Serum ghrelin levels in acromegaly: effects of surgical and long-acting octreotide therapy

The orexigenic peptide, ghrelin, is regulated by acute and chronic nutritional state. Although exogenously administered ghrelin stimulates pituitary GH secretion, little is known about the role of ghrelin in endogenous GH secretion or how high GH and IGF-I levels in acromegaly could affect ghrelin secretion and vice versa. Therefore, we evaluated fasting and post oral glucose tolerance test serum ghrelin levels in 19 patients with active acromegaly at baseline and after either surgery in 9 of these or administration of long-acting octreotide (Sandostatin LAR) in the other 10 patients. After surgical cure, fasting ghrelin rose from 312 +/- 56 pg/ml to 548 +/- 97 pg/ml (P = 0.013). Fasting serum ghrelin levels were higher in all patients after surgery and ranged between 112% and 349% of presurgery levels. Ghrelin levels fell significantly during long-acting octreotide therapy from 447 +/- 34 pg/ml to 206 +/- 15 pg/ml (P < 0.0001); ghrelin levels on octreotide ranged between 26% and 70% of baseline levels. Serum ghrelin levels were suppressed significantly during the oral glucose tolerance test in both groups. Pretherapy ghrelin levels correlated negatively with serum insulin levels (r = -0.494; P = 0.03) and insulin resistance as estimated by the homeostasis model assessment score (r = -0.573; P = 0.01). In patients without diabetes mellitus, serum insulin levels in the surgical group were 19.7 +/- 5.4 microU/ml before surgery and fell to 9.7 +/- 0.93 microU/ml after surgery (P = 0.05); levels in the octreotide group were 13.9 +/- 2.8 microU/ml before and fell to 11.2 +/- 2.8 microU/ml on octreotide (P = 0.03). Pretherapy ghrelin levels did not correlate with weight or body mass index, but after therapy in the surgery group ghrelin correlated negatively with weight (r = -0.823, P = 0.012) as has been demonstrated by others in healthy subjects. Ghrelin secretion is dysregulated in active acromegaly; lowered serum levels of ghrelin in active acromegaly rise along with the postsurgery normalization of GH and IGF-I and improved insulin resistance. In contrast to surgical therapy, long-acting octreotide therapy persistently suppressed serum ghrelin levels. It remains to be determined whether altered circulating ghrelin concentrations could impact on body composition changes in acromegaly.     

Ghrelin secretion in humans is sexually dimorphic,suppressed by somatostatin,and not affected by the ambient growth hormone levels

We studied plasma ghrelin and GH concentrations over a 24-h period in young healthy men and women and in patients with acromegaly. Healthy subjects were restudied after administration of GH-lowering agents, octreotide or GHRH antagonist. Ghrelin concentrations in women studied during the late follicular stage of the cycle were about 3-fold higher than in men. Suppression of GH secretion by GHRH antagonist did not alter ghrelin concentration profiles. In the presence of high GH levels (acromegaly), ghrelin levels were similar to those found in healthy men. Administration of somatostatin analog octreotide suppressed both GH and ghrelin concentration profiles. We conclude that: 1) ghrelin secretion is sexually dimorphic in humans, with women in the late follicular stage having higher levels than men; 2) ghrelin secretion is suppressed by somatostatin; and 3) GH has no influence over ghrelin secretion.     

Regulation of ghrelin secretion by somatostatin analogs in rats

OBJECTIVE: Ghrelin is a hormone present in the plasma in two forms: octanoylated and des-octanoylated ghrelin. In pathophysiological conditions such as Prader-Willi syndrome and ghrelinoma, elevated ghrelin plasma levels are associated with pathological obesity. Clinical studies have shown that somatostatin downregulates ghrelin plasma levels in healthy volunteers. The aim of this study was to investigate the effects of two somatostatin analogues, SOM230 and octreotide, on ghrelin secretion in rats. METHODS: Ghrelin secretion was either unstimulated or stimulated by overnight fasting. Treatment with SOM230 and octreotide was either acute (s.c. injection 1 h before blood sampling) or prolonged (continuous s.c. infusion via 14-day osmotic minipumps). RESULTS: Acute treatment with octreotide dose-dependently inhibited unstimulated and stimulated secretion of total and active ghrelin. SOM230 (30 microg/kg) inhibited active ghrelin in fasted rats. Lower doses had no effect. After 7 days of treatment, active ghrelin was strongly inhibited by both compounds in fasted animals, with a stronger effect for octreotide. Lower inhibition was achieved in fed rats. After 14 days, the inhibition with octreotide in fasted rats was lower and SOM230 had no effect. Somatostatin receptor expression analysis in the rat glandular stomach revealed a predominant sst(1) and sst(2) expression, low expression of sst(3) and sst(4), and hardly detectable sst(5) mRNA expression. CONCLUSIONS: Somatostatin analogues may be useful for the inhibition of physiologically elevated ghrelin plasma levels. This inhibition appears to be mediated by sst(2) receptors in the rat, and desensitizes after 14 days of treatment.     

