Abstract. Menetrier's disease is characterized by giant gastric folds with foveolar hyperplasia and cystic dilatation, hypoproteinemia, and enhanced mucus secretion. The etiology remains unresolved and an effective treatment has yet to be established. Here we show that histamine H 2 -receptor deficient mice developed gastric pathophysiological changes resembling Menetrier's disease for up to 17 months of observation. Mutant mice were found to have an increased stomach weight, enlarged gastric folds with cystic dilatation, hypergastrinemia, hypoalbuminemia, increased mucus secretion and overexpression of mucosal transforming growth factor (TGF) a . Both a cholecystokinin (CCK) 2 -receptor antagonist and an epidermal growth factor (EGF)-receptor tyrosine kinase inhibitor significantly reduced the increase in stomach weight. It appears that lack or downregulation of histamine H 2 -receptors might be involved in the pathogenesis of Menetrier's disease.

The effect of various nutrients and hormones on motilin release was examined in normal volunteers and postvagotomy patients to investigate the mechanism of motilin secretion in the postprandial state. The ingestion of a mixed meal, protein and fat elevated the plasma motilin level, but the oral glucose load and arginine infusion lowered it. Although gastrin infusion showed no effect on the plasma motilin concentration, the infusion of insulin or glucagon inhibited motilin release in vivo. The patients, who underwent a selective or truncal vagotomy, also revealed a rise in plasma motilin after meal ingestion, suggesting that motilin could be released even in the absence of gastric acid and vagal stimulus. The perifusion experiments demonstrated that motilin release from human duodenal mucosa into the perfusate was stimulated markedly by low pH and 15 mM taurocholate, but not affected by the perifusion of 20 mM glucose, 20 mM arginine, 100 mU/l insulin or 30 nM glucagon. These results indicate that the motilin release induced by meal ingestion depend upon the balance of food components and that in normal subjects duodenal acidification, bile acid and unknown factors contained in the mixed meal may participate at least in part in postprandial motilin release. The inhibitory effect of glucose on motilin release may be attributable to a certain mediator mechanism which remains to be studied.

Synthetic LRH was infused into normal women and women with obesity and anorexia nervosa to determine the distribution volume (DV), metabolic clearance rate (MCR) and half disappearance time (t\m=1/2\)of plasma LRH.In normal women, the DV of LRH was 12.1 \m=+-\0.9 (mean \ m=+-\se) 1, the MCR was 1478.9 \m=+-\39.8 ml/min (28.5 \m=+-\1.2 ml/min/kg body weight) and the initial t \ m=1/ 2\ was 5.6 \m=+-\0.4 min.In obese patients the DV (20.6 \ m=+-\ 1.5 1) was significantly higher than that in normal subjects (P < 0.005), but the MCR and t\m=1/2\were not significantly different from those in normal subjects.In patients with anorexia nervosa the DV and MCR were 6.5 \m=+-\1.1 l and 621.8 \m=+-\110.5 ml/min (17.9 \ m=+-\2.4 ml/ min/kg body weight), respectively, which were both significantly lower than those in normal subjects (P < 0.02), while the t\m=1/2\(7.3 \m=+-\0.1 min) was longer than in normal subjects (P < 0.02).These data suggest that 1) the abnormal responses of some hormones to provocation tests observed in obese patients and patients with anorexia nervosa should be evaluated in consideration of changes in the DV and metabolic clearance of hormones in these conditions, and 2) in patients with anorexia nervosa changes in MCR and t \ m=1/ 2\ may reflect low metabolism of LRH.Various endocrine and metabolic abnormalities have been found in obese subjects (Beck et al. 1964;Copinschi et al. 1967) and underweight subjects (Frankel & Jenkins 1975). As we previously reported, the release of some pituitary hormones in response to various stimuli is impaired in obese patients (Chikamori 1976), and elevation of the plasma growth hormone (GH) level and decrease in luteinizing hormone (LH) secretion are noted in many patients with anorexia nervosa (Nishimura et al. 1979). These abnormalities in hormone secre¬ tion have been considered as secondary changes due to change in the body weight or dysfunction of the hypothalamo-pituitary axis. However, the plasma concentration of a hormone reflects a ba¬ lance between the rates of its secretion and meta¬ bolism, and thus endocrine function should be evaluated on the basis not only of the plasma concentration but also of metabolic clearance of the hormone released from the endocrine gland.For investigation of this problem, it is necessary to study changes in the distribution volume (DV) and metabolic clearance rate of hypothalamic or pituitary hormones in patients with obesity and anorexia nervosa. At present few purified pituitary hormones are available for iv injection into hu¬ mans, but hypothalamic releasing hormone is read¬ ily available.The metabolic clearance of synthetic luteinizing hormone releasing hormone (LRH) in normal sub¬ jects has been studied (Miyachi et al. 1973;Keye et al. 1973), but litüe is known about changes in metabolic clearance of LRH in diseased states (Pimstone et al. 1977). Therefore, we studied the DV, metabolic clearance rate (MCR) and half disap-

No abstract

No abstract