Aart-Jan van der Lely

Rapid reversal of acute psychosis in the Cushing syndrome with the cortisol-receptor antagonist mifepristone (RU 486).

The progesterone-receptor antagonist, RU 486 (mifepristone), is also, at higher concentrations, an effective antagonist of glucocorticoid action in vitro and in vivo (1-3). In normal humans, RU 486...

Unacylated ghrelin and obestatin increase islet cell mass and prevent diabetes in streptozotocin-treated newborn rats

The ghrelin gene products, namely acylated ghrelin (AG), unacylated ghrelin (UAG), and obestatin (Ob), were shown to prevent pancreatic beta-cell death and to improve beta-cell function under treatment with cytokines, which are major cause of beta-cell destruction in diabetes. Moreover, AG had been described previously to prevent streptozotocin (STZ)-induced diabetes in rats; however, the effect of either UAG or Ob has never been examined in this context. In the present study, we investigated the potential of UAG and Ob to increase islet beta-cell mass and to reduce diabetes at adult age in STZ-treated neonatal rats. One-day-old rats were injected with STZ and subsequently administered with either AG, UAG or Ob for 7 days. On day 70, plasma glucose levels, plasma and pancreatic insulin levels, pancreatic islet area and number, insulin and pancreatic/duodenal homeobox-1 (Pdx1) gene expression, and antiapoptotic BCL2 protein expression were determined. Similarly to AG, both UAG and Ob counteracted STZ-induced high glucose levels and improved plasma and pancreatic insulin levels, which were reduced by the diabetogenic compound. UAG and Ob increased islet area, islet number, and beta-cell mass with respect to STZ treatment alone. Finally, in STZ-treated animals, UAG and Ob up-regulated insulin and Pdx1 mRNA and increased the expression of BCL2 similarly to AG. Taken together, our results suggest that in STZ-treated newborn rats, UAG and Ob improve glucose metabolism and preserve islet cell mass, granting a therapeutic potential in medical conditions associated with impaired beta-cell function.

Distribution pattern of somatostatin and cortistatin mRNA in human central and peripheral tissues

background  Somatostatin receptors (sst) and their endogenous ligand, somatostatin (SS), are widely expressed throughout the human body. Recently, the cDNA of a novel SS‐like peptide, named cortistatin (CST), has been cloned. This CST was found to be expressed in more restricted areas, like brain cortex, testes, kidney, stomach and leucocytes. Further studies demonstrated a selective expression of CST in tissues and cells of the human immune system, while SS was not expressed.

Somatostatin receptor imaging for neuroendocrine tumors

Tumors and metastases that express the somatostatin receptor subtypes sst2 sst3 or sst5 can be visualized in vivo after injection of radiolabeled octapeptide somatostatin analogs, like 111In-pentetreotide. 111In-pentetreotide scintigraphy also allows for more accurate staging of the disease by demonstrating tumor sites, which were not shown by conventional imaging. 111In-pentetreotide scintigraphy may also detect resectable tumors that would have remained unrecognized using conventional radiological imaging techniques; it may prevent surgery with curative intent in those patients whose tumors have metastasized to a greater extend than could be detected with conventional radiological imaging and it may be used to select patients for treatment with the currently available octapeptide somatostatin analogs or with tumor targeted radioactive treatment with radiolabelled somatostatin analogs.111In-pentetreotide scintigraphy has also been used to select patients with pituitary tumors for medical treatment with octapeptide analogs, but its clinical usefulness for this purpose seems to be limited. It further allows scar tissue to be differentiated from tumor recurrence after the pituitary surgery or radiotherapy. However, a large variety of lesions in and around the pituitary region also express somatostatin receptors and, therefore, can be visualized by 111In-pentetreotide scintigraphy.

Risk Factors for Meningitis After Transsphenoidal Surgery

To evaluate possible risk factors for meningitis, we retrospectively reviewed 228 transsphenoidal operations (in which a standard regimen of amoxicillin prophylaxis was used) for sellar pathology. The incidence of meningitis was 3.1% (seven of 228 cases). Cultures of preoperative specimens from the anterior nasal vestibule in three of seven patients yielded Staphylococcus aureus, but none of these patients developed S. aureus meningitis. Two of three patients with significant preoperative paranasal sinus abnormalities developed meningitis compared with only five of 225 patients without significant paranasal sinus abnormalities (P < .005). Three of 22 patients with intraoperative cerebrospinal fluid (CSF) leakage developed meningitis compared with four of 206 patients without intraoperative CSF leakage (P < .05). Six of seven patients with postoperative CSF rhinorrhea and only one of 221 patients without postoperative CSF rhinorrhea developed meningitis (P < .00001). In conclusion, postoperative CSF leakage is an important risk factor for meningitis after transsphenoidal surgery. Cultures of preoperative specimens from the anterior nasal vestibule did not have any predictive value in our study.