The pulsatile GH secretion in acromegaly: Hypothalamic or pituitary origin?*

OBJECTIVE: We studied the effects of different modes of octreotide therapy on the pulsatile pattern of GH release in an attempt to define better its regulation by growth hormone-releasing hormone (GHRH) and somatostatin and its effects on IGF-I plasma levels in acromegaly. DESIGN: In six acromegalic patients not cured by previous treatment we compared the 24-hour GH secretion profiles under basal conditions with subcutaneous (s.c.) bolus injections of 100 micrograms octreotide every 8 hours and with continuous s.c. infusions of the same daily dose. Blood samples were taken every 10 minutes over 24 hours followed by a GHRH test (100 micrograms GHRH i.v.) with blood sampling every 15 minutes for another 2 hours. After a 4-week interval all patients were treated either by the bolus or continuous mode of octreotide application in a randomized cross-over design. On day 4 of treatment blood sampling and GHRH test were repeated. Octreotide treatment was withdrawn for another 4 weeks; all patients then received the alternate application mode and were measured under similar conditions. MEASUREMENTS: Serum GH and plasma IGF-I concentrations were analysed by serial array averaging. IGF-I levels were measured in two different assays with and without previous protein extraction. For GH pulse detection three different algorithms (Cluster, Pulsar, Desade) were applied. RESULTS: With both treatments, the initially elevated basal 24-hour mean serum GH concentrations (58.0 +/- 9.7 mU/l mean +/- SEM) decreased significantly (bolus: 11.5 +/- 4.9 mU/l, P < 0.001 vs basal; continuous infusion: 7.6 +/- 1.9 mU/l, P < 0.001 vs basal) after 4 days. GH suppression was significantly more pronounced following continuous infusion than bolus (P < 0.05). IGF-I plasma concentrations were lowered significantly (P < 0.05) with both forms of treatment which did not differ between themselves. Bolus and continuous infusion treatment significantly inhibited (P < 0.05) the amplitudes of pulsatile GH release, but did not change the pulse frequency. In two of the patients, GHRH stimulation did not increase GH serum levels suggesting a constitutive activation of adenylyl cyclase. CONCLUSION: Continuous subcutaneous octreotide treatment in acromegaly suppresses mean GH levels better than bolus injection. The number of GH pulses remains unaffected by both modes of treatment providing evidence against a somatostatinergic mechanism of pulsatile GH secretion in these patients. The unchanged frequency of pulsatile GH release in the patients unresponsive to exogenous GHRH indicates that this pattern might be independent of hypothalamic GHRH and somatostatin and suggests a pituitary-derived mechanism for GH pulse generation in acromegaly.     

Octreotide long-acting repeatable and lanreotide Autogel are equally effective in controlling growth hormone secretion in acromegalic patients

OBJECTIVE: Recently a new depot preparation of the long-acting somatostatin analogue, lanreotide Autogel was introduced for the treatment of acromegaly. Like octreotide long-acting repeatable (LAR), it has high binding affinity for the somatostatin receptor subtype SSTR 2 and less binding affinity for SSTR 5. We hypothesized that the ability to suppress growth hormone (GH) secretion in patients with acromegaly would be similar for these depot preparations. PATIENTS AND STUDY DESIGN: Seven patients (mean age+/-S.E.M. 48.4+/-7 years) on long-term octreotide LAR treatment at a monthly injection interval for a mean of 2.8 years were enrolled in the study. They underwent a GH secretory profile study with 10 min sampling for 24 h, 28 days after an injection. At 2, 4 and 6 weeks after the next injection fasting GH profiles (every 30 min for 3.5 h) and serum IGF-I measurements were measured. These investigations were repeated 12 months later, when the patients were on an individually titrated stable dose of lanreotide Autogel. RESULTS: Secretory characteristics and total 24 h GH secretion, estimated by deconvolution analysis of the 10 min 24 h plasma GH concentrations, did not show differences between these two long-acting somatostatin analogues. Both drugs were equally effective in GH and IGF-I suppression as measured at 2, 4 and also at 6 weeks following an injection. CONCLUSION: The efficacy of lanreotide Autogel and octreotide LAR was equal, notwithstanding that these drugs are administered in a different way and have different pharmacokinetics.     

