Insulin, glucose, and pancreatic polypeptide responses to a test meal in restricting type anorexia nervosa before and after weight restoration

Prolonged malnutrition in individuals with anorexia nervosa (AN) has been associated with alterations in endocrine function that may play a sustaining role in the disorder. We hypothesized that abnormalities in endocrine responses to ingestion of a meal in AN are reversible and depend on weight restoration. We measured meal-induced endocrine responses in AN subjects at three time points during hospitalization: before refeeding (n = 13, mean BMI 16.7 kg/m(2)), after 2 wk of refeeding (mean BMI 18.0 kg/m(2)), and in the weight-restored state (mean BMI 20.3 kg/m(2)). Control subjects (n = 13, BMI 19-24.9 kg/m(2)) were tested once. Tests were 2.5-h sessions in which blood was drawn every 15 min before, during, and after a approximately 650-kcal test breakfast. Relative to controls, peak levels of glucose were depressed and peak levels of insulin in response to ingestion of the test meal were delayed, with response patterns in the third trial most similar to controls. Pancreatic polypeptide (PP) levels were increased in AN relative to controls regardless of weight status. The delay in insulin release and elevated PP levels did not correct with short-term refeeding and may contribute to the high relapse rates and maintenance of AN.     

Relationship between intravenous ethanol, alcohol-induced inhibition of pancreatic secretion and plasma concentration of immunoreactive pancreatic polypeptide, vasoactive intestinal peptide, and somatostatin in man

We have studied in seven men, consuming less than 50 g alcohol daily, the effect of intravenous (i.v.) ethanol on (a) hormonally (secretin + CCK PZ) submaximally stimulated pancreatic secretion and (b) blood levels of pancreatic polypeptide (PP), vasoactive intestinal peptide (VIP) and somatostatin. After intravenous ethanol (600 mg/kg), pancreatic secretion decreased in all subjects and plasma levels of PP and VIP increased significantly. Moreover, there was a significant correlation between the mean inhibition of chymotrypsin output and the mean increase in PP plasma levels during the first 45 min following ethanol infusion. Therefore i.v. infusion of alcohol elicits release of PP and VIP and PP release could explain in part at least the alcohol-induced pancreatic inhibition observed in non-alcoholic men.     

Lunch induces an increase in the plasma prolactin concentration, but not vasoactive intestinal peptides or cholecystokinin

Ingestion of lunch is known to be associated with acute release of prolactin (PRL). The neuroendocrine mechanism of this release was examined by measuring changes in serum vasoactive intestinal peptides (VIP) and cholecystokinin (CCK) after the noon meal in six normal men. The serum PRL concentration was significantly increased (40% above the level before lunch) from 30 min to 1 h 45 min after beginning to eat. However, the ingestion of lunch had no remarkable effects on the plasma immunoreactive concentration of VIP and CCK. Thus the changes in the plasma concentration of these two gut-brain peptides did not coincided with acute PRL release after ingestion of lunch, suggesting either that these two gut-brain peptides are probably not involved in PRL release after lunch, or that the level of these two gut-brain peptides in the general circulation may not represent that in the hypophyseal portal plasma.     

Occurrence of VIP and peptide HM in human pancreas and their influence on pancreatic endocrine secretion in man

By immunohistochemistry it was found that VIP- and peptide HI/peptide HM (PHI/PHM)-like immunoreactivity occurred in autonomic neurons in the human pancreas. Antisera against both VIP and PHI/PHM reacted with neuronal cells in local ganglia and these ganglia also contained PHI/PHM- and VIP-immunoreactive fibre plexuses. VIP- and PHI/PHM-positive fibres were also seen close to the Langerhans' islets. In addition, PHI/PHM- but not VIP-like immunoreactivity was observed in the endocrine cells often located in the periphery of the islets. The nature of these PHI/PHM-positive cells remains to be established. I.v. infusion of VIP at constant rates of 300 and 900 pmol/kg X h for 30 min in 6 healthy volunteers resulted in plateau values of 102 +/- 26 and 291 +/- 25 pM, respectively. These levels of VIP which are above those found in the circulation under physiological conditions stimulated secretion of insulin, C-peptide and pancreatic glucagon dose-dependently. On the contrary prolonged (60 min) infusion of PHM in doses resulting in plasma levels up to 1340 +/- 405 pM had no effect on pancreatic hormone secretion. These findings suggest that VIP is a likely neurotransmitter in the control of endocrine pancreatic secretion while PHM has a less prominent role, if any.     

