The recent cloning of the gene encoding the sodium/iodide symporter (NIS) has enabled better characterization of the molecular mechanisms underlying iodide transport, thus opening the way to clarifying its role in thyroid diseases. Several studies, at both the mRNA and the protein expression levels, have demonstrated that TSH, the primary regulator of iodide uptake, upregulates NIS gene expression and NIS protein abundance, both in vitro and in vivo. However, other factors, including iodide, retinoic acid, transforming growth factor-beta, interleukin-1alpha and tumour necrosis factor alpha, may participate in the regulation of NIS expression. Investigation of NIS mRNA expression in different thyroid tissues has revealed increased levels of expression in Graves' disease and toxic adenomas, whereas a reduction or loss of NIS transcript was detected in differentiated thyroid carcinomas, despite the expression of other specific thyroid markers. NIS mRNA was also detected in non-thyroid tissues able to concentrate radioiodine, including salivary glands, stomach, thymus and breast. The production of specific antibodies against the NIS has facilitated study of the expression of the symporter protein. Despite of the presence of high levels of human (h)NIS mRNA, normal thyroid glands exhibit a heterogeneous expression of NIS protein, limited to the basolateral membrane of the thyrocytes. By immunohistochemistry, staining of hNIS protein was stronger in Graves' and toxic adenomas and reduced in thyroid carcinomas. Measurement of iodide uptake by thyroid cancer cells is the cornerstone of the follow-up and treatment of patients with thyroid cancer. However, radioiodide uptake is found only in about 67% of patients with persistent or recurrent disease. Several studies have demonstrated a decrease in or a loss of NIS expression in primary human thyroid carcinomas, and immunohistochemical studies have confirmed this considerably decreased expression of the NIS protein in thyroid cancer tissues, suggesting that the low expression of NIS may represent an early abnormality in the pathway of thyroid cell transformation, rather than being a consequence of cancer progression. The relationship between radioiodine uptake and NIS expression by thyroid cancer cells require further study. New strategies, based on manipulation of NIS expression, to obtain NIS gene reactivation or for use as NIS gene therapy in the treatment of radiosensitive cancer, are also being investigated.

Persistent or recurrent disease is rare in low risk patients with papillary thyroid cancer, and follow-up of these patients is a matter of debate. Neck ultrasonography (US), serum thyroglobulin (Tg), and whole body scan (WBS) after T(4) withdrawal were performed in 456 patients, followed up to 5 yr. At the end of the first year, 335 patients were Tg negative, and 121 were Tg positive; 65 of 96 patients with Tg levels between 1 and 10 ng/ml became spontaneously Tg negative after 2 yr. During follow-up, WBS discovered node metastases in 13 subjects, and US discovered node metastases in 38 subjects (31 Tg positive and 7 Tg negative). WBS did not add any information, because all WBS-positive patients were also US and Tg positive. Fifty percent of metastases were less than 1 cm and not palpable. Finally, the negative predictive value of both negative Tg and US at first follow-up was 98.8%. We suggest a first follow-up based upon US assessment and stimulated (after T(4) withdrawal or recombinant human TSH) serum Tg determination; subsequently, 1) US should not be mandatory at each examination in initially Tg- and US-negative subjects, but is strongly suggested in all other cases; 2) Tg determination should be repeated 1 yr later, after exogenous or endogenous TSH stimulation only in initially Tg-positive patients without any other evidence of residual disease; and 3) Tg measurement during therapy should be sufficient in all other cases.

Context: Subjects with normal glucose tolerance (NGT) but 1-h postload glucose ≥ 155 mg/dL (NGT-1h-high) exhibit an intermediate cardiometabolic risk profile between individuals with NGT and impaired glucose tolerance (IGT). Objective: This study aimed to evaluate whether NGT-1h-high subjects have different cardiometabolic characteristics and an increased risk of type 2 diabetes compared with individuals with isolated impaired fasting glucose (IFG). Setting, Design, and Patients: A cross-sectional analysis was performed on 595 nondiabetic subjects who underwent an oral glucose tolerance test and an euglycemic hyperinsulinemic clamp in an ambulatory care setting. In addition, a longitudinal analysis was performed on 392 individuals, who were reexamined after a followup of 5.2 ± 0.9 y. Main Outcome Measures: Insulin sensitivity, beta-cell function, and risk of developing diabetes were measured. Results: Subjects with NGT-1h-high have a significant reduction of peripheral insulin sensitivity and beta-cell function, assessed by the disposition index, compared with either 1-h postload glucose < 155 mg/dL (NGT-1h-low) or IFG individuals, but not compared with IGT. Among the 392 subjects studied in the longitudinal analysis the incidence rate of type 2 diabetes over the follow-up period was 2.9, 16.7, 12.5, and 31.4% for subjects with NGT-1h-low, NGT-1h-high, IFG, and IGT, respectively. In a Cox proportional hazard regression analysis the risk of developing diabetes for NGT-1h-high subjects was 4.02 (95% confidence interval [CI] 1.06–15.26); an even higher risk (6.67; 95% CI, 2.09–21.24) was observed in subjects with IGT, but not in the isolated IFG group (1.91; 95% CI, 0.44–8.29). Conclusions: NGT-1h-high subjects exhibit a higher risk of developing diabetes than those with IFG or NGT-1h-low, likely due to decreased insulin sensitivity and beta-cell function.

Sodium/iodide symporter (NIS) is a key protein in iodide transport by thyroid cells and this activity is a prerequisite for effective radioiodide treatment of thyroid cancer. In the majority of thyroid cancers, however, iodide uptake is reduced, probably as a result of decreased NIS protein expression. To identify the mechanisms that negatively affect NIS expression in thyroid tumors, we performed electrophoresis mobility shift assays and immunoblot analysis of nuclear protein extracts from normal and tumoral thyroid tissues from 14 unrelated patients. Two proteins closely related to the transcription factors AP2 and Sp1 were identified in the nuclear extracts. Expression of both AP2 and Sp1 in nuclear extracts from thyroid tumors was significantly higher than that observed in corresponding normal tissues. These observations raise the possibility that NIS expression, and subsequently iodide transport, are reduced in thyroid tumors at least in part owing to alterations in the binding activity of AP2 and Sp1 transcription factors to NIS promoter.

Context: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and is associated with insulin resistance and cardiovascular disease. Among the potential factors that may account for the increased cardiometabolic risk, IGF-I is a plausible candidate because the liver is the main site of its production. Objective: Our objective was to examine the relationship between NAFLD and IGF-I levels and to test the hypothesis that free fatty acids-induced insulin resistance might impair insulin-induced increase of GH receptor (GHR) expression in human hepatoma cells. Subjects, Design, and Setting: Five hundred three nondiabetic Caucasians participated in this ambulatory-care cross-sectional study. Main Outcome Measures: Cardiometabolic risk factors and liver ultrasound scanning were assessed. Insulin-induced expression of GHR in HuH7 human hepatoma cells exposed for 24 h to palmitate was determined by Western blotting and real-time PCR. Results: After adjustment for age and gender, individuals with NAFLD had significantly higher body mass index, waist circumference, fasting insulin, triglycerides, homeostasis model assessment index, liver enzymes, and lower high-density lipoprotein cholesterol compared with control subjects. IGF-I levels were significantly lower in individuals with NAFLD (P = 0.001). Exposure of HuH7 hepatoma cells to palmitate caused a dose-dependent reduction in the insulin-induced increase of GHR expression. Conclusions: These data show that IGF-I levels are reduced in subjects with NAFLD and suggest that hepatic insulin resistance may affect IGF-I levels by modulating GH-stimulated synthesis of hepatic IGF-I.