Octreotide suppresses both growth hormone (GH) and GH-releasing hormone (GHRH) in acromegaly due to ectopic GHRH secretion

Two patients with acromegaly secondary to ectopic GHRH secretion by metastatic carcinoid tumors were studied before and during therapy with the somatostatin analog octreotide (SMS 201-995). GH and GHRH secretory patterns were assessed during intermittent sc administration, continuous sc infusion (CSI), and continuous iv infusion of octreotide. Octreotide reduced serum GH and plasma GHRH levels in the two patients, although there was differential sensitivity of GH and GHRH. Intermittent sc therapy transiently lowered serum GH in both patients. A higher iv dose was required to reduce plasma GHRH by 50% than to reduce serum GH by 50% (2.0 vs. 0.05 micrograms/kg.h, respectively; patient 1). A similar pattern was found during CSI octreotide administration in the same patient. Chronic therapy with intermittent sc and CSI octreotide was assessed by serial 24-h profiles of GH and GHRH secretion in patient 2. Mean hourly serum GH levels decreased from a pretreatment level of 31.5 +/- 3.5 (+/- SE) to 9.5 +/- 1.5 micrograms/L during CSI therapy (1000 micrograms/day or 0.40 micrograms/kg.h). In contrast, plasma GHRH levels were less effectively suppressed. The mean serum GH levels and the variation in hourly GH values were reduced to a greater extent with CSI than with intermittent sc therapy. Serum insulin-like growth factor I also declined from 5.9 x 10(3) to 2.5 x 10(3) U/L during chronic CSI therapy (patient 2). CSI therapy with octreotide can be more effective than intermittent sc therapy in controlling GH excess in the rare syndrome of ectopic GHRH secretion, although serum GH may not decline to normal.     

Pharmacologic Therapies for Acromegaly

Acromegaly is associated with insulin resistance and an increased incidence of cardiovascular disease. However, it remains unclear to what extent the effects of growth hormone (GH) excess on cardiovascular morbidity and mortality are mediated through insulin resistance versus through other direct or indirect effects of GH. Adequate control of GH excess by surgery or pharmacologic interventions is associated with decreased insulin resistance, reflected in decreased plasma insulin levels and fasting glucose levels or improved glucose tolerance. Despite divergent effects of both somatostatin and somatostatin analogs on GH, insulin and glucagon secretion, and glucose absorption, treatment with the somatostatin analogs octreotide and lanreotide has only limited effects on glucose metabolism. However, glucose sensitivity has only been formally examined using a hyperinsulinemic euglycemic clamp in a minority of these studies. Treatment with the GH-receptor antagonist pegvisomant ameliorates insulin sensitivity, reflected in decreased fasting plasma insulin levels and fasting glucose levels. Nonetheless, the effect of pegvisomant on glucose sensitivity has not been formally tested by hyperinsulinemic clamp conditions. In acromegaly, preliminary observations on new octreotide analogs with greater specificity for somatostatin-receptor subtypes indicate that these compounds achieve better control of GH hypersecretion than octreotide, but may also negatively influence insulin release. Assessment of insulin secretion and glucose levels in acromegalic patients during administration of these compounds is thus mandatory.     

Ghrelin administration affects circulating pituitary and gastro-entero-pancreatic hormones in acromegaly

OBJECTIVE: Ghrelin, a gut-brain peptide involved in the control of energy homeostasis, affects antero-pituitary and gastro-entero-pancreatic (GEP) hormone secretion in healthy subjects. We aimed to verify whether such hormonal responses are retained in acromegaly, a disease characterized by high GH, subnormal ghrelin and abnormal GEP hormone levels. DESIGN AND METHODS: The effect of ghrelin (3.3 microg/kg given after overnight fasting as an i.v. bolus) on GH, prolactin (PRL), adrenocorticotropin (ACTH), cortisol, insulin, glucose, total somatostatin (SS) and pancreatic polypeptide (PP) circulating levels were evaluated in seven non-diabetic patients with newly diagnosed acromegaly and in nine healthy controls. RESULTS: Ghrelin elicited a prompt, marked increase of serum GH and PRL levels in all normal (from 1.6+/-0.6 to 52.9+/-7.8 and from 9.7+/-0.8 to 24.2+/-4.8 microg/l (means+/-S.E.M.), respectively) and acromegalic subjects (from 11.2+/-4.9 to 91.6+/-21.0 and from 42.9+/-26.1 to 113.8+/-79.0 microg/l, respectively). Both plasma ACTH and serum cortisol levels rose significantly in the controls, whereas the cortisol response was blunted in the acromegalic patients. Glucose levels rose earlier and insulin levels fell later in all subjects, with a significantly greater net insulin decrease in acromegalic than in healthy subjects (-80+/-21 vs -17+/-4 pmol/l, P<0.01). A prompt PP rise and a biphasic SS response occurred in all controls, whereas in the acromegalic group the PP response (from 26.1+/-5.0 to 92.2+/-39.0 pmol/l) and the SS response (from 11.9+/-3.0 to 19.7+/-4.0 ng/l) were quite variable. CONCLUSIONS: Ghrelin affects both pituitary and GEP hormones in acromegalic patients as in normal subjects. These findings suggest that ghrelin actions on the energy balance are mediated by complex interactive endocrine loops that involve also the gut and pancreas.     

