How to cite this article: Marwa S Al L,Obesity, Insulin Resistance and Vitamin D Deficiency may be Reversible Risk Factors for Thyroid Cancer.J Endocrinol Thyroid Res. 2017; 1(5): 555574.. DOI:10.19080/JETR.2017.01.555574
Background: The incidence of thyroid cancer has been rising significantly over the past few decades; insulin resistance (IR), obesity and vitamin D deficiency (VDD) are found to be associated with many cancer types, this paper introduce a review for papers done in this field to show the association between IR, obesity, and VDD as reversible risk factors for thyroid cancer.
Methods: This paper was designed to review the previous studies in this field to evaluate the possible association between IR, obesity, VDD and thyroid cancer, possible mechanisms and the clinical applications.
Conclusion: Obesity, IR, and VDD are proved to be implicated in thyroid cancer incidence, but there relation to thyroid cancer aggressiveness still controversial, and whether vitamin D3 supplementation, physical activity, Drugs that decrease insulin resistance and diet may affect thyroid cancer prognosis and incidence still raw area for more researches.
Thyroid cancer is the comments endocrine malignancy, it’s incidence is rapidly increasing among all other malignancies, This rise may partly due to increase detection of thyroid cancers from enhanced usage of ultrasonography and fine-needle biopsies , and changes in exposure to environmental factors as ionizing radiation, and a family history of thyroid cancer. The aim of this paper is discuss if obesity, IR and Vitamin D deficiency (VDD) are possible risk factors for thyroid cancer and if so can we prevent thyroid cancer through weight control, Diet, Vitamin D supplementations, usage of metformin to decrease insulin resistance?
Obesity is proved to be associated with the development and progression of many malignancies as endometrial cancer, breast cancer, esophageal cancer, colon, adenocarcinoma, liver cell carcinoma, prostate cancer, leukemia, melanoma, and non-Hodgkin lymphoma . Recently, several studies have suggested a positive association between obesity and the prevalence of thyroid cancer [2-5], the underlying mechanism has not been confirmed. IGF-1, IR, cytokines, TSH, adiponectin, estrogens and leptin have been suggested as associated factors [6,7]. Obesity leads to a pro-inflammatory state, decrease adiponectin, and IR, which, leads to hyperinsulinemia and increase IGF1 levels, that may increase the risk for thyroid malignancies
Several studies have been done to show the relationships between obesity and clinical outcomes of thyroid cancer especially PTC [8-10]. There results remain still controversial. Some studies showed an association between obesity and more aggressive tumor stages [8,11,12], they suggested that overweight or obese patients with (PTC) more than 1cm in size had more risk of developing recurrent disease or loco-regional persistence . However, other studies showed a higher body mass index (BMI) was not accompanied with more aggressive pathological features, or the recurrence or persistence of disease [9,13]. Other one reported that obesity might be associated with less aggressive tumor invasion .
So as these studies have not shown consistent results, and whether or not the severity of obesity influences the prognosis and the aggressiveness of pathological stages of thyroid cancer so we need more studies to uncover this issue.
IR is a characteristic finding of most patients with simple
obesity, impaired glucose tolerance, type 2 diabetes mellitus, as
well as other disorders . Insulin stimulates proliferation of
thyroid cells in culture. The presence of insulin resistance (IR)
is associated with larger thyroid gland volume and an increased
prevalence of thyroid nodules. [15,16] and may be involved in
the pathogenesis of thyroid cancer development . It was
noticed that insulin receptors are overexpressed in most thyroid
tumors as an early stage in thyroid carcinogenesis .
IR may be due to chronic activation of the pro-inflammatory
pathway . Chronic activation of the NF-kB pro-inflammatory
pathway and/or JNK1 have been implicated . IGF-IR is
usually expressed at high levels in thyroid cancer cells , Vella
et al.  showed that thyroid cancers overexpress IGF-I, IGF-IR,
and IGF-II and IR . The concomitant increase expression of
IGF-IR and IR in thyroid cancer cells causes over expression of
IR/IGF-IR hybrid receptors that, in most cases, exceed the IGFIR
content so In cells with a high IR/IGF-IR content, blocking
antibodies specific to these receptors inhibit IGF-I-induced cell
So changes in the IGF system and the association with high
circulating levels of insulin/IGFs have been reported in thyroid
cancer, which may have important implications in endocrine
cancer prevention and treatment .
TSH itself is a major regulator of growth and differentiation of
thyroid cells, and plays a role in nodule formation. In the presence
of insulin in cell cultures, TSH is a well-known mitogen and also
suppresses apoptotic cell death in response to various stimuli
, This effect, is mediated in part via IGF-I dependent pathway;
therefore, IGF-1 might be expression of insulin receptor was
increased in hypo functioning benign thyroid adenomas which
lost differentiated functions such as iodine uptake. Therefore,
over expression or activation of insulin receptor may be an early
event in thyroid tumorigenesis and nodular formation . So,
hyperinsulinemia may act by enhancing thyroid proliferation,
independently of the patient BMI
Patients using Metformin had a lower risk for formation
of thyroid nodules and a smaller thyroid volume [23-25]. Also
Karimifar et al.  reported that metformin can reduce small
solid thyroid nodules size and prevent an increase in the thyroid
Metformin have complex effects that include not only
lowering IR but also direct effects on cancer cells , Benveng
et al.  noticed reduction in overall cancer incidence or
mortality when metformin is used in the treatment of diabetes
Metformin was found to antagonize the growth-stimulatory
effect of insulin in vitro and inhibition of cell cycle progression
and induction . A recent cross-sectional study also reported a
significant correlation between glycated hemoglobin and thyroid
volume or the number of nodules .
