Radioactive iodine treatment for Graves' hyperthyroidism: incidence of Graves orbitopathy.

PURPOSE: There are limited recent data on the effect of radioactive iodine (RAI) for Graves' disease on Graves' orbitopathy (GO) development or reactivation. This audit investigates the GO incidence in patients with Graves' disease after RAI treatment, and explores risk factors present, and steroid prophylaxis use. METHODS: A retrospective audit of Graves' disease patients treated with RAI over a 5-year period. Data collected: smoking status, thyroid-stimulating hormone receptor antibody (TRAb) status, GO history, Graves' disease duration, eye features pre- and post-treatment, prophylactic corticosteroids, RAI dose given, post-RAI thyroid status, duration until hypothyroid. RESULTS: One hundred one patients were included, with a median Graves' disease duration 36 months. 34/101 (33.7%) were active/ex-smokers, 86/101 (85.1%) were TRAb-positive, 11/101 (10.9%) had a GO history; 32 (31.7%) had eye features present. Median RAI dose given was 596MBq. 8/101 (7.9%) patients received prophylactic corticosteroid; 89/101 (88.1%) achieved hypothyroid state in the year after RAI. GO developed in 5/101 (5.0%), of which 4/5 (80%) were de novo in high-risk individuals who did not receive steroids. One was a GO reactivation despite steroids. Two required intravenous steroids with/without orbital radiotherapy, one completed oral steroid taper; the remainder were treated conservatively. CONCLUSION: Our cohort had a lower GO incidence in patients with Graves' disease receiving RAI, with majority arising de novo . It is essential that all patients are assessed for Graves orbitopathy risk factors and counselled adequately prior to RAI. The decision to initiate steroids should be undertaken in a multi-disciplinary setting involving endocrinologists and ophthalmologists.

PYY3-36 and oxyntomodulin can be additive in their effect on food intake in overweight and obese humans.

OBJECTIVE: Peptide YY(3-36) (PYY(3-36)), a Y2 receptor agonist, and oxyntomodulin, a glucagon-like peptide 1 (GLP-1) receptor agonist, are cosecreted by intestinal L-cells after each meal. Separately each hormone acts as an endogenous satiety signal and reduces appetite in humans when infused intravenously. The aim of the current study was to investigate whether the anorectic effects of PYY(3-36) and oxyntomodulin can be additive. RESEARCH DESIGN AND METHODS: Twelve overweight or obese human volunteers underwent a randomized, double-blinded, placebo-controlled study. An ad libitum test meal was used to measure energy intake during intravenous infusions of either PYY(3-36) or oxyntomodulin or combined PYY(3-36)/oxyntomodulin. RESULTS: Energy intake during coadministration of PYY(3-36) and oxyntomodulin was reduced by 42.7% in comparison with the saline control and was significantly lower than that during infusions of either hormone alone. CONCLUSIONS: The anorectic effects of PYY(3-36) and oxyntomodulin can be additive in overweight and obese humans. Coadministration of Y2 receptor agonists and GLP-1 receptor agonists may be a useful treatment strategy for obesity.

Sustained appetite improvement in malnourished dialysis patients by daily ghrelin treatment.

Malnutrition is a common complication in patients on dialysis and is strongly associated with poor prognosis. Effective therapy could substantially improve morbidity and mortality, but neither enteral nor parenteral supplementation provide long-term benefit because of the strong appetite suppression seen in such patients. We performed a double-blinded randomized crossover study of a week-long treatment with daily subcutaneous ghrelin, a gut hormone that regulates hunger through the hypothalamus, in a group of 12 malnourished dialysis patients. Ghrelin administration increased ghrelin levels in circulation, modestly reduced blood pressure for up to 2 h, and immediately and significantly increased appetite, with an increase in energy intake noted at the first study meal. Persistence of this effect throughout the week was confirmed with food diaries and final study meals. Energy expenditure, measured with free-living pulse and motion monitors, was unchanged by ghrelin. Our study shows that daily treatment with ghrelin achieves a sustained positive change in energy balance in malnourished dialysis patients. Direct manipulation of appetite with ghrelin or its analogs represents an attractive and promising therapeutic strategy for this difficult clinical problem.

Gut and hormones and obesity.

Following the discovery of secretin in 1902, a host of further peptide hormones that are synthesised and released from the gastrointestinal tract have been identified. While their roles in the regulation of gastrointestinal function have been known for some time, it is now evident that many of these hormones also physiologically regulate energy balance. Our understanding of how gut hormones signal to the brain has advanced significantly in recent years. Several hormones, including peptide YY, pancreatic polypeptide, oxyntomodulin, glucagon-like peptide 1 and cholecystokinin function as satiety signals. In contrast, only ghrelin, produced by the stomach, has emerged as a putative hunger signal, appearing to act both as a meal initiator and a long-term body weight regulator. Recent research suggests that gut hormones can be manipulated to regulate energy balance in man and that obese subjects retain sensitivity to the actions of gut hormones. The worldwide obesity pandemic continues unabated, despite public health initiatives and current best therapy. Future gut hormone-based therapies may provide an effective and well-tolerated treatment for obesity.