Somatostatin infusion lowers plasma ghrelin without reducing appetite in adults with Prader-Willi syndrome

Prader-Willi syndrome (PWS) is characterized by life-threatening childhood-onset hyperphagia, obesity and, uniquely, high plasma levels of ghrelin, the orexigenic gastric hormone. Somatostatin suppresses ghrelin secretion in normal subjects. We therefore examined the effect of somatostatin on plasma ghrelin and appetite in four male PWS adults fasted overnight in a double-blind, placebo-controlled, randomized cross-over study. Subjects received an intravenous infusion of somatostatin (250 microg/hr) or saline for 300 min, and had blood samples taken every 30 min for measurement of plasma ghrelin and PYY3-36 (anorexigenic intestinal hormone) by radio-immunoassay, and glucose. Appetite was measured by counting sandwiches eaten over a 60 min free food access period from +120 min. Despite somatostatin lowering fasting plasma ghrelin by 60 +/- 2% (P = 0.04) to levels seen in non-PWS men, there was no associated reduction in food intake (105 +/- 9% of food intake during saline infusion, P = 0.6). Somatostatin also lowered plasma PYY levels by 45 +/- 16% (P = 0.04), and produced post-prandial hyperglycemia (P = 0.04). We conclude that either hyperghrelinemia may not contribute to hyperphagia in PWS adults, or perhaps concomitant reductions in anorexigenic gastrointestinal hormones by somatostatin counteracted any anorexigenic effect of lowering orexigenic ghrelin. Somatostatin analogues may therefore not be an effective therapy for obesity in PWS. Larger chronic studies with long-acting somatostatin analogues will be needed to determine their benefits and risks in treating PWS obesity.     

Continuous subcutaneous octreotide infusion markedly suppresses IGF-I levels whilst only partially suppressing GH secretion in diabetics with retinopathy

The response to GH releasing hormone (GHRH 1-29) and 24-h serum GH and IGF-I levels were measured in 9 insulin-dependent diabetics with retinopathy and 6 normal volunteers before and after different treatment regimens with octreotide, a long-acting somatostatin analogue. Octreotide, 50 micrograms by sc injection, completely suppressed GHRH-stimulated GH release in both groups. Thrice daily sc injections for up to 20 weeks were associated with variable plasma octreotide levels and failed completely to suppress GH secretion in either the patients or the normal controls. Three days of continuous sc pump infusion (500 micrograms/24-h) resulted in consistently high plasma octreotide levels and completely suppressed 24-h GH in 4 normal subjects, whilst treatment for up to 16 weeks only partially suppressed GH levels in 6 patients (AUC mU.l-1.h-1; 209 +/- 81 vs 121 +/- 82; P = 0.01). Mean +/- SD IGF-I levels (micrograms/l) in the patients (but not controls) were suppressed into the hypopituitary range by median 6 weeks (range 2-16) pump administration (203 +/- 62 vs 60 +/- 25; P = 0.02). Pump treatment achieved total GH suppression in normal subjects; diabetics with retinopathy seem more resistant to the GH suppressing effects of the drug. However, the reduction of serum IGF-I with prolonged treatment may be of clinical value in arresting the progress of diabetic retinopathy.     

Estimation of efficacy of the octreotide LAR administration in the patients with somatotropinoma