Metformin also has indirect anticancer property as Rotondi
et al. proved that metformin inhibit the TNF-α-induced CXCL8
secretion in primary cultures of human thyroid cells, Rotondi
et al. In addition to in vitro study done by Chen et al. 
showed that Rezzónico et al.  found that nodule size marked
decreased in patients treated with both metformin and L-T4
compared to patients’ recieving metformin alone. The shrinkage
of thyroid nodule was accompanied by decrease in TSH level
and normalization of the homeostasis model assessment HOMA
Clinical trials showed that metformin therapy was associated
with higher remission rate and survival in diabetic patients with
thyroid cancer , and a favorable outcome in diabetic patients
with cervical lymph node metastasis of DTC .
Another large observational study in Taiwanese patients with
T2DM showed that metformin reduced thyroid cancer risk .
In a mouse model, metformin could block progression of obesityactivated
thyroid cancer . On the other hand Becker et al.
 indicated neither use of metformin nor of other antidiabetic
drugs was associated with a decreased risk of thyroid cancer
Recently retrospective analysis found that metformin
attenuated a 131I-induced decrease of peripheral blood cells in
patients with DTC . Chen et al.  reported that sorafenib, a
multikinase inhibitor used as alternative therapy for radioiodineresistant
DTC, combined with 2 metformin synergistically
decreased the proliferation of anaplastic thyroid cancer cell lines
and the outgrowth of derived cancer stem cells .
In papillary thyroid cancer the therapeutic potential of
metformin has also been identified both in vitro and in vivo Cho
et al. Another study on medullary thyroid carcinoma (MTC) cell
lines showed that metformin inhibited growth in 2 MTC-derived
cells, suggesting that metformin inhibits growth and prevents
development of metastases in MTC . In addition, 2 metformin
may inhibit the growth, migration, and mesenchymal transition
of thyroid cancer cell lines by the mTOR pathway beyond insulin/
IGF-1 pathway .
In conclusion several studies demonstrated that metformin
was found to reduce the nodular volume and thyroid nodules
size, inhibit the growth of thyroid carcinoma and potentiate the
antimitogenic effect of chemotherapeutic agents and also may
have a TSH-lowering effect. So these findings suggest a broader
use of this drug not only for type 2 diabetics with or withoutproliferative thyroid disease but also for those with metabolic
syndrome and obesity. However, more studies are required to
show the effects of metformin in these patients.
Recently the researchers give attention to the relationship
between cancer and vitamin D levels, and the potential use of
vitamin D receptor as a therapeutic target, a correlation between
vitamin D and cancer prevention has been shown in breast,
prostate, and colorectal cancer .
Several studies strongly suggest that vitamin D3 deficiency
(VDD) increases the risk of developing malignancies [36-
38], while others studies reported that there is no association
between VDD and thyroid cancer incidence [39,40], prognosis
and aggressiveness [40,41]. However, Mawer et al.  suggest
that adequate vitamin D3 levels may provide protection against
cancer and may improve cancer prognosis . Expression of
the VDR gene and 25-hydroxyvitamin D3 1-α-hydroxylase, the
rate limiting enzyme in the production of active vitamin D3, has
been found in several tissues and tumor types . The active
form of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25D), exerts
antitumor activity by binding to the vitamin D receptor (VDR).
The antitumor activities of 1,25D include inhibition of cancer cell
proliferation and angiogenesis, promotion of cell differentiation
and apoptosis [44,45].
Şahin et al.  discovered that increased risk of thyroid
cancer in patients with more IR than with Vitamin D3 deficiency
and Whether they are coexisting or contributing is controversial
 but this study involved a small number of thyroid
cancer patients. Low vitamin D levels have been observed in
autoimmune thyroid diseases,  with no correlation of thyroid
autoantibodies and vitamin D levels.
Izkhakov et al.  showed that VDR mRNA expressed
much more in malignant thyroid tissues than in normal thyroid
tissues, that indicates a possible correlation between thyroid
cancer prognosis and VDR gene expression ; however, there
were no clinic pathological differences between patients with
low levels of gene expression and those with high levels of gene
expression. Clinckspoor et al.  reported that lower vitamin
D3 metabolism was associated with the progression of thyroid
cancer of follicular .
The very recent study Choi et al.  showed that
overexpression of VDR mRNA correlates with subtypes of
papillary thyroid carcinoma that have the worse prognosis,
classic and tall cell variant, and factors associated with poor
prognosis such as extra thyroidal extension, lateral neck node
metastasis, BRAF V600E mutation and tumor recurrence .
So VDD may be implicated in increasing thyroid cancer
incidence but whether it affect aggressiveness of the cancer ornot still controversial, and its deficiency should be associated
with IR to cause thyroid malignancy still also not known .
Obesity, IR, and VDD are proved to be implicated in
thyroid cancer incidence, but there relation to thyroid cancer
aggressiveness still controversial, and whether vitamin D3
supplementation, physical activity, Drugs that decrease insulin
resistance and diet may affect thyroid cancer prognosis and
incidence still raw area for more researches