Des-acyl ghrelin analogs prevent high-fat-diet-induced dysregulation of glucose homeostasis

There is clinical evidence that des‐acyl ghrelin (DAG) favorably modulates glucose and lipid metabolism, although its mode of action is unknown. A murine model of prediabetes was used to assess possible mechanisms of action for DAG and a newly developed bioactive analog, AZP531. C57BL/6J mice were infused with saline, DAG, or AZP531 continuously for 4 wk, and fed either normal diet (ND) or normal diet for 2 wk followed by a high‐fat diet (HFD) for 2 wk. Compared with mice in the ND group, HFD increased body and fat mass, caused glucose intolerance and insulin resistance, had proinflammatory effects in white adipose tissue, and caused lipid accumulation in brown adipose tissue. DAG and AZP531 treatment prevented HFD‐induced proinflammatory effects, stimulated expression of mitochondrial function markers in brown adipose tissue, and prevented development of a prediabetic metabolic state. AZP531 also prevented a HFD‐induced increase in acyl ghrelin levels. Our data indicate DAG analogs as potential treatment for the prevention of metabolic syndrome.—Delhanty, P. J. D., Huisman, M., Baldeon‐Rojas, L.Y., van den Berge, I., Grefhorst, A., Abribat, T., Leenen, P. J. M., Themmen, A. P. N., van der Lely, A.‐J. Des‐acyl ghrelin analogs prevent high‐fat diet‐induced dysregulation of glucose homeostasis. FASEB J. 27, 1690–1700 (2013). www.fasebj.org

Postoperative metyrapone test in the early assessment of outcome of pituitary surgery for Cushing's disease

The prediction of relapse during the early months after transsphenoidal surgery for Cushings disease remains difficult. We have evaluated the usefulness of the postoperative metyrapone test in this situation.

Peptide receptors in gut endocrine tumours

A great number of gut endocrine tumours show high expression of receptors for neuropeptides, such as SRIF and VIP. The expression of ssts is essential for the control of hormonal hypersecretion and tumour growth by octapeptide somatostatin analogues. Five different sst subtypes, named sst1-5, have been cloned and characterized. The therapeutic efficacy of the octapeptide analogues is determined by the expression of sst2 (sst3) and sst5 on the tumour. In general, there is a predominant expression of sst1 and sst2 mRNA in gut endocrine tumours. In vivo sst scintigraphy, after injection of [111In]pentetreotide, provides a useful tool for the diagnostic work-up of patients with these tumours. This technique can be used for the localization of the primary tumour(s), for the determination of the extent of metastatic spread and for the selection of potential candidates for therapy with (radiolabelled) octapeptide analogues. Differentiated gut endocrine tumours also show a high expression of VIP-Rs. However, undifferentiated tumours show VIP-R expression to a smaller degree. In vivo scintigraphy with 123I-labelled VIP is a sensitive technique for the in vivo identification of gut endocrine tumours and their metastases. The functional role of the tumoral VIP-Rs is still unclear and at present there are no known therapeutic applications for VIP-R agonists or antagonists in humans.

Pasireotide, a multi-somatostatin receptor ligand with potential efficacy for treatment of pituitary and neuroendocrine tumors

Somatostatin receptors are an important target for medical treatment of pituitary and neuroendocrine tumors. To date, five somatostatin receptor (sst) subtypes have been identified. The currently available somatostatin analogues octreotide and lanreotide have predominantly affinity for sst2. Pasireotide is a sst multireceptor ligand with affinity for sst1, sst2, sst3 and sst5 and this broader binding profile may translate into a higher efficacy with respect to suppression of hormone production and cell growth in certain tumors. Experimental animal studies and in vitro studies with cultured tumor cells have shown that pasireotide strongly suppresses growth hormone and adrenocorticotropin production. In addition, pasireotide can influence tumor cell growth via effects on apoptosis and angiogenesis. In this review, the role of somatostatin receptors in pituitary and neuroendocrine tumors is briefly discussed followed by an overview of possible applications of pasireotide based on recent trials in patients with acromegaly, Cushings disease and neuroendocrine tumors.

The continuous 7‐hour intravenous dexamethasone suppression test in the differential diagnosis of ACTH‐dependent Cushing's syndrome

A recent report showing disappointingly low sensitivity and specificity for the oral high dose dexamethasone test in the differential diagnosis of Cushings syndrome prompted us to re‐evaluate the results obtained in our centre using the continuous 7‐hour intravenous dexamethasone suppression test for this purpose.