Acromegaly is caused by excessive secretion of growth hormone by a hypophyseal adenoma type of somatotropinoma. IGF-I is formed in the liver and mediates most biological actions of GH. Treatment of adenomas, which secrete GH, involves pharmacotherapy followed by surgery. Modern pharmacotherapy leaning is based on somatostatin analogues (factor restrictive secretion GH): octreotide, octreotide LAR and lanreotide. The aim of our study was estimation of efficiency of octreotide LAR in the patients with somatotropinoma prepared to neurosurgery intervention. We examined 16 patients (10 of women and 6 men) with the features of active acromegaly. In all cases the increased concentration of HGH and IGF-I were observed. The presence of pituitary adenoma in all patients was confirmed by MRI. The patients were treated with octreotide LAR monthly in dose 20 mg and 30 mg respectively. Before and after application of somatostatin analogues the concentration HGH, IGF-I, PRL in serum were marked. The concentration of GH before octreotide LAR therapy in all patients increased remarkable and ranged from 15.6 to 78.6 ng/ml, mean: 31.20 +/- 16.84 (norm: 0-10 ng/ml), also, in all cases the serum IGF-I level was increased and ranged from 451 to 1107.6 ng/ml, mean: 801.75 +/- 207.82 (norm: 100-400 ng/ml). The prolactin concentration ranged from 7.4 to 49.9 ng/ml, mean: 22.8 +/- 13.7 (norm: 2-20 ng/ml) and in 8 (50%) cases the increased of PRL concentration in serum was observed. After the administration of octreotide LAR the level of: GH [mean: 12.99 +/- 17.16 ng/ml (p < 0.001)], of IGF-I [mean 422.8 +/- 229 ng ml (p < 0.01)] statistical important decreased and prolactin in 8 with increased concentration [mean: 12.45 +/- 5.57 (p < 0.01)] were observed. Long acting somatostatin analogues--octreotide LAR is particular efficient in lowering of growth hormone and IGF-I in patients with somatotropinoma and shows efficiency in normalization of increased prolactin concentration. Because of extreme effectiveness of octreotide LAR, it should be used the routine treatment at the patients suffering from active acromegaly and preparing to neurosurgical treatment.     

The GH-releasing effect of ghrelin,a natural GH secretagogue,is only blunted by the infusion of exogenous somatostatin in humans

OBJECTIVE: Ghrelin, a 28-amino-acid peptide purified from the stomach and showing a unique structure with an n-octanoyl ester at the serine 3 residue, is a natural ligand of the GH secretagogue (GHS) receptor (GHS-R). Ghrelin strongly stimulates GH secretion in both animals and humans, showing a synergistic effect with GH-releasing hormone (GHRH) but no interaction with synthetic GHS. However, the activity of ghrelin as well as that of non-natural GHS is not fully specific for GH; ghrelin also induces a stimulatory effect on lactotroph and corticotroph secretion, at least in humans. DESIGN: To further clarify the mechanisms underlying the GH-releasing activity of this natural GHS, we studied the effects of somatostatin (SS, 2.0 microg/kg/h from -30 to +90 min) on the endocrine responses to ghrelin (1.0 microg/kg i.v. at 0 min) in seven normal young male volunteers [age (mean +/- SEM) 28.6 +/- 2.9 years; body mass index (BMI) 22.1 +/- 0.8 kg/m2]. In the same subjects, the effect of SS on the GH response to GHRH (1.0 microm/kg i.v. at 0 min) was also studied. MEASUREMENTS: Blood samples were taken every 15 min from -30 up to +120 min. GH levels were assayed at each time point in all sessions; PRL, ACTH and cortisol levels were assayed after ghrelin administration alone and during SS infusion. RESULTS: The GH response to ghrelin (hAUC0'-->120' 2695.0 +/- 492.6 microg min/l) was higher (P < 0.01) than that after GHRH (757.1 +/- 44.1 microg min/l). SS infusion almost abolished the GH response to GHRH (177.0 +/- 37.7 microg min/l, P < 0.01); the GH response to ghrelin was inhibited by SS (993.8 +/- 248.5 microg min/l, P < 0.01) but GH levels remained higher (P < 0.05) than with GHRH. Ghrelin induced significant increases in PRL, ACTH and cortisol levels and these responses were not modified by SS. CONCLUSIONS: Ghrelin, a natural GHS-R ligand, exerts a strong stimulatory effect on GH secretion in humans and this effect is only blunted by an exogenous somatostatin dose which almost abolishes the GH response to GHRH. The stimulatory effect of ghrelin on lactotroph and corticotroph secretion is refractory to exogenous somatostatin, indicating that these effects occur through pathways independent of somatostatinergic influence.     

