Maralyn Druce

Ghrelin increases food intake in obese as well as lean subjects

OBJECTIVE:To investigate whether effects on food intake are seen in obese subjects receiving exogenous administration of ghrelin.DESIGN:Randomised, double-blind, placebo-controlled study of intravenous ghrelin at doses 1 pmol/kg/min and 5 pmol/kg/min.SUBJECTS:In all, 12 healthy lean subjects (mean body mass index (BMI) 20.5±0.17 kg/m2) and 12 healthy overweight and obese subjects (mean BMI 31.9±1.02 kg/m2).MEASUREMENTS:Food intake, appetite and palatability of food, ghrelin and other obesity-related hormones, growth hormone.RESULTS:Low-dose infusion of ghrelin increased ad libitum energy intake at a buffet meal in the obese group only (mean increase 36.6±9.4%, P<0.01.) High-dose ghrelin infusion increased energy intake in both groups (mean increase 20.1±10.6% in the lean and 70.1±15.5% in the obese, P<0.01 in both cases.) Ghrelin infusion increased palatability of food in the obese group.CONCLUSION:Ghrelin increases food intake in obese as well as lean subjects. Obese people are sensitive to the appetite-stimulating effects of ghrelin and inhibition of circulating ghrelin may be a useful therapeutic target in the treatment of obesity.

Subcutaneous administration of ghrelin stimulates energy intake in healthy lean human volunteers.

Background:The gastric hormone ghrelin appears a useful agent to stimulate food intake in people with anorexia of illness. The loss of ghrelins acyl group renders it inactive, thus it has been thought that subcutaneous administration may be problematic.Objective:To investigate whether human subjects are sensitive to the effects of ghrelin administered by single subcutaneous injection.Study design:Randomized, double-blind, placebo-controlled trial.Subjects:Sixteen healthy lean volunteers (eight men and eight women).Protocol:Fasted subjects received subcutaneous injections of ghrelin (3.6 nmol/kg) or saline. After 30 min, a buffet breakfast was served.Results:Ghrelin injection increased energy intake by 27% (ghrelin 5076±691 kJ versus saline 4230±607 kJ, P=0.04). Ghrelin appeared to enhance the perceived palatability of the food offered (palatability score: ghrelin 81.1±3.6 versus saline 70.0±4.4; P=0.03).Conclusions:These results suggest that subcutaneous ghrelin is effective at stimulating energy intake and improving palatability and may be of direct use in the treatment of appetite loss.

The regulation of appetite

The worsening global obesity epidemic, particularly the increase in childhood obesity, has prompted research into the mechanisms of appetite regulation. Complex pathways modulate energy balance, involving appetite centres in the hypothalamus and brain stem, and hormonal signals of energy status released by the gut and by the periphery. Better understanding of appetite regulation improves understanding of the aetiology of obesity. Manipulation of this homoeostatic system offers potentially useful treatments for obesity.

Heterogeneous Genetic Background of the Association of Pheochromocytoma/Paraganglioma and Pituitary Adenoma: Results From a Large Patient Cohort

Context: Pituitary adenomas and pheochromocytomas/paragangliomas (pheo/PGL) can occur in the same patient or in the same family. Coexistence of the two diseases could be due to either a common pathogenic mechanism or a coincidence. Objective: The objective of the investigation was to study the possible coexistence of pituitary adenoma and pheo/PGL. Design: Thirty-nine cases of sporadic or familial pheo/PGL and pituitary adenomas were investigated. Known pheo/PGL genes (SDHA-D, SDHAF2, RET, VHL, TMEM127, MAX, FH) and pituitary adenoma genes (MEN1, AIP, CDKN1B) were sequenced using next generation or Sanger sequencing. Loss of heterozygosity study and pathological studies were performed on the available tumor samples. Setting: The study was conducted at university hospitals. Patients: Thirty-nine patients with sporadic of familial pituitary adenoma and pheo/PGL participated in the study. Outcome: Outcomes included genetic screening and clinical characteristics. Results: Eleven germline mutations (five SDHB, one SDHC, one SDHD, two VHL, and two MEN1) and four variants of unknown significance (two SDHA, one SDHB, and one SDHAF2) were identified in the studied genes in our patient cohort. Tumor tissue analysis identified LOH at the SDHB locus in three pituitary adenomas and loss of heterozygosity at the MEN1 locus in two pheochromocytomas. All the pituitary adenomas of patients affected by SDHX alterations have a unique histological feature not previously described in this context. Conclusions: Mutations in the genes known to cause pheo/PGL can rarely be associated with pituitary adenomas, whereas mutation in a gene predisposing to pituitary adenomas (MEN1) can be associated with pheo/PGL. Our findings suggest that genetic testing should be considered in all patients or families with the constellation of pheo/PGL and a pituitary adenoma.

