The pathophysiological consequences of somatostatin receptor internalization and resistance

Somatostatin receptors expressed on tumor cells form the rationale for somatostatin analog treatment of patients with somatostatin receptor-positive neuroendocrine tumors. Nevertheless, although somatostatin analogs effectively control hormonal hypersecretion by GH-secreting pituitary adenomas, islet cell tumors, and carcinoid tumors, significant differences are observed among patients with respect to the efficacy of treatment. This may be related to a differential expression of somatostatin receptor subtypes among tumors. In addition, the property of somatostatin receptor subtypes to undergo agonist-induced internalization has important consequences for visualizing, as well as for therapy, of receptor-positive tumors using radioisotope- or chemotherapeutic-compound-coupled somatostatin analogs. This review covers the pathophysiological role of somatostatin receptor subtypes in determining the efficacy of treatment of patients with somatostatin receptor-positive tumors using somatostatin analogs, as well as the preclinical and clinical consequences of agonist-induced receptor internalization for somatostatin receptor-targeted radio- and chemotherapy. Herein, the development and potential role of novel somatostatin analogs is discussed

The role of IGF-I in the development of cardiovascular disease in type 2 diabetes mellitus: is prevention possible?

The incidence of peripheral, cerebro- and cardiovascular disease (CVD) in patients with type 2 diabetes mellitus is approximately twice as high as in the non-diabetic population. Conventional cardiovascular risk factors such as plasma lipids, lipoproteins and hypertension only partially explain this excessive risk of developing atherosclerosis and CVD. Meta-analysis of studies performed in non-diabetic populations indicates that the risk of CVD increases continuously with glucose levels above 4.2 mmol/l. The glucose hypothesis suggests that treatment which normalizes glucose levels prevents or delays the long-term complications of diabetes mellitus. However, the outcome of the UK Prospective Diabetes Study demonstrates that glucose control does not completely prevent CVD.In healthy subjects, serum IGF-I levels peak in early adulthood, after which they gradually decrease with increasing age. Several observations suggest that there is a premature and progressive age-related decline in serum IGF-I bioactivity in type 2 diabetics, which eventually results in a (relative) IGF-I deficiency. In type 2 diabetics, close relationships have been demonstrated between glycaemic control and serum IGF-I levels, with worse control being associated with lower IGF-I levels. Several studies (in non-diabetics) suggest that lowered circulating IGF-I levels account for a poor outcome of CVD. We previously observed in a population-based study that a genetically determined lowered IGF-I expression increases the risk of myocardial infarction with type 2 diabetes.This genetic approach overcomes the problem tha

Polymorphisms in the glucocorticoid receptor gene and their associations with metabolic parameters and body composition

Most actions of glucocorticoids (GCs) are mediated by the glucocorticoid receptor (GR). The interindividual response to GCs varies considerably, as demonstrated by a variable suppressive response to 0.25-mg dexamethasone (DEX). Several polymorphisms in the gene coding for the GR have been described. It is unclear to what extent the observed response variability is due to GR polymorphisms or to other factors. However, at least three polymorphisms seem to be associated with altered GC sensitivity and changes in body composition and metabolic parameters. The N363S polymorphism has been associated with increased sensitivity to GCs, increased insulin response to DEX, a tendency towards lower bone mineral density, and increased body mass index (BMI). However, other reports found no associations with BMI. Another polymorphism, previously described as a BclI restriction fragment length polymorphism, recently was identified as a C --> G nucleotide change. The G allele also was associated with increased sensitivity to GCs. In middle-aged subjects

De levenscyclus van de zalm in relatie tot enkele neuro-endocriene ziekten bij de mens

Rede, uitgesproken bij de openbare aanvaarding van het ambt van gewoon hoogleraar in de inwendige geneeskunde, in het bijzonder de klinische en experimentele neuro-endocrinologie aan de Erasmus Universiteit te Rotterdam op woensdag 3 februari 198

Cortisol en vetweefsel

In dit proefschrift wordt een poging ondernomen om de werking van cortisol op de vetcel nader te onderzoeken, onder meer tegen de achtergrond van de karakteristieke vetverdeling in de vorm van de zogenaamde rompadipositas zoals die bij vele patienten met het syndroom van Cushing gevonden word

The future endocrine patient. Reflections on the future of clinical endocrinology

In recent years the future position of clinical endocrinology has been extensively discussed by Western European endocrine societies. Clinical endocrinology seems to suffer from being too intellectual, generating too little income, and lacking too few spectacular interventions. In this manuscript we describe 'the endocrine patient' of the past, the present, and the future. Complete therapeutic breakthroughs resulting in 'cure' are compared with 'halfway technologies' which help in creating the (life-long) chronic endocrine patient. The potential use of molecular diagnostics in optimalizing hormone replacement therapy is discussed. Clinical endocrinology is at risk of developing into a subspecialty where life-style drugs created for new diseases or conditions are offered, but also actively pursued by otherwise healthy individuals (e.g. in normal short stature, regulation of appetite, body composition, sexuality, reproduction and aging). The potential opportunities and risks for clinical endocrinology in creating 'the endocrine patient' of the future are discussed

Role of somatostatin receptors in normal and tumoral pituitary corticotropic cells

Normal and tumoral pituitary corticotropic cells express sst2and sst5, of which sst5is the predominantly expressed receptor subtype. Somatostatin (SS) inhibits pituitary adrenocorticotropin hormone (ACTH) secretion in vitro, but the sensitivity to SS is strongly regulated by glucocorticoids. In pathological conditions of a low endogenous cortisol level, i.e. in patients with adrenal insufficiency and in patients with Nelson's syndrome, SS and sst2-preferring SS analogs (SSA), such as octreotide, are able to lower circulating ACTH and cortisol levels. On the other hand, sst2-preferring SSA seem not effective in lowering ACTH and cortisol levels in patients with untreated Cushing's disease (CD), in which circulating cortisol levels are high. This is likely due to the downregulation of sst2receptors by glucocorticoids. sst5receptor expression is more resistant to the inhibitory effect of glucocorticoids. In recent years, novel sst subtype-selective and universal SSA have been developed. In particular, SSA with a high sst5-binding affinity are potent inhibitors of ACTH secretion by pituitary corticotropic adenoma cells. This knowledge has initiated clinical trials evaluating the efficacy of these novel SSA in patients with CD, with the aim to lower circulating ACTH and cortisol levels by targeting multiple ssts on the corticotropic adenoma cells. In this minireview, the effects of SS in the regulation of normal and tumoral ACTH secretion, the role of sst subtypes involved herein, as well as the potentials of novel SSA in the treatment of patients with recurrent or persisting CD are discussed