Juan J. Díez

Serum concentrations of leptin, adiponectin and resistin, and their relationship with cardiovascular disease in patients with end‐stage renal disease

Background and Objective  High levels of some adipocytokines have been reported in patients with chronic renal failure, but little information is available on adipocytokine concentrations in uraemic patients under different modalities of therapy. Our aims were (1) to quantify the serum concentrations of leptin, adiponectin and resistin in uraemic patients on peritoneal dialysis (PD) and haemodialysis (HD), in comparison with patients on conservative management, and (2) to study the relationships between adipocytokine levels and previous atherosclerotic vascular disease.

Serum concentrations of adipocytokines in patients with hyperthyroidism and hypothyroidism before and after control of thyroid function

objective  Adipose tissue is a hormonally active system that produces and releases different bioactive substances. Leptin, adiponectin and resistin are some of the recently discovered adipocytokines that participate in the regulation of intermediate metabolism. The aim of this study was to evaluate the circulating levels of leptin, adiponectin and resistin in patients with thyroid dysfunction before and after normalization of thyroid function with appropriate therapy.

MECHANISMS IN ENDOCRINOLOGY: Biological role, clinical significance, and therapeutic possibilities of the recently discovered metabolic hormone fibroblastic growth factor 21

Fibroblast growth factor 21 (FGF21), a 181 amino acid circulating protein, is a member of the FGF superfamily, with relevant metabolic actions. It acts through the interaction with specific FGF receptors and a cofactor called β-Klotho, whose expression is predominantly detected in metabolically active organs. FGF21 stimulates glucose uptake in adipocytes via the induction of glucose transporter-1. This action is additive and independent of insulin. β-Cell function and survival are preserved, and glucagon secretion is reduced by this protein, thus decreasing hepatic glucose production and improving insulin sensitivity. Lipid profile has been shown to be improved by FGF21 in several animal models. FGF21 increases energy expenditure in rodents and induces weight loss in diabetic nonhuman primates. It also exerts favorable effects on hepatic steatosis and reduces tissue lipid content in rodents. Adaptive metabolic responses to fasting, including stimulation of ketogenesis and fatty acid oxidation, seem to be partially mediated by FGF21. In humans, serum FGF21 concentrations have been found elevated in insulin-resistant states, such as impaired glucose tolerance and type 2 diabetes. FGF21 levels are correlated with hepatic insulin resistance index, fasting blood glucose, HbA1c, and blood glucose after an oral glucose tolerance test. A relationship between FGF21 levels and long-term diabetic complications, such as nephropathy and carotid atheromatosis, has been reported. FGF21 levels decreased in diabetic patients after starting therapy with insulin or oral agents. Increased FGF21 serum levels have also been found to be associated with obesity. In children, it is correlated with BMI and leptin levels, whereas in adults, FGF21 levels are mainly related to several components of the metabolic syndrome. Serum FGF21 levels have been found to be elevated in patients with ischemic heart disease. In patients with renal disease, FGF21 levels exhibited a progressive increase as renal function deteriorates. Circulating FGF21 levels seem to be related to insulin resistance and inflammation in dialysis patients. In summary, FGF21 is a recently identified hormone with antihyperglycemic, antihyperlipidemic, and thermogenic properties. Direct or indirect potentiation of its effects might be a potential therapeutic target in insulin-resistant states.

Gonadal dysfunction in men with chronic kidney disease: clinical features, prognostic implications and therapeutic options

Gonadal dysfunction is a frequent finding in men with chronic kidney disease and with end-stage renal disease. Testosterone deficiency, usually accompanied by elevation of serum gonadotropin concentrations, is present in 26-66% of men with different degrees of renal failure. Uremia-associated hypogonadism is multifactorial in its origin, and rarely improves with initiation of dialysis, although it usually normalizes after renal transplantation. Experimental and clinical evidence suggests that testosterone may have important clinical implications with regards to kidney disease progression, derangements in sexual drive, libido and erectile dysfunction, development of anemia, impairment of muscle mass and strength, and also progression of atherosclerosis and cardiovascular disease. Additionally, low testosterone levels in hemodialysis patients have been associated with increased mortality risk in some studies. Currently, we count with available therapeutic options in the management of uremic hypogonadism, from optimal delivery of dialysis and adequate nutritional intake, to hormone replacement therapy with different testosterone preparations. Other potential options for treatment include the use of antiestrogens, dopamine agonists, erythropoiesis-stimulating factors, vitamins, essential trace elements, chorionic gonadotropin and renal transplantation. Potential adverse effects of androgen replacement therapy in patients with kidney disease comprise, however, erythrocytosis, prostate and breast cancer growth, reduced fertility, gynecomastia, obstructive sleep apnea and fluid retention. Androgen preparations should be used with caution with stringent monitoring in uremic men. Although there are encouraging data suggesting plausible benefits from testosterone replacement therapy, further studies are needed with regards to safety and effectiveness of this therapy.