Gut hormones as potential new targets for appetite regulation and the treatment of obesity.

Food intake and bodyweight are tightly regulated by the brainstem, hypothalamus and reward circuits. These centres integrate diverse cognitive inputs with humoral and neuronal signals of nutritional status. Our knowledge of the role of gut hormones in this complex homeostatic system has expanded enormously in recent years. This review discusses both the role of gut hormones in appetite regulation, and the current state of development of gut hormone-based obesity therapies, with a particular focus on pancreatic polypeptide, peptide YY, amylin, glucagon-like peptide-1, oxyntomodulin, cholecystokinin and ghrelin. Several gut hormone-based treatments for obesity are under investigation in phase II and III clinical trials, and many more are in the pipeline.

Subcutaneous oxyntomodulin reduces body weight in overweight and obese subjects: a double-blind, randomized, controlled trial.

This study investigated the effect of subcutaneously administered oxyntomodulin on body weight in healthy overweight and obese volunteers. Participants self-administered saline or oxyntomodulin subcutaneously in a randomized, double-blind, parallel-group protocol. Injections were self-administered for 4 weeks, three times daily, 30 min before each meal. The volunteers were asked to maintain their regular diet and level of physical exercise during the study period. Subjects' body weight, energy intake, and levels of adipose hormones were assessed at the start and end of the study. Body weight was reduced by 2.3 +/- 0.4 kg in the treatment group over the study period compared with 0.5 +/- 0.5 kg in the control group (P = 0.0106). On average, the treatment group had an additional 0.45-kg weight loss per week. The treatment group demonstrated a reduction in leptin and an increase in adiponectin. Energy intake by the treatment group was significantly reduced by 170 +/- 37 kcal (25 +/- 5%) at the initial study meal (P = 0.0007) and by 250 +/- 63 kcal (35 +/- 9%) at the final study meal (P = 0.0023), with no change in subjective food palatability. Oxyntomodulin treatment resulted in weight loss and a change in the levels of adipose hormones consistent with a loss of adipose tissue. The anorectic effect was maintained over the 4-week period. Oxyntomodulin represents a potential therapy for obesity.

Ghrelin increases energy intake in cancer patients with impaired appetite: acute, randomized, placebo-controlled trial.

There is a pressing need for more effective appetite-stimulatory therapies for many patient groups including those with cancer. We have previously demonstrated that the gastric hormone ghrelin potently enhances appetite in healthy volunteers. Here, we performed an acute, randomized, placebo-controlled, cross-over clinical trial to determine whether ghrelin stimulates appetite in cancer patients with anorexia. Seven cancer patients who reported loss of appetite were recruited from oncology clinics at Charing Cross Hospital. The main outcome measures were energy intake from a buffet meal during ghrelin or saline infusion and meal appreciation as assessed by visual analog scale. A marked increase in energy intake (31 +/- 7%; P = 0.005) was observed with ghrelin infusion compared with saline control, and every patient ate more. The meal appreciation score was greater by 28 +/- 8% (P = 0.02) with ghrelin treatment. No side effects were observed. The stimulatory effects of ghrelin on food intake and meal appreciation seen in this preliminary study suggest that ghrelin could be an effective treatment for cancer anorexia and possibly for appetite loss in other patient groups.

Identification of hypothalamic nuclei involved in the orexigenic effect of melanin-concentrating hormone.

The hypothalamic neuropeptide melanin-concentrating hormone (MCH) increases feeding when injected intracerebroventricularly in rats. To identify the hypothalamic nuclei responsible for the orexigenic effect, we injected the peptide into discrete hypothalamic nuclei known to express the MCH receptor, MCH1R. MCH (0.6 nmol) elicited a rapid and significant increase in feeding in satiated rats following injection into the arcuate nucleus (0-1 h: 421 +/- 60%; P < 0.01). An elevation in feeding was also observed following injection into the paraventricular nucleus, which was sustained up to 4 h post injection (0-4 h: 218 +/- 29%; P < 0.01). A significant increase in feeding during this time period was also observed following injection into the dorsomedial nucleus (0-4 h: 155 +/- 12%; P < 0.05). No significant alteration in feeding was observed following injection into the supraoptic nucleus, lateral hypothalamic area, medial preoptic area, anterior hypothalamic area, or ventromedial nucleus of the hypothalamus. To identify the neurotransmitters that may be potentially involved in this effect, we examined their release from hypothalamic explants in vitro following exogenous MCH administration. MCH (1 micro M) increased the release of the orexigenic neurotransmitters neuropeptide Y (37.8 +/- 6.0 fmol/explant vs. basal 30.2 +/- 4.3 fmol/explant; P < 0.05) and agouti-related peptide (4.1 +/- 0.6 fmol/explant vs. basal 2.4 +/- 0.2 fmol/explant; P < 0.05) and decreased the release of the anorectic neurotransmitters alpha-MSH (41.7 +/- 6.8 fmol/explant vs. basal 65.9 +/- 11.0 fmol/explant; P < 0.01) and cocaine- and amphetamine-regulated transcript (112.3 +/- 12.4 fmol/explant vs. basal 167.4 +/- 13.0 fmol/explant; P < 0.001). These studies suggest that the orexigenic effect of MCH may be mediated via activation or inhibition of these feeding circuits within the arcuate nucleus and paraventricular nucleus of the hypothalamus.