Serum leptin levels in acromegalic patients before and during somatostatin analogs therapy

GH excess is characterized by alterations of body composition such as decreased body fat mass; however, scant data are present regarding its effect on serum leptin levels. To better elucidate this topic, leptin secretion was studied in 20 acromegalic patients, before and after 6 months of treatment with somatostatin analogs (SR-lanreotide 30 mg and octreotide LAR). Basal GH, IGF-I, insulin, blood glucose and lipid levels were measured and the area under the curve (AUC) for insulin and glucose and oral glucose insulin sensitivity (OGIS) during oral glucose tolerance test (OGTT) were calculated. After 6 months of somatostatin analogs therapy, a significant reduction in GH and IGF-I plasma levels was observed (p<0.0005, both) with a significant increase of leptin levels (7.4+/-1.3 vs 13.2+/-1.6 ng/ml; p<0.05). Interestingly, the typical correlation of leptin with body mass index (BMI) was not present in active acromegaly, whereas it was restored after somatostatin analogs treatment; moreover, the gender difference in leptin secretion between men and women was preserved in active and controlled acromegaly. In conclusion, the gender-based leptin differences are preserved and leptin secretion/BMI ratio is normalized in acromegalic patients after somatostatin analogs therapy.     

Impact of octreotide, a long-acting somatostatin analogue, on glucose tolerance and insulin sensitivity in acromegaly

OBJECTIVE: We aimed to investigate the impact of a long-acting somatostatin analogue, octreotide, on glucose tolerance and on insulin sensitivity in acromegaly. DESIGN: We performed a non-randomized controlled trial. PATIENTS: Seven patients with active acromegaly were assessed before and during octreotide therapy given in a dose of 500 micrograms three times daily subcutaneously. MEASUREMENTS: The effects of octreotide on carbohydrate metabolism were assessed by performing a glucose tolerance test and a euglycaemic hyperinsulinaemic clamp. These latter tests were undertaken 8 hours after the last dose, allowing GH and glucagon to return to pretreatment levels during the study. RESULTS: Octreotide significantly reduced (P less than 0.05) mean +/- SEM 12-h GH (from 42 +/- 13 to 10 +/- 3 mIU/I) and IGF-I (from 4.2 +/- 0.5 to 2.1 +/- 0.5 U/ml) concentrations. Glucose tolerance was normalized in four of five patients with impaired glucose tolerance without a significant change in mean insulin concentrations. The improvement in fasting and mean blood glucose during glucose tolerance testing was dependent on the pretherapy blood glucose concentrations (r = -0.95, P = 0.002). The glucose infusion rate during the hyperinsulinaemic (5 U/h) clamp was significantly increased (P less than 0.05, 15.3 +/- 1.8 vs 24.2 +/- 5.4 mumol/kg min) following octreotide treatment. Insulin infusion during the glucose clamp completely suppressed hepatic glucose production during but not before octreotide treatment (7.9 +/- 2.4 vs 0.7 +/- 2.2 mumol/kg min, P = 0.02). Insulin-mediated stimulation of peripheral glucose uptake was unaffected by treatment. Mean GH and glucagon levels during both clamp studies were not significantly different. CONCLUSIONS: Octreotide improves whole body insulin sensitivity by an increased ability of insulin to suppress hepatic glucose production without affecting the substantial impairment of peripheral insulin action. Octreotide has beneficial effects on carbohydrate metabolism in acromegalic patients with glucose intolerance.     

Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa.

OBJECTIVE: Ghrelin is a new gastric hormone that has been identified as an endogenous ligand for the growth hormone (GH) secretagogue receptor subtype 1a (GHS-R1a). Ghrelin administration however not only stimulates GH secretion but also induces adiposity in rodents by increasing food intake and decreasing fat utilization. We hypothesized that impaired ghrelin secretion in anorexia nervosa may be involved in the pathogenesis of this eating disorder. To examine this hypothesis and to further investigate the role for ghrelin in regulating energy homeostasis, we analyzed circulating ghrelin levels in patients with anorexia nervosa and examined possible correlations with clinical parameters before and after weight gain. METHODS: Plasma ghrelin levels were measured in overnight fasting plasma samples from 36 female patients with anorexia nervosa (age: 25.0+/-1.2 years, BMI: 15.2+/-0.2 kg/m(2)) before and after weight gain following psychotherapeutic treatment intervention in a psychosomatic institution. Plasma ghrelin levels were also measured in fasting plasma samples from 24 age-matched female controls (31+/-1.4 years, BMI: 22.9+/-0.45 kg/m(2)). For quantification of ghrelin levels a commercially available radioimmunoassay (Phoenix Pharmaceuticals, USA) was used. RESULTS: Fasting plasma ghrelin levels in anorectic patients were significantly higher (1057+/-95 pg/ml) than in normal age-matched female controls (514+/-63 pg/ml n=24, P=0.02). Therapeutic intervention in a psychosomatic institution caused an BMI increase of 14% (P<0.001) leading to a significant decrease in circulating ghrelin levels of 25%, (P=0.001). A significant negative correlation between Deltaghrelin and DeltaBMI was observed (correlation coefficient: -0.47, P=0.005, n=36). CONCLUSION: We show for the first time that fasting plasma levels of the novel appetite-modulating hormone ghrelin are elevated in anorexia nervosa and return to normal levels after partial weight recovery. These observations suggest the possible existence of ghrelin resistance in cachectic states such as caused by eating disorders. Future studies are necessary to investigate putative mechanisms of ghrelin resistance such as a possible impairment of intracellular ghrelin receptor signaling in pathophysiological states presenting with cachexia.     

