obesity, insulin resistance, diabetes, and anti-hyperglycemic medications on the risk of thyroid cancer development.

Role of GLIS3 in thyroid development and in the regulation of gene expression in thyroid specific Glis3KO mice

“…We also reported that, in addition to congenital hypothyroidism, these mice develop neonatal diabetes and hypoinsulinemia [39,58]. IGF-1 and insulin, together with TSH, have been reported to play a critical role in the regulation of gene expression and proliferation in thyroid follicular cells [51][52][53][54][55][56] raising the possibility that the pancreatic phenotype, including hypoinsulinemia, and conceivably changes in other tissues in ubiquitous Glis3-de cient mice might in uence the function and gene expression in thyroid follicular cells. This hypothesis was supported by observations showing that in contrast to ubiquitous Glis3-KO(LID) mice, thyroid follicular cell proliferation, expression of cell cycle genes, including Ccnb1, Ccnb2, and Cdca2, and activation of the mTOR, a pathway that promotes cell proliferation, were not repressed in Glis3-Pax8Cre(LID) mice but induced to a similar degree as in WT(LID) mice (Fig.…”

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

“…The increase in glucose uptake across the plasma membrane, which is necessary to support energy needs for cancer development, was reported in thyroid cancer cells, in which an elevated expression of GLUT1 and GLUT3 could be mainly involved in the oncogenesis process [125]. Additionally, hyperglycemia can affect cancer cellular growth and proliferation via many other mechanisms, such as increasing oxidative stress and inflammatory cytokines, the protection of cancer cells from apoptosis, the stimulation of cell motility, and adhesion [122].…”

“…An association between THs and diabetes has also been demonstrated in pregnant women with gestational diabetes or pre-existing T2D, with possible adverse effects for both maternal and fetal health [120,121]. The relationship between IR and/or T2D, obesity, and thyroid cancer has been recently explored and, although the etiology of such an association is unclear, it may involve high insulin levels, increased body fat, hyperglycemia, and antidiabetes medications including exogenous insulin use [122]. As for anti-diabetes drugs, the role of metformin in thyroid cancer remains controversial due to its growth-inhibitory effects, which are implicated in AMPK-related pathways, the mammalian target of NF-κB, rapamycin and mitochondrial glycerophosphate dehydrogenase [123].…”

Drug repositioning in thyroid cancer treatment: the intriguing case of anti-diabetic drugs

“…Only few clinical studies up to now evaluated the relationship between insulin therapy and thyroid cancer risk ( Kushchayeva et al, 2022 ). A 2014 studies based on data from the reimbursement databases of all Taiwanese diabetic patients from 1996 to 2009 evaluated the incidence of thyroid cancer according to the use, duration and dosage of therapy with human insulin.…”