Adiponectin, also called GBP-28, apM1, AdipoQ and Acrp30, is a novel adipose tissue-specific protein that has structural homology to collagen VIII and X and complement factor C1q, and that circulates in human plasma at high levels. It is one of the physiologically active polypeptides secreted by adipose tissue, whose multiple functions have started to be understood in the last few years.A reduction in adiponectin expression is associated with insulin resistance in some animal models. Administration of adiponectin has been accompanied by a reduction in plasma glucose and an increase in insulin sensitivity. In addition, thiazolidinediones, drugs that enhance insulin sensitivity through stimulation of the peroxisome proliferator-activated receptor-g, increase plasma adiponectin and mRNA levels in mice. On the other hand, this adipocyte protein seems to play a protective role in experimental models of vascular injury. In humans, adiponectin levels are inversely related to the degree of adiposity and positively associated with insulin sensitivity both in healthy subjects and in diabetic patients. Plasma adiponectin levels have been reported to be decreased in some insulin-resistant states, such as obesity and type 2 diabetes mellitus, and also in patients with coronary artery disease. On the contrary, chronic renal failure, type 1 diabetes and anorexia nervosa are associated with increased plasma adiponectin levels. Concentrations of plasma adiponectin have been shown to correlate negatively with glucose, insulin, triglyceride levels and body mass index, and positively with high-density lipoprotein-cholesterol levels and insulin-stimulated glucose disposal. Weight loss and therapy with thiazolidinediones increased endogenous adiponectin production in humans.Adiponectin increases insulin sensitivity by increasing tissue fat oxidation, resulting in reduced circulating fatty acid levels and reduced intracellular triglyceride contents in liver and muscle. This protein also suppresses the expression of adhesion molecules in vascular endothelial cells and cytokine production from macrophages, thus inhibiting the inflammatory processes that occur during the early phases of atherosclerosis. In view of these data, it is possible that hypoadiponectinemia may play a role in the development of atherosclerotic vascular disease. In summary, the ability of adiponectin to increase insulin sensitivity in conjunction with its antiinflammatory and anti-atherogenic properties have made this novel adipocytokine a promising therapeutic tool for the future, with potential applications in states associated with low plasma adiponectin levels.

Thyroid hormones (TH) are essential for an adequate growth and development of the kidney. Conversely, the kidney is not only an organ for metabolism and elimination of TH, but also a target organ of some of the iodothyronines' actions. Thyroid dysfunction causes remarkable changes in glomerular and tubular functions and electrolyte and water homeostasis. Hypothyroidism is accompanied by a decrease in glomerular filtration, hyponatremia, and an alteration of the ability for water excretion. Excessive levels of TH generate an increase in glomerular filtration rate and renal plasma flow. Renal disease, in turn, leads to significant changes in thyroid function. The association of different types of glomerulopathies with both hyper-and hypofunction of the thyroid has been reported. Less frequently, tubulointerstitial disease has been associated with functional thyroid disorders. Nephrotic syndrome is accompanied by changes in the concentrations of TH due primarily to loss of protein in the urine. Acute kidney injury and chronic kidney disease are accompanied by notable effects on the hypothalamus-pituitary-thyroid axis. The secretion of pituitary thyrotropin (TSH) is impaired in uremia. Contrary to other non-thyroidal chronic disease, in uraemic patients it is not unusual to observe the sick euthyroid syndrome with low serum triodothyronine (T 3 ) without elevation of reverse T 3 (rT 3 ). Some authors have reported associations between thyroid cancer and kidney tumors and each of these organs can develop metastases into the other. Finally, data from recent research suggest that TH, especially T 3 , can be considered as a marker for survival in patients with kidney disease.