Investigation of Structure-Activity Relationships of Oxyntomodulin (Oxm) Using Oxm Analogs

Oxyntomodulin (Oxm) is an intestinal peptide that inhibits food intake and body weight in rodents and humans. These studies used peptide analogs to study aspects of structure and function of Oxm, and the sensitivity of parts of the Oxm sequence to degradation. Analogs of Oxm were synthesized and studied using receptor binding and degradation studies in vitro. Their effects on food intake and conditioned taste avoidance were measured in vivo in rodents. Oxm breakdown by the enzyme dipeptidyl peptidase IV (DPPIV) was demonstrated in vitro and in vivo. In vitro degradation was reduced and in vivo bioactivity increased by inhibitors of DPPIV. Modifications to the N terminus of Oxm modulated binding to the glucagon-like peptide (GLP)-1 receptor and degradation by DPPIV. Modifications to the midsection of Oxm modulated binding to the GLP-1 receptor and degradation by neutral endopeptidase. These modifications also altered bioactivity in vivo. The C-terminal octapeptide of Oxm was shown to contribute to the properties of Oxm in vitro and in vivo but was not alone sufficient for the effects of the peptide. Elongation and acylation of the C terminus of Oxm altered GLP-1 receptor binding and duration of action in vivo, which may be due to changes in peptide clearance. An Oxm analog was developed with enhanced pharmaceutical characteristics, with greater potency and longevity with respect to effects on food intake. These studies suggest that Oxm is a potential target for antiobesity drug design.

Fibrosis and carcinoid syndrome: from causation to future therapy

Carcinoid tumors are part of a heterogeneous group of gastrointestinal and pancreatic endocrine tumors that are characterized by their capacity to produce and secrete hormones, 5-hydroxytryptamine, tachykinins and other mediators. These substances are thought to be responsible for the collection of symptoms, which include diarrhea, flushing and wheezing, that is known as carcinoid syndrome. Fibrosis that occurs either local to or distant from the primary tumor is one of the hallmarks of carcinoid tumors that originate from the midgut. The fibrotic process can occur in the mesentery as a desmoplastic response and may lead to obstruction of the small bowel, but it can also occur in the lungs, skin or retroperitoneum. Importantly, up to one-third of patients develop cardiac valvulopathy. One or more products that are secreted by the tumor and enter into the circulation are likely to have a role in this process. This Review discusses the incidence and prevalence of fibrosis in carcinoid syndrome and explores evidence to date for causative agents, in particular the roles of 5-hydroxytryptamine and elements of the downstream signaling pathway. Improved understanding of the etiology of carcinoid-tumor-related fibrosis may lead to better treatments for this condition than those we currently have.

Novel and evolving therapies in the treatment of malignant phaeochromocytoma: experience with the mTOR inhibitor everolimus (RAD001).

Phaeochromocytoma and paraganglioma are rare neuroendocrine tumours (NETS). They may be benign or malignant but the pathological distinction is mainly made when metastases are present. Available treatments in the form of surgery, chemotherapy, and radionuclide therapy may improve symptoms and biochemical markers, but the results for the control of tumour bulk are less favourable. Furthermore, responses to treatment are frequently short-lived. This short review outlines the main molecular and histological features of malignant phaeochromocytoma and the difficulties in differentiating between benign and malignant disease. We list current therapies used for malignant pheochromocytoma; however, these generally achieve relatively low success rates. Hence, there is a need for new and more effective therapies. In vitro studies have implicated the PI3/Akt/mTOR pathway in the pathogenesis of malignant NETS, including phaeochromocytoma. Everolimus (RAD001, Novartis UK) is a compound that inhibits mTOR (mammalian Target Of Rapamycin) signalling. We have used RAD001 in four patients with progressive malignant paraganglioma/phaeochromocytoma in addition to other therapies (with institutional approval for compassionate use), and evaluated the effects of this treatment. We outline these four cases and review the theoretical background for this therapy, although the outcomes were relatively disappointing.

