Effect of Pioglitazone on Thyroid Hormones and IGF-I in Patients with Type 2 Diabetes

Changes in thyroid function affect insulin sensitivity, although the studies on the nature of this relationship show somewhat conflicting results. Hyperthyroidism is associated with increased hepatic glucose output, resulting in hyperinsulinemia and insulin resistance [1]. However, insulin resistance is also seen in hypothyroidism [2]. Few studies have examined the effect of improved insulin sensitivity on thyroid hormone status in humans.


Introduction
Changes in thyroid function affect insulin sensitivity, although the studies on the nature of this relationship show somewhat conflicting results. Hyperthyroidism is associated with increased hepatic glucose output, resulting in hyperinsulinemia and insulin resistance [1]. However, insulin resistance is also seen in hypothyroidism [2]. Few studies have examined the effect of improved insulin sensitivity on thyroid hormone status in humans.
The peroxisome proliferation activated receptors (PPARα, β and γ) are a group of nuclear receptors involved in regulation of lipid metabolism and adipose tissue differentiation. Like PPARs, thyroid hormone receptors (TR) belong to the nuclear receptor super family, and act by binding to DNA and modulating gene expression [3]. Both are co-expressed in the brain, liver and adipocytes. In order to bind to DNA and activate transcription, both PPAR and TR require heterodimerization with the retinoid X receptor (RXR). In addition to activating transcription through its own response elements, PPARα is able to selectively down-regulate the transcriptional activity of TR through competitive binding to RXR [4].
PPAR agonists and T3 have been found to act either in a synergistic or opposing manner on various genes involved in lipid metabolism. Their signaling pathways converge through their mutual competition for heterodimerization with RXR. Chu et al. have demonstrated such an interaction in animal studies [5].
Pioglitazone is a PPARγ-activator used in the treatment of type 2 diabetes (T2D). It increases insulin sensitivity in various tissues, partly by redistributing fatty acids from those tissues to the subcutaneous adipose tissue. It also has some agonistic effects on PPARα [6]. In our earlier studies we have noted an increase in eye protrusion in a subgroup Abstract Background: Thyroid hormones cause insulin resistance. Pioglitazone is a peroxisome proliferator activated receptor gamma (PPARγ) agonist, used as treatment of type 2 diabetes (T2D) to increase insulin sensitivity. PPARs and thyroid hormone receptors (TRs) induce intracellular effects through similar molecular mechanisms, and the former may inhibit activation of the latter. Pioglitazone has been shown to increase eye protrusion, a symptom linked both to disturbed thyroid hormone levels and orbital edema secondary to increased IGF-I.

Aims:
We investigated whether attenuation of insulin resistance with pioglitazone affects thyroid hormone status and IGF-I.

Methods
: 48 patients with T2D were treated with pioglitazone for 26 weeks. Thyroid hormones and IGF-I were analyzed before and after treatment.

Conclusion: Pioglitazone lowers free T4 and increases IGF-I in T2D
. This may be due to impeded activation of the TR due to PPAR activation. Increased TSH is most likely secondary to reduce T4 activity. Increased IGF-I may cause orbital edema, as previously noted in patients treated with pioglitazone.
of patients with T2D treated with pioglitazone [7]. This phenomenon was more pronounced in patients with lower levels of adiponectin, reflecting a higher degree of insulin resistance. Given the known effects of PPARγ agonists on adipose tissue differentiation, it is possible that treatment induces orbital adipogenesis. This has been indicated in one study on endogenous PPARγ ligands [8]. In a study on insulin resistant women with polycystic ovary syndrome, pioglitazone increased GH but not total IGF-I [9], whereas in our previous studies on patients with T2D total IGF-I was increased [10,11]. Increased levels of IGF-I are associated with edema, especially in the face and orbita [12,13]. Stimulation of the IGF-I receptor may contribute to ophthalmopathy in Grave's disease, at least in those patients with elevated levels of TSHbinding inhibitory immunoglobulins [14]. We investigated whether attenuation of insulin resistance with pioglitazone affects thyroid hormone status and IGF-I.

Assays
HbA 1c was analyzed with the Variant II chromatographic method [15] and IGF-I with in-house radio-immunoassay (RIA) [16]. Adiponectin was analyzed using RIA (Research Adiponectin Assay, Linco, St. Charles, Missouri, USA). The limit of sensitivity for the assay was 1 ng/ml and both the inter-and intra assay coefficients of variation were < 10%. TSH and free T4 were analyzed using chemiluminescence (UniCelDxl 800 97, DxI Beckman Coulter, Brea, CA, USA), total CV 6.2 and 3.4% respectively.

Statistics
Paired t-tests were used to compare IGF-I (SD and μg/L) at baseline and after treatment as it was normally distributed; all other parameters were compared using non-parametric tests as they were not normally distributed. Pearson's correlation coefficients were calculated between continuous variables. P<0.05 was considered statistically significant. All data are presented as means ± SEM unless otherwise stated.

Discussion
Pioglitazone improved glycemic control (HbA 1c ) and insulin sensitivity (adiponectin). There was an increase in IGF-I, which regression analysis showed was partially related to improved glycemic control. Based on previous studies [9], increased GH may also have contributed to this increase.
After pioglitazone treatment, TSH increased while free T4 decreased. We hypothesize that pioglitazone's binding of PPARγ, which increases formation of PPAR-RXR dimers, impedes formation of TR-RXR complexes and thus reducing thyroid hormone function. The increased TSH most likely reflects pituitary response to feedback signals of reduced free T4 levels and TR activation, with the purpose restore thyroid hormone homeostasis. A concomitant increase in thyrotropin releasing hormone (TRH) may contribute to increased growth hormone and thereby IGF-I. Increased eye protrusion is more likely related to increased adipogenesis due to pioglitazone, and orbital edema secondary to increased IGF-I, to than changes in thyroid hormone status.

Significance of this Paper
Pioglitazone is a PPARγ agonist used in the treatment of type 2 diabetes, as it increases insulin sensitivity. Treatment is associated with increased eye protrusion, a condition often seen in Graves' disease. Given this, and the association of IGF-I with orbital edema, we studied the effect of pioglitazone treatment on thyroid hormones and IGF-I. We here report, for the first time, that pioglitazone decreases free T4, secondarily increasing TSH. We also report an increase in IGF-I. Especially the latter finding may explain the increased orbital protrusion seen in patients on pioglitazone therapy.  Adiponectin (µg/ml) 6.2 ± 0.4 13.2 ± 0.9 7.1 ± 0.6 <0.001 Table 1: Clinical characteristics and laboratory analyses at baseline and after 26 weeks of pioglitazone treatment. Data presented as mean ± SEM except for age and duration of diabetes, presented as mean (range). Δ = change in the variable after treatment compared with baseline, na = not applicable.