Marie Degerblad

CONTEXT: Ghrelin is produced primarily by enteroendocrine cells in the gastric mucosa and increases gastric emptying in patients with gastroparesis. MAIN OBJECTIVE: The objective of the study was to evaluate the effect of ghrelin on gastric emptying, appetite, and postprandial hormone secretion in normal volunteers. DESIGN: This was a randomized, double-blind, crossover study. SUBJECTS: Subjects included normal human volunteers and patients with GH deficiency. INTERVENTION: Intervention included saline or ghrelin (10 pmol/kg.min) infusion for 180 min after intake of a radioactively labeled omelette (310 kcal) or GH substitution in GH-deficient patients. MAIN OUTCOME MEASURES: Measures consisted of gastric empty-ing parameters and postprandial plasma levels of ghrelin, cholecystokinin, glucagon-like peptide-1, peptide YY, and motilin. RESULTS: The emptying rate was significantly faster for ghrelin (1.26 +/- 0.1% per minute), compared with saline (0.83% per minute) (P < 0.001). The lag phase (16.2 +/- 2.2 and 26.5 +/- 3.8 min) and half-emptying time (49.4 +/- 3.9 and 75.6 +/- 4.9 min) of solid gastric emptying were shorter during ghrelin infusion, compared with infusion of saline (P < 0.001). The postprandial peak in plasma concentration for cholecystokinin and glucagon-like peptide-1 occurred earlier and was higher during ghrelin infusion. There was no significant effect of ghrelin on plasma motilin or peptide YY. There was no difference in gastric emptying before and after GH substitution. CONCLUSION: Our results demonstrate that ghrelin increases the gastric emptying rate in normal humans. The effect does not seem to be mediated via GH or motilin but may be mediated by the vagal nerve or directly on ghrelin receptors in the stomach. Ghrelin receptor agonists may have a role as prokinetic agents.

The aim of the present trial was to study the individual responsiveness to GH treatment in terms of body composition and to search for possible predictors of the response in GH-deficient adults. Sixty-eight patients (44 men and 24 women) with a mean age of 44.3 (1.2) yr and verified GH deficiency participated in a 2-phase treatment trial with an initial randomized, double blind, placebo-controlled, 6-month period, followed by an open treatment period, thereby ensuring all patients 12 months of GH treatment. Recombinant human GH was administered sc daily at bedtime, with a target dose of 12 micrograms/kg x day. GHBP was measured by ligand-mediated immunofunctional assay, and serum insulin-like growth factor I (IGF-I) was determined by RIA after acid-ethanol extraction, using a truncated IGF-I analog as the radioligand. Lean body mass (LBM) and body fat (BF) were determined by dual energy x-ray absorptiometry, and total body water (TBW) was determined by bioelectrical impedance. During the placebo control period, serum IGF-I,LBM, and TBW increased (P < 0.001), whereas BF decreased (P < 0.001) and serum GHBP was unchanged in the group treated with GH compared with the patients treated with placebo. After 12 months of GH treatment, the individual changes in BF ranged from -12.5 to 4.3 kg and from -4.5 to 10.1 kg in LBM. Age (P < 0.05) and baseline GHBP level (P < 0.01) were inversely correlated with the increase in LBM. The GH-induced increment in IGF-I and TBW was greater in men than in women (P < 0.01), whereas the decreases in BF were similar in men and women. This trial demonstrates the variability in responsiveness to GH administration in GH-deficient adults. The best response to GH was obtained in younger patients with low GHBP levels. Furthermore, men responded better than women.

OBJECTIVE: To study retrospectively long-term outcomes of patients with adrenocorticotropic hormone-producing pituitary tumors that were treated with stereotactic Leksell gamma knife unit radiosurgery. METHODS: Eighty-nine patients aged 5 to 67 years were treated between 1976 and 1985. Eighteen patients aged 18 to 68 years (mean age, 41 yr) were followed in detail. Fifteen patients were women. None had previously received conventional radiotherapy, but pituitary microsurgery had been performed in two patients, and one patient had had an adrenalectomy. In the remaining 15 patients, radiosurgery was the primary therapy. RESULTS: Sixty-four patients had one stereotactic treatment, and 25 patients had two or more treatments. No complications were observed during treatment and the immediate follow-up period. At follow-up, 17 patients had died 1 to 20 years after the first treatment. No deaths were related to the treatment. In our 18 patients, the follow-up time after the first radiosurgical treatment was 12 to 22 years (mean follow-up period, 17 yr). Urinary cortisol levels gradually normalized in 83% of the patients. No recurrences were observed. Pituitary hormone insufficiencies developed in about two of every three patients and occurred even more than 10 years after treatment. Eight patients had transient hyperprolactinemia. The patients' vision and visual fields were unaffected, and none of them had signs of radiation-induced side effects such as brain tumors or brain necrosis. CONCLUSION: Stereotactic radiosurgery is a safe and effective method in the treatment of patients with adrenocorticotropic hormone-producing pituitary tumors, and the effect of treatment is long-lasting. Stereotactic radiosurgery is mainly a complement to microsurgery because of its gradually appearing effect and the occurrence of pituitary insufficiency. New pituitary deficiencies may be found more than 10 years after treatment.