Diagnosis and localisation of insulinoma: the value of modern magnetic resonance imaging in conjunction with calcium stimulation catheterisation

CONTEXT Preoperative localisation of insulinoma improves cure rate and reduces complications, but may be challenging. OBJECTIVE To review diagnostic features and localisation accuracy for insulinomas. DESIGN Cross-sectional, retrospective analysis. SETTING A single tertiary referral centre. PATIENTS Patients with insulinoma in the years 1990-2009, including sporadic tumours and those in patients with multiple endocrine neoplasia syndromes. INTERVENTIONS Patients were identified from a database, and case notes and investigation results were reviewed. Tumour localisation by computed tomography (CT), magnetic resonance imaging (MRI), octreotide scanning, endoscopic ultrasound (EUS) and calcium stimulation was evaluated. MAIN OUTCOME MEASURE(S) Insulinoma localisation was compared to histologically confirmed location following surgical excision. RESULTS Thirty-seven instances of biochemically and/or histologically proven insulinoma were identified in 36 patients, of which seven were managed medically. Of the 30 treated surgically, 25 had CT (83.3%) and 28 had MRI (90.3%), with successful localisation in 16 (64%) by CT and 21 (75%) by MRI respectively. Considered together, such imaging correctly localised 80% of lesions. Radiolabelled octreotide scanning was positive in 10 out of 20 cases (50%); EUS correctly identified 17 lesions in 26 patients (65.4%). Twenty-seven patients had calcium stimulation testing, of which 6 (22%) did not localise, 17 (63%) were correctly localised, and 4 (15%) gave discordant or confusing results. CONCLUSIONS Preoperative localisation of insulinomas remains challenging. A pragmatic combination of CT and especially MRI predicts tumour localisation with high accuracy. Radionuclide imaging and EUS were less helpful but may be valuable in selected cases. Calcium stimulation currently remains useful in providing an additional functional perspective.

Subcutaneous oxyntomodulin analogue administration reduces body weight in lean and obese rodents

Objective:To determine the efficacy of a long-acting oxyntomodulin (OXM) analogue, OXM6421, in inhibiting food intake and decreasing body weight in lean and diet-induced obese (DIO) rodents.Research design and methods:The glucagon-like peptide-1 (GLP-1) receptor binding affinity and efficacy, sensitivity to enzymatic degradation in vitro and persistence in the circulation after peripheral administration were investigated for OXM6421 and compared with native OXM. The chronic effect of OXM6421 on food intake, body weight and energy expenditure was examined in lean rats, and its anti-obesity potential was evaluated in DIO mice.Results:OXM6421 showed enhanced GLP-1 receptor binding affinity and cyclic adenosine monophosphate (cAMP) stimulation, and higher resistance to enzymatic degradation by dipeptidyl peptidase IV (DPP-IV) and neutral endopeptidase (NEP) compared with native OXM. OXM6421 persisted longer in the circulation than OXM after peripheral administration. Acute administration of OXM6421 potently inhibited food intake in lean rodents, with cumulative effects lasting up to 24 h. In lean rats, daily subcutaneous (s.c.) administration of OXM6421 caused greater weight loss than the pair-fed animals, and a higher rate of oxygen consumption than both the pair-fed and the saline controls. In DIO mice, continuous s.c. infusion of OXM6421 resulted in a significant weight loss, accompanied by an improvement in glucose homeostasis and an increase in circulating adiponectin levels. Once-daily s.c. administration of OXM6421 for 21 days caused sustained weight loss in DIO mice.Conclusion:OXM6421 induces negative energy balance in both lean and obese rodents, suggesting that long-acting OXM analogues may represent a potential therapy for obesity.

Diagnosing unilateral primary aldosteronism - comparison of a clinical prediction score, computed tomography and adrenal venous sampling.

In patients with primary aldosteronism (PA), adrenalectomy is potentially curative for those correctly identified as having unilateral excessive aldosterone production. It has been suggested that a recently developed and published clinical prediction score (CPS) may correctly identify some patients as having unilateral disease, without recourse to adrenal venous sampling.