Enhancement of intragastric acid stability of a fat emulsion meal delays gastric emptying and increases cholecystokinin release and gallbladder contraction

Preprocessed fatty foods often contain calories added as a fat emulsion stabilized by emulsifiers. Emulsion stability in the acidic gastric environment can readily be manipulated by altering emulsifier chemistry. We tested the hypothesis that it would be possible to control gastric emptying, CCK release, and satiety by varying intragastric fat emulsion stability. Nine healthy volunteers received a test meal on two occasions, comprising a 500-ml 15% oil emulsion with 2.5% of one of two emulsifiers that produced emulsions that were either stable (meal A) or unstable (meal B) in the acid gastric environment. Gastric emptying and gallbladder volume changes were assessed by MRI. CCK plasma levels were measured and satiety scores were recorded. Meal B layered rapidly owing to fat emulsion breakdown. The gastric half-emptying time of the aqueous phase was faster for meal B (72 +/- 13 min) than for meal A (171 +/- 35 min, P < 0.008). Meal A released more CCK than meal B (integrated areas, respectively 1,095 +/- 244 and 531 +/- 111 pmol.min.l(-1), P < 0.02), induced a greater gallbladder contraction (P < 0.02), and decreased postprandial appetite (P < 0.05), although no significant differences were observed in fullness and hunger. We conclude that acid-stable emulsions delayed gastric emptying and increased postprandial CCK levels and gallbladder contraction, whereas acid-instability led to rapid layering of fat in the gastric lumen with accelerated gastric emptying, lower CCK levels, and reduced gallbladder contraction. Manipulation of the acid stability of fat emulsion added to preprocessed foods could maximize satiety signaling and, in turn, help to reduce overconsumption of calories.     

Disturbed cholecystokinin secretion in patients with eating disorders

It has been shown that the gastrointestinal hormone cholecystokinin (CCK) induces satiety and reduces food intake in laboratory animals and humans. In the light of this evidence we studied CCK release in patients suffering from eating disorders. The secretion of CCK into the general circulation was measured in 10 anorectic, in 7 bulimic patients, and in 8 healthy controls before and after a high-caloric liquid testmeal. Baseline CCK values were similar in controls (0.6 +/- 0.2 pmol/l) and bulimics (0.6 +/- 0.1 pmol/l) and were significantly increased in the anorectic group (1.8 +/- 0.4 pmol/l) (p less than or equal to 0.005). After eating peak plasma levels increased to 6.1 +/- 0.9 pmol/l in the anorectic, to 3.8 +/- 0.5 pmol/l in the bulimic and to 2.7 +/- 0.6 pmol/l in the control group. All postprandial CCK values were significantly higher in the anorectic group. The secretion of CCK-8-S, an important peptide in the CCK family, was significantly elevated, too. This disturbed CCK secretion in patients suffering from anorexia nervosa, even if it is a secondary, diet-induced defect, may perpetuate this disorder.     

High plasma cholecystokinin response following ingestion of test meal by patients with non-insulin dependent diabetes mellitus

Postprandial responses of plasma cholecystokinin (CCK) in patients with non-insulin dependent diabetes mellitus (NIDDM) were studied with a CCK specific radioimmunoassay. After the ingestion of a liquid test meal, plasma CCK levels increased from the basal level of 9.8 +/- 1.1 pg/ml to a peak of 19.4 +/- 1.8 pg/ml at 20 min in healthy subjects (n = 10). The ingestion of a test meal in patients with NIDDM (n = 10) resulted in a significantly greater increase of plasma CCK than in healthy subjects and a significant increase of plasma CCK from a basal level of 14.2 +/- 4.4 pg/ml to a peak of 47.4 +/- 12.4 pg/ml at 10 min.     

Cosecretion of peptide histidine methionine (PHM) and vasoactive intestinal peptide (VIP) in patients with VIP-producing tumors

Regional specific antibodies and chromatography were used to analyze the concentration and molecular forms of vasoactive intestinal peptide (VIP) and peptide histidine methionine (PHM) in plasma from 39 patients with VIP-producing tumors. Plasma VIP concentrations ranged from 29 to 2550 pmol/l and the corresponding PHM immunoreactive values measured with C-terminally directed antibody were 42 to 2100 pmol/l which correlated closely with the VIP concentrations. N-terminal PHM concentrations were significantly higher than the C-terminal values ranging from 92 to 5850 pmol/l and correlated poorly with the corresponding VIP concentrations. Infusion experiments with PHM disclosed that the higher levels of N-terminal immunoreactivity could not be explained by slower metabolic clearance or by degradation to smaller N-terminal immunoreactive forms. N-terminally directed PHM antibody revealed, in addition to intact PHM, a larger immunoreactive form in patient plasma which constituted the major proportion of the total immunoreactivity. In conclusion, VIP and PHM are cosecreted from VIPomas and measurement of PHM, especially N-terminal immunoreactivity, may be useful in this condition.     