BACKGROUND: Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are major incretins with important effects on glucoregulatory functions. The aim of this study was to investigate effects of GIP and GLP-1 on gastric emptying and appetite after a mixed meal, and effects on insulin secretion and glucose disposal in humans. METHODS: Randomized crossover single-blind study in 17 healthy volunteers receiving GIP (2 or 5 pmol kg(-1) min(-1), n = 8), GLP-1 (0.75 pmol kg(-1) min(-1), n = 9) or NaCl for 180 min with a radionuclide-labeled omelette and fruit punch (370 kcal). Outcome measures were gastric emptying rate, insulinogenic index, hunger, satiety, desire to eat, and prospective food consumption. Blood was analyzed for GIP, GLP-1, glucagon, C-peptide, peptide YY (PYY) and ghrelin. KEY RESULTS: Glucose-dependent insulinotropic polypeptide 2 and 5 pmol kg(-1) min(-1) decreased gastric half-emptying time from 128.5 ± 34.0 min in controls to 93.3 ± 6.3 and 85.2 ± 11.0 min (P < 0.05). Glucose-dependent insulinotropic polypeptide 5 pmol kg(-1) min(-1) decreased postprandial glucose (P < 0.001) and insulin (P < 0.05) with increased insulinogenic index. Glucose-dependent insulinotropic polypeptide had no effects on hunger, desire to eat, satiety or prospective consumption. Glucagon-like peptide-1 0.75 pmol kg(-1) min(-1) increased half-emptying time from 76.6 ± 7.6 min to 329.4 ± 71.6 (P < 0.01). Glucagon-like peptide-1 decreased plasma glucose and insulin (both P < 0.05-0.001), and increased insulinogenic index markedly. Hunger, desire to eat and prospective consumption were decreased (P < 0.05), and satiety borderline increased (P < 0.06). CONCLUSION & INFERENCES: The incretin effect of GIP and GLP-1 differs as GLP-1 exerts a strong glucoregulatory incretin through inhibition of gastric emptying, which GIP does not. Thus, GLP-1 as incretin mimetic may offer unique benefits in terms of weight loss in treatment of type 2 diabetes.

Six patients (21-50 years) with growth hormone deficiency and panhypopituitarism were given recombinant growth hormone, somatotropin, 0.04-0.1 U.kg.body wt-1.day-1, for 12 months. All patients reported improved well-being with increased working capacity. Bone mineral density, as measured by single photon absorptiometry at two sites on the forearm, showed increased values in 5/6 patients after 12 months when measured at the most distal site (predominantly trabecular bone) and in 4/6 at the more proximal site (predominantly cortical bone). Five patients continued therapy for an additional year and after 18 months a significant increase in bone mineral density was seen at both the distal and proximal sites. The mean annual increase in bone mineral density was 12.0 +/- 0.6 (SEM)% and 3.8 +/- 1.3% at the distal and proximal sites, respectively. In a growth hormone deficient control group without growth hormone therapy, the corresponding values were -2.4 +/- 0.6% and -1.9 +/- 0.4%, respectively. Lean body mass, estimated anthropometrically, increased significantly after 12 months and total body potassium, measured by whole body counting technique, increased in 4/6 patients. During growth hormone treatment, the IGF-1 values were above the mean values for age and 50% of the values were above the mean +2 SD. B-glucose, P-insulin, serum IGF-2, procollagen-III peptide and phosphate increased and urea, creatinine and IGF-binding protein-1 decreased during treatment. The beneficial effects of growth hormone substitution, especially on bone mineral density, indicate that growth hormone substitution should be considered in all patients with hypopituitarism and growth hormone deficiency, irrespective of age.