Association Between a Novel Variant of the Human Type 2 Deiodinase Gene Thr92Ala and Insulin Resistance

Mentuccia, D.; Proietti-Pannunzi, Laura; Tanner, Kandice; Bacci, Vincenzo; Pollin, Toni I.; Poehlman, Éric T.; Shuldiner, Alan R.; Celi, Francesco S.

doi:10.2337/diabetes.51.3.880

Cited by 197 publications

(170 citation statements)

References 30 publications

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“…Focus was then turned to the KPF induction of Dio2. D2 is an important component of the thermogenic gene expression profile in stimulated BAT and probably in HSM (3,(21)(22)(23). First, we verified that Dio2 induction by KPF resulted in a 8.5-to 50-fold increase in D2 activity in more than one cell line, including HSM myoblasts, MSTO-211H cells, and RMS-13 cells (Fig.…”

Section: Resultssupporting

confidence: 61%

The Small Polyphenolic Molecule Kaempferol Increases Cellular Energy Expenditure and Thyroid Hormone Activation

et al. 2007

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Disturbances in energy homeostasis can result in obesity and other metabolic diseases. Here we report a metabolic pathway present in normal human skeletal muscle myoblasts that is activated by the small polyphenolic molecule kaempferol (KPF). Treatment with KPF leads to an ϳ30% increase in skeletal myocyte oxygen consumption. The mechanism involves a several-fold increase in cyclic AMP (cAMP) generation and protein kinase A activation, and the effect of KPF can be mimicked via treatment with dibutyryl cAMP. Microarray and real-time PCR studies identified a set of metabolically relevant genes influenced by KPF including peroxisome proliferator-activated receptor ␥ coactivator-1␣, carnitine palmitoyl transferase-1, mitochondrial transcription factor 1, citrate synthase, and uncoupling protein-3, although KPF itself is not a direct mitochondrial uncoupler. The cAMP-responsive gene for type 2 iodothyronine deiodinase (D2), an intracellular enzyme that activates thyroid hormone (T3) for the nucleus, is approximately threefold upregulated by KPF; furthermore, the activity half-life for D2 is dramatically and selectively increased as well. The net effect is an ϳ10-fold stimulation of D2 activity as measured in cell sonicates, with a concurrent increase of ϳ2.6-fold in the rate of T3 production, which persists even 24 h after KPF has been removed from the system. The effects of KPF on D2 are independent of sirtuin activation and only weakly reproduced by other small polyphenolic molecules such as quercetin and fisetin. These data document a novel mechanism by which a xenobiotic-activated pathway can regulate metabolically important genes as well as thyroid hormone activation and thus may influence metabolic control in humans. Diabetes 56:767-776, 2007

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Section: Resultssupporting

confidence: 61%

The Small Polyphenolic Molecule Kaempferol Increases Cellular Energy Expenditure and Thyroid Hormone Activation

et al. 2007

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“…The common Thr92Ala D2 polymorphism (7) has been associated with traits of impaired thyroid hormone action at various end-organ targets (7-10), the hypothalamic-pituitary level (11), and in circulating levels of thyroid hormones (12). Nonetheless, results are conflicting (13)(14)(15)(16) and the data refer to steady-state serum thyroid hormone levels.…”

Section: Introductionmentioning

confidence: 88%

The Thr92Ala 5′ Type 2 Deiodinase Gene Polymorphism Is Associated with a Delayed Triiodothyronine Secretion in Response to the Thyrotropin-Releasing Hormone–Stimulation Test: A Pharmacogenomic Study

Butler

Smith

Linderman

et al. 2010

Thyroid

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Background: The common Thr92Ala D2 polymorphism has been associated with changes in pituitary-thyroid axis homeostasis, but published results are conflicting. To investigate the effects of the Thr92Ala polymorphism on intrathyroidal thyroxine (T4) to triiodothyronine (T3) conversion, we designed prospective pharmacogenomic intervention aimed to detect differences in T3 levels after thyrotropin (TSH)-releasing hormone (TRH)-mediated TSH stimulation of the thyroid gland. Methods: Eighty-three healthy volunteers were screened and genotyped for the Thr92Ala polymorphism. Fifteen volunteers of each genotype (Thr/Thr, Thr/Ala, and Ala/Ala) underwent a 500 mcg intravenous TRH stimulation test with serial measurements of serum total T3 (TT3), free T4, and TSH over 180 minutes. Results: No differences in baseline thyroid hormone levels were seen among the study groups. Compared to the Thr/Thr group, the Ala/Ala group showed a significantly lower TRH-stimulated increase in serum TT3 at 60 minutes (12.07 AE 2.67 vs. 21.07 AE 2.86 ng/dL, p ¼ 0.029). Thr/Ala subjects showed an intermediate response.Compared to Thr/Thr subjects, the Ala/Ala group showed a blunted rate of rise in serum TT3 as measured by mean time to 50% maximum delta serum TT3 (88.42 AE 6.84 vs. 69.56 AE 6.06 minutes, p ¼ 0.028). Subjects attained similar maximal (180 minutes) TRH-stimulated TT3 levels. TRH-stimulated TSH and free T4 levels were not significantly different among the three genotype groups. Conclusions: The commonly occurring Thr92Ala D2 variant is associated with a decreased rate of acute TSHstimulated T3 release from the thyroid consistent with a decrease in intrathyroidal deiodination. These data provide a proof of concept that the Thr92Ala polymorphism is associated with subtle changes in thyroid hormone homeostasis.

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“…Data reporting an association between this change and the risk of hypertension (120,121) or insulin resistance/diabetes are conflicting (58,(122)(123)(124). In a recent large case-controlled study of 1057 diabetics and 516 controls, the frequency of Thr92Ala was higher in the diabetic group.…”

Section: Gene Polymorphismsmentioning

confidence: 99%

Physiological role and regulation of iodothyronine deiodinases: A 2011 update

Marsili

Zavacki

Harney

et al. 2011

J Endocrinol Invest

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Thyroxine (T4) is a prohormone secreted by the thyroid. T4 has a long half life in circulation and it is tightly regulated to remain constant in a variety of circumstances. However, the availability of iodothyronine selenodeiodinases allow both the initiation or the cessation of thyroid hormone action and can result in surprisingly acute changes in the intracellular concentration of the active hormone T3, in a tissue-specific and chronologically-determined fashion, in spite of the constant circulating levels of the prohormone. This fine-tuning of thyroid hormone signaling is becoming widely appreciated in the context of situations where the rapid modifications in intracellular T3 concentrations are necessary for developmental changes or tissue repair. Given the increasing availability of genetic models of deiodinase deficiency, new insights into the role of these important enzymes are being recognized. In this review, we have incorporated new information regarding the special role played by these enzymes into our current knowledge of thyroid physiology, emphasizing the clinical significance of these new insights.

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Association Between a Novel Variant of the Human Type 2 Deiodinase Gene Thr92Ala and Insulin Resistance

Cited by 197 publications

References 30 publications

The Small Polyphenolic Molecule Kaempferol Increases Cellular Energy Expenditure and Thyroid Hormone Activation

The Small Polyphenolic Molecule Kaempferol Increases Cellular Energy Expenditure and Thyroid Hormone Activation

The Thr92Ala 5′ Type 2 Deiodinase Gene Polymorphism Is Associated with a Delayed Triiodothyronine Secretion in Response to the Thyrotropin-Releasing Hormone–Stimulation Test: A Pharmacogenomic Study

Physiological role and regulation of iodothyronine deiodinases: A 2011 update

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