The hypothalamic mechanisms of the hypophysiotropic action of ghrelin.

Ghrelin is an endogenous ligand for the growth hormone secretagogue (GHS) receptor, expressed in the hypothalamus and pituitary. Ghrelin, like synthetic GHSs, stimulates food intake and growth hormone (GH) release following systemic or intracerebroventricular administration. In addition to GH stimulation, ghrelin and synthetic GHSs are reported to stimulate the hypothalamo-pituitary-adrenal (HPA) axis in vivo. The aims of this study were to elucidate the hypothalamic mechanisms of the hypophysiotropic actions of ghrelin in vitro and to assess the relative contribution of hypothalamic and systemic actions of ghrelin on the HPA axis in vivo. Ghrelin (100 and 1,000 nM) stimulated significant release of GH-releasing hormone (GHRH) from hypothalamic explants (100 nM: 39.4 +/- 8.3 vs. basal 18.3 +/- 3.5 fmol/explant, n = 49, p < 0.05) but did not affect either basal or 28 mM KCl-stimulated somatostatin release. Ghrelin (10, 100 and 1,000 nM) stimulated the release of both corticotropin-releasing hormone (CRH) (100 nM: 6.0 +/- 0.8 vs. basal 4.2 +/- 0.5 pmol/explant, n = 49, p < 0.05) and arginine vasopressin (AVP) (100 nM: 49.2 +/- 5.9 vs. basal 35.0 +/- 3.3 fmol/explant, n = 48, p < 0.05), whilst ghrelin (100 and 1,000 nM) also stimulated the release of neuropeptide Y (NPY) (100 nM: 111.4 +/- 25.0 vs. basal 54.4 +/- 9.0 fmol/explant, n = 26, p < 0.05) from hypothalamic explants in vitro. The HPA axis was stimulated in vivo following acute intracerebroventricular administration of ghrelin 2 nmol [adrenocorticotropic hormone (ACTH) 38.2 +/- 3.9 vs. saline 18.2 +/- 2.0 pg/ml, p < 0.01; corticosterone 310.1 +/- 32.8 ng/ml vs. saline 167.4 +/- 40.7 ng/ml, p < 0.05], but not following intraperitoneal administration of ghrelin 30 nmol, suggesting a hypothalamic site of action. These data suggest that the mechanisms of GH and ACTH regulation by ghrelin may include hypothalamic release of GHRH, CRH, AVP and NPY.

Gut hormone PYY(3-36) physiologically inhibits food intake.

Food intake is regulated by the hypothalamus, including the melanocortin and neuropeptide Y (NPY) systems in the arcuate nucleus. The NPY Y2 receptor (Y2R), a putative inhibitory presynaptic receptor, is highly expressed on NPY neurons in the arcuate nucleus, which is accessible to peripheral hormones. Peptide YY(3-36) (PYY(3-36)), a Y2R agonist, is released from the gastrointestinal tract postprandially in proportion to the calorie content of a meal. Here we show that peripheral injection of PYY(3-36) in rats inhibits food intake and reduces weight gain. PYY(3-36) also inhibits food intake in mice but not in Y2r-null mice, which suggests that the anorectic effect requires the Y2R. Peripheral administration of PYY(3-36) increases c-Fos immunoreactivity in the arcuate nucleus and decreases hypothalamic Npy messenger RNA. Intra-arcuate injection of PYY(3-36) inhibits food intake. PYY(3-36) also inhibits electrical activity of NPY nerve terminals, thus activating adjacent pro-opiomelanocortin (POMC) neurons. In humans, infusion of normal postprandial concentrations of PYY(3-36) significantly decreases appetite and reduces food intake by 33% over 24 h. Thus, postprandial elevation of PYY(3-36) may act through the arcuate nucleus Y2R to inhibit feeding in a gut-hypothalamic pathway.