Prandial regulation of ghrelin secretion in humans: does glucagon contribute to the preprandial increase in circulating ghrelin?

OBJECTIVE: Glucagon secretion is stimulated by fasting and inhibited postprandially, a pattern that mimics the secretory profiles of both ghrelin and GH. We thus hypothesized that glucagon may be a determinant of the changes in circulating ghrelin and GH that occur in relation to meals. The objective of the study was to explore this hypothesis by determining the ghrelin and GH response to a bolus of glucagon or saline in healthy subjects. SUBJECTS AND MEASUREMENTS: Nine healthy volunteers, mean age 47 years (range 33-58) and body mass index (BMI) 24 kg/m2 (range 20.9-27.6) were recruited and received either 1 mg glucagon (n = 9) or 1 ml saline (n = 6) subcutaneously on separate days between 0800 and 0830 h after an overnight fast. Venous blood was then sampled at 15-min intervals during the first hour, followed by 30-min intervals up to 4 h for glucose, insulin, GH, cortisol, somatostatin and ghrelin. RESULTS: Mean +/- SE basal ghrelin was 213.1 +/- 34.3 pmol/l and decreased significantly by 15 min after glucagon administration to 179.3 +/- 28 pmol/l (P = 0.01), then remaining suppressed relative to the basal value until 240 min after glucagon. Plasma insulin increased from a basal value of 46.7 +/- 7.7 pmol/l to a peak of 327.1 +/- 54.9 pmol/l (P < 0.0001). There was an inverse statistical relationship between the increase in insulin over the first 120 min and the decrease in ghrelin (P = 0.005), while somatostatin, GH and glucose were not significant contributors to the decrease in ghrelin (P > 0.05). Mean +/- SE basal GH was 7.3 +/- 2.9 microg/l and increased by 150 min after glucagon to a peak of 20.5 +/- 6.8 microg/l (P = 0.006). Changes in neither ghrelin nor glucose were related to the increase in GH (P = 0.7). Saline administration did not produce any significant change in ghrelin, insulin or somatostatin although the expected diurnal reduction in cortisol (P < 0.05) was observed. CONCLUSIONS: Our study found no evidence that glucagon stimulates ghrelin secretion in humans and supports the hypothesis that insulin is a negative regulator of ghrelin secretion in the postprandial state. We did not find a negative relationship between endogenous somatostatin and ghrelin despite earlier reports that exogenously administered somatostatin analogues suppress plasma ghrelin. Finally, glucagon-induced GH secretion is not mediated by an increase in plasma ghrelin.     

Carbohydrate tolerance and serum lipids in acromegaly before and during treatment with high dose octreotide.

Carbohydrate tolerance and serum lipids were studied in 14 patients with acromegaly before and in response to treatment with high dose somatostatin analogue (octreotide) over a 14-week period. Patients were assessed with respect to growth hormone (GH) profile, IGF1, HbA1, fasting lipids, and the GH, glucose, and insulin response to a standard 75 g oral glucose tolerance test (OGTT) before and during therapy. Prior to treatment mean fasting serum insulin levels were 11.7 +/- 2.8 (+/- SE) mU I-1 with a mean insulin response to OGTT of 49.8 +/- 10.8 mU I-1. Twelve of the 14 patients responded to octreotide with a reduction in mean 24-h serum GH (32.9 +/- 9.3 to 4.3 +/- 0.9 mU I-1), suppression of GH at 60 min during OGTT (3.0 +/- 0.8 mU I-1) and normalization of serum IGF1 (71 +/- 7 to 27 +/- 3 (normal 9-48 nmol I-1)). In this group the fasting insulin levels fell to 2.2 +/- 0.7 mU I-1 (p less than 0.01), and mean insulin response during OGTT was reduced (46.6 +/- 15.0 to 12.3 +/- 2.3 mU I-1) (p less than 0.01). Despite the reduction in insulin secretion there was no significant deterioration in fasting blood glucose (4.8 +/- 0.2 vs 4.6 +/- 0.4 mmol I-1), HbA1 (7.2 +/- 0.3 vs 6.8 +/- 0.3%) or mean blood glucose response to OGTT (7.9 +/- 0.7 vs 8.2 +/- 0.5 mmol I-1). Fasting triglycerides were reduced with treatment from 1.5 +/- 0.2 to 1.1 +/- 0.1 mmol I-1 (p = 0.04) in the responsive group, but serum cholesterol levels were not significantly altered (5.3 +/- 0.3 vs 5.2 +/- 0.3 mmol I-1).     