Plasma somatostatin and vasoactive intestinal polypeptide responses to an oral mixed test meal in obese patients

Ten obese and 10 control subjects were studied in basal conditions and after ingestion of a standard mixed test meal. Blood glucose, insulin, somatostatin (SLI) and vasoactive intestinal polypeptide (VIP) concentrations were determined before and 30, 60, 90, 120, 180 and 240 min after the start of the meal. Basal SLI levels in the obese (14.4 +/- 0.7 ng/l) were not significantly different from those in the controls (15.5 +/- 0.8 ng/l), whereas after the meal a blunted secretory response was recorded. Baseline plasma VIP levels were higher in the obese (29.7 +/- 1.5 ng/l) than in the control subjects (19.8 +/- 1.3 ng/l) and, similarly to the controls, were unaffected by meal ingestion. Data suggest that in the course of obesity an enhanced VIP secretion in association with a diminished SLI responsiveness to meals occurs.     

Inhibition of gastric emptying by acarbose is correlated with GLP-1 response and accompanied by CCK release

We investigated the effect of acarbose, an alpha-glucosidase and pancreatic alpha-amylase inhibitor, on gastric emptying of solid meals of varying nutrient composition and plasma responses of gut hormones. Gastric emptying was determined with scintigraphy in healthy subjects, and all studies were performed with and without 100 mg of acarbose, in random order, at least 1 wk apart. Acarbose did not alter the emptying of a carbohydrate-free meal, but it delayed emptying of a mixed meal and a carbohydrate-free meal given 2 h after sucrose ingestion. In meal groups with carbohydrates, acarbose attenuated responses of plasma insulin and glucose-dependent insulinotropic polypeptide (GIP) while augmenting responses of CCK, glucagon-like peptide-1 (GLP-1), and peptide YY (PYY). With mixed meal + acarbose, area under the curve (AUC) of gastric emptying was positively correlated with integrated plasma response of GLP-1 (r = 0.68, P < 0.02). With the carbohydrate-free meal after sucrose and acarbose ingestion, AUC of gastric emptying was negatively correlated with integrated plasma response of GIP, implying that prior alteration of carbohydrate absorption modifies gastric emptying of a meal. The results demonstrate that acarbose delays gastric emptying of solid meals and augments release of CCK, GLP-1, and PYY mainly by retarding/inhibiting carbohydrate absorption. Augmented GLP-1 release by acarbose appears to play a major role in the inhibition of gastric emptying of a mixed meal, whereas CCK and PYY may have contributory roles.     

Enteric release of vasoactive intestinal peptide after a peptone meal in the dog

Vasoactive intestinal peptide (VIP) concentrations were measured by radioimmunoassay in plasma from portal and peripheral venous blood obtained from six alert, non-anesthetized dogs before and after gastric infusion of a 10% peptone meal. Mean basal portal and cephalic vein plasma VIP concentrations were $\text{42 ± 11.7}$ and $\text{42 ± 8.0}\text{(S.E.M.) pg/ml}$, respectively. No significant changes in peripheral venous plasma VIP concentrations were noted after the peptone meal throughout the duration of the collection period. In contrast, however, the mean VIP concentration in portal plasma increased promptly after the peptone meal with a peak of $\text{79 ± 8.2}\text{pg/ml}$ ($\text{P < 0.02}$) occurring 8 min after infusion of the meal. This was followed by a gradual decline in portal plasma VIP levels, with a return to prefeeding concentrations at 60 min ($\text{44 ± 6.3}\text{pg/ml}$). Results of these studies demonstrate that following gastric infusion of a peptone meal in the dog, portal, but not peripheral, plasma VIP concentrations increase significantly. Failure to detect augmentation of peripheral vein VIP levels after the meal is probably due to hepatic clearance of VIP.     

Effect of CCK-1 receptor blockade on ghrelin and PYY secretion in men

Cholecystokinin (CCK), peptide YY (PYY), and ghrelin have been proposed to act as satiety hormones. CCK and PYY