We aimed to analyze the natural course of subclinical hypothyroidism, quantify the incidence rate of overt hypothyroidism, and evaluate the risk factors for the development of definitive thyroid failure in elderly patients. One hundred seven patients (93 women and 14 men) over age 55 yr with subclinical hypothyroidism and no previous history of thyroid disease were prospectively studied. Subjects were followed up for 6-72 months (mean, 31.7 months) with repeated determinations of TSH and free T(4). Twenty-eight patients (26.8%) developed overt hypothyroidism, and 40 (37.4%) showed normalization of their TSH values. The incidence rate of overt hypothyroidism was 9.91 cases per 100 patient-years in the whole population, and 1.76, 19.67, and 73.47 cases per 100 patient-years in subjects with initial TSH values between 5.0-9.9, 10.0-14.9, and 15.0-19.9 mU/liter, respectively. Kaplan-Meier analysis showed that the development of definitive thyroid hypofunction was significantly related to the presence of symptoms of hypothyroidism, goiter, positive thyroid antibodies (P < 0.05), and mainly low normal free T(4) (P < 0.01) and high TSH (P < 0.0001) concentrations at baseline. A stepwise multivariate Cox regression analysis showed that the only significant factor for progression to overt hypothyroidism was serum TSH concentration (P < 0.0001). In conclusion, TSH concentration is the most powerful predictor for the outcome of spontaneous subclinical hypothyroidism in patients over age 55 yr. Subjects with mildly elevated TSH have a low incidence rate of overt hypothyroidism. We recommend follow-up with clinical and biochemical monitoring in these patients.

In order to identify genetic factors related to thyroid cancer susceptibility, we adopted a candidate gene approach. We studied tag- and putative functional SNPs in genes involved in thyroid cell differentiation and proliferation, and in genes found to be differentially expressed in thyroid carcinoma. A total of 768 SNPs in 97 genes were genotyped in a Spanish series of 615 cases and 525 controls, the former comprising the largest collection of patients with this pathology from a single population studied to date. SNPs in an LD block spanning the entire FOXE1 gene showed the strongest evidence of association with papillary thyroid carcinoma susceptibility. This association was validated in a second stage of the study that included an independent Italian series of 482 patients and 532 controls. The strongest association results were observed for rs1867277 (OR[per-allele] = 1.49; 95%CI = 1.30–1.70; P = 5.9×10−9). Functional assays of rs1867277 (NM_004473.3:c.−283G>A) within the FOXE1 5′ UTR suggested that this variant affects FOXE1 transcription. DNA-binding assays demonstrated that, exclusively, the sequence containing the A allele recruited the USF1/USF2 transcription factors, while both alleles formed a complex in which DREAM/CREB/αCREM participated. Transfection studies showed an allele-dependent transcriptional regulation of FOXE1. We propose a FOXE1 regulation model dependent on the rs1867277 genotype, indicating that this SNP is a causal variant in thyroid cancer susceptibility. Our results constitute the first functional explanation for an association identified by a GWAS and thereby elucidate a mechanism of thyroid cancer susceptibility. They also attest to the efficacy of candidate gene approaches in the GWAS era.

Tumor-induced hypoglycemia (TIH) is a rare clinical entity that may occur in patients with diverse kinds of tumor lineages and that may be caused by different mechanisms. These pathogenic mechanisms include the eutopic insulin secretion by a pancreatic islet b-cell tumor, and also the ectopic tumor insulin secretion by non-islet-cell tumor, such as bronchial carcinoids and gastrointestinal stromal tumors. Insulinoma is, by far, the most common tumor associated with clinical and biochemical hypoglycemia. Insulinomas are usually single, small, sporadic, and intrapancreatic benign tumors. Only 5-10% of insulinomas are malignant. Insulinoma may be associated with the multiple endocrine neoplasia type 1 in 4-6% of patients. Medical therapy with diazoxide or somatostatin analogs has been used to control hypoglycemic symptoms in patients with insulinoma, but only surgical excision by enucleation or partial pancreatectomy is curative. Other mechanisms that may, more uncommonly, account for tumor-associated hypoglycemia without excess insulin secretion are the tumor secretion of peptides capable of causing glucose consumption by different mechanisms. These are the cases of tumors producing IGF2 precursors, IGF1, somatostatin, and glucagon-like peptide 1. Tumor autoimmune hypoglycemia occurs due to the production of insulin by tumor cells or insulin receptor autoantibodies. Lastly, massive tumor burden with glucose consumption, massive tumor liver infiltration, and pituitary or adrenal glands destruction by tumor are other mechanisms for TIH in cases of large and aggressive neoplasias.