THE EFFECT OF CALCITONIN ON GROWTH HORMONE SECRETION IN ACROMEGALY

To determine whether human calcitonin inhibits GH secretion in acromegaly, as previously described for healthy subjects, the effect of an i.v. bolus injection of calcitonin or saline on GH levels in patients with active acromegaly was studied and compared to that of an i.v. bolus injection of the synthetic somatostatin analogue, octreotide. After the injection of calcitonin, GH levels decreased by 46% of initial values, whereas octreotide reduced GH levels by 87% and saline had no significant effect. Administration of calcitonin to acromegalics did not cause the transient rise in plasma PRL and TSH levels seen in normal subjects. Octreotide induced a decrease in plasma PRL in three out of seven patients. It is concluded that human calcitonin suppresses GH secretion in acromegaly, but not to normal levels; moreover the effect is less than that found for octreotide. In addition, acromegalic patients did not exhibit the PRL and TSH-releasing activity of calcitonin found in normal subjects, while octreotide inhibited PRL secretion in some acromegalic patients.     

Effect of the somatostatin analog D-Trp8,D-Cys14 on glucose insulin, pancreatic glucagon and growth hormone plasma levels in acromegalics and mild diabetics

The effect of the somatostatin analog (GHRIH-A) D-Trp8, D-Cys14 on plasma levels of growth hormone, pancreatic glucagon, insulin and glucose was studied in four acromegalic patients and in four maturity-onset mild diabetics. Acromegalics received a bolus iv injection of 25 microgram of GHRIH-A, followed by a continuous infusion of 25 microgram in saline over an hour. Mild diabetics were submitted in two different days to two tests: arginine (30 g in 30 min) +/- GHRIH-A (bolus iv injection of 25 microgram followed by an infusion of 25 microgram/h over 120 min) and arginine + saline. GHRIH-A lead to a significant (2 p less than 0.01) fall in GH basal secretion in acromegalics, and significantly reduced the GH response to arginine in maturity-onset diabetics. The inhibitory effect of insulin secretion was less impressive, but significative in both groups. No significant changes in plasma pancreatic glucagon values were noted. In mild diabetics, GHRIH-A infusion induced a small but significant increase in the blood glucose increment due to arginine. Our data suggest that this somatostatin analog may be potentially useful only when GH suppression is the main therapeutic goal to be reached, as in acromegaly and in severe diabetic retinopathy, but not in metabolic control of mild diabetic patients with a good residual insulin secretion.     

The novel somatostatin ligand (SOM230) regulates human and rat anterior pituitary hormone secretion

Currently available somatostatin analogs predominantly bind to the somatostatin receptor subtype (SSTR)2 subtype, and control GH and IGF-I secretion in approximately 65% of patients with acromegaly, their efficacy relating to receptor density and subtype expression. SOM230 is a somatostatin ligand with high affinity to four SSTR subtypes. In primary cultures of rat pituicytes, SOM230 dose-dependently inhibited GH release (P = 0.002) with an IC50 of 1.2 nM. Ten nanomoles SOM230 inhibited GH and TSH release by 40 +/- 7% (P < 0.001) and 47 +/- 21% (P = 0.09), respectively. No effect of SOM230 was observed on prolactin (PRL) or LH release. In cultures of human fetal pituitary cells, SOM230 inhibited GH secretion by 42 +/- 9% (P = 0.002) but had no effect on TSH release. SOM230 inhibited GH release from GH-secreting adenoma cultures by 34 +/- 8% (P = 0.002), PRL by 35 +/- 4% from PRL-secreting adenomas (P = 0.01), and alpha-subunit secretion from nonfunctioning pituitary adenomas by 46 +/- 18% (P = 0.34). In contrast, octreotide inhibited GH, PRL, and alpha-subunit from the respective adenoma by 18 +/- 12 (P = 0.39), 22 +/- 4 (P = 0.04), and 20 +/- 10% (P = 0.34). In all culture systems, no significant difference in the inhibitory action of SOM230, octreotide, and somatostatin 14 on hormone release was observed. SOM230, similar to somatostatin, has high-affinity binding to SSTR1, 2, 3, and 5 and, in keeping with this, has an equivalent inhibitory effect on pituitary hormone secretion. As a consequence of its broader binding profile, SOM230 is likely to find clinical utility in treating tumors resistant to SSTR-2-preferential analogs.