Insulin therapy in renal disease

Diabetes mellitus (DM) is the main cause of end‐stage renal disease (ESRD). Conversely, chronic renal failure (CRF) is also associated with diverse alterations in carbohydrate and insulin metabolism. CRF‐induced metabolic disorders should be borne in mind when treating diabetic patients, to ensure the introduction of adequate therapy adjustments that are in line with the onset of renal function decline. Moreover, several specific therapies employed in CRF may also influence pharmacological therapy of DM in uraemic patients. Adequate glycaemic control has also been associated with a reduction in the onset and progression of diabetic nephropathy as well as in the morbidity and mortality in uraemic diabetic patients during dialysis. Intensive insulin therapy can notably improve glycemic control and it should be considered part of the management of insulin‐treated CRF diabetic patients. Insulin analogues have been recently evaluated in CRF diabetic patients, with encouraging results. In this study, we review the more relevant aspects related to insulin therapy in diabetic patients with different degrees of renal failure and in patients with ESRD, both in conservative therapy and dialysis.

Eating behavior disorders in uremia: a question of balance in appetite regulation.

Eating and appetite disorders are frequent complications of the uremic syndrome which contribute to malnutrition in dialysis patients. The data suggest that uremic anorexia may occur with or without abdominal and visceral fat accumulation despite a lower food intake. This form of obesity (i.e., with low food intake and malnutrition) is more common in dialysis patients than obesity with high food intake. This article reviews the current knowledge regarding mechanisms responsible for appetite regulation in normal conditions and in uremic patients. Anorexia in dialysis patients has been historically considered as a sign of uremic toxicity due to ‘‘inadequate’’ dialysis as judged by uncertain means (‘‘middle molecule’’ accumulation, Kt/V, ‘‘peak‐concentration hypothesis,’’ and others). We propose the tryptophan‐serotonin hypothesis, based on a uremia‐induced disorder in patients’ amino acid profile—low concentrations of large neutral and branched‐chain amino acids with high tryptophan levels. A high rate of tryptophan transport across the blood‐brain barrier increases the synthesis of serotonin, a major appetite inhibitor. Inflammation may also play a role in the genesis of anorexia and malnutrition. For example, silent infection with Helicobacter pylori may be a source of cytokines with cachectic action; its eradication improves appetite and nutrition. The evaluation of appetite should take into account cultural and social aspects. Uremic patients showed a universal trend to carbohydrate preference and red meat refusal compared to healthy people. In contrast, white meat was less problematic. Uremic patients also have a remarkable attraction for citrics and strong flavors in general. Eating preferences or refusals have been related to the predominance of some appetite peptide modulators. High levels of cholecystokinin (CCK) (a powerful anorexigen) are associated with early satiety for carbohydrates and neuropeptide Y (NPY) (an orexigen) with repeated food intake. Obesity and elevated body mass index often falsely suggest a good nutritional status. In uremic patients (a hyperinsulinemia state), disorders in the regulation of fat distribution (insulin, leptin, insulin‐like growth factor [IGF]‐1, fatty acids, and disorders in receptors for insulin, lipoprotein lipase, mitochondrial uncoupling protein‐2, and β3‐adrenoreceptors) may cause abdominal fat accumulation without an increase in appetite. Finally, appetite regulation in uremia is highly complex. Disorders in adipose tissue, gastrointestinal and neuropeptides, retained or hyperproduced inflammatory end products, and central nervous system changes may all play a role. Uremic anorexia may be explained by a hypothalamic hyperserotoninergic state derived from a high concentration of tryptophan and low branched‐chain amino acids.

Serum concentrations of tumour necrosis factor‐alpha (TNF‐α) and soluble TNF‐α receptor p55 in patients with hypothyroidism and hyperthyroidism before and after normalization of thyroid function

backgbound Tumour necrosis factor‐α (TNF‐α) is a cytokine with numerous immunological and metabolic activities. Receptors for TNF‐α have been demonstrated in thyroid follicular cells and TNF‐α and its receptors have been implicated in the cytotoxic mechanisms that characterize the thyroid destruction in autoimmune thyroid disease. In patients with Graves’ disease, serum levels of TNF‐α have been reported to be elevated and administration of TNF‐α to humans has been shown to induce hormonal alterations resembling those seen in the nonthyroidal illness syndrome.

MANAGEMENT OF ENDOCRINE DISEASE A clinical update on tumor-induced hypoglycemia

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 β-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.

Serum insulin-like growth factor type 1, insulin-like growth factor-binding protein-1, and insulin-like growth factor-binding protein-3 concentrations in patients with thyroid dysfunction.

Thyroid hormones play a role in the regulation of insulin-like growth factor type 1 (IGF-1) and insulin-like growth factor-binding protein-3 (IGFBP-3) expression, and both IGF-1 and IGFBPs have been shown to be related to the function and growth of the thyroid. Our aim was to evaluate serum concentrations of IGF-1, IGFBP-1, and IGFBP-3 in patients with thyroid dysfunction before and after normalization of thyroid function. The study was performed in 86 patients with thyroid dysfunction (43 hyperthyroid and 43 hypothyroid patients) and 17 euthyroid subjects. Serum growth hormone (GH), insulin, IGF-1, IGFBP-1, and IGFBP-3 were measured in all patients before and after normalizing serum thyroid hormone concentrations. Hyperthyroid patients showed IGF-1 (198.8 +/- 17.0 microg/L) and IGFBP-3 levels (4.2 +/- 0.2 mg/L) similar to those found in the control group (217.9 +/- 20.3 microg/L and 4.2 +/- 0.3 mg/L, respectively). After therapy these levels significantly decreased to 156.6 + 11.1 microg/L (p < 0.01) and 3.3 +/- 0.1 mg/L (p < 0.001), respectively. IGFBP-1 concentrations were clearly higher than those found in controls (22.7+/- 2.6 vs. 5.7 +/- 1.5 microg/L, p < 0.001) and exhibited a significant reduction after therapy for thyroid hyperfunction (11.0 +/- 1.7 microg/L, p < 0.001). Patients with hypothyroidism showed serum concentrations of IGF-1 (161.5 +/- 13.1 microg/L, p < 0.05) and IGFBP-3 (3.2 +/- 0.3 microg/L, p < 0.05) significantly lower than those found in healthy volunteers. However, replacement therapy with levothyroxine did not induce any significant modification of these concentrations (152.6 +/- 10.6 microg/L and 3.2 +/- 0.2 mg/L, respectively). Similarly, patients with thyroid hypofunction exhibited raised levels of IGFBP-1 (15.5 +/- 0.9 microg/L, p < 0.05 vs. control group) that were significantly decreased after therapy (8.8 +/- 1.4 microg/L, p < 0.01). The results of the present study show that thyroid status affects GH/IGF axis. Hypothyroidism is associated with significant reductions of IGF-1 and IGFBP-3, and IGFBP-1 is elevated in both hypothyroidism and hyperthyroidism.

Spontaneous recovery from post-traumatic hypopituitarism

Recovery of the pituitary function from post-traumatic hypopituitarism is an exceptional event. We present the case of a 32 year-old man who was involved in a road traffic accident in which he suffered a severe head injury. Four days following the trauma the patient developed post-traumatic central diabetes insipidus and desmopressin was started. At discharge of the intensive care unit, the patient was referred to us for endocrine assessment. Three months after the head injury, the hormonal evaluation of the hypothalamic-pituitary axis by means of insulin stress test with the simultaneous administration of TRH and GnRH resulted in a reduced responses of GH, Cortisol, TSH, FSH, and LH with low baseline serum concentrations of free T4 and testosterone. Both serum basal and stimulated PRL concentrations were normal. Magnetic resonance imaging demonstrated deformity of the sella turcica with displacement of the pituitary gland by a post-traumatic retention cyst. A new evaluation of the pituitary function performed 6 months after the trauma showed spontaneous recovery of the gonadal, thyroid and adrenal function. However, GH response was reduced both to insulin-induced hypoglycemia, Clonidine and GHRH tests. Presence of normal serum PRL levels, normal PRL response to TRH and reduced GH responses to pituitary and hypothalamic stimuli suggests both hypothalamic and pituitary damage. The present case shows an unusual case of partial spontaneous resolution of a post-traumatic hypopituitarism. Based on this clinical observation we recommend periodic evaluation of the pituitary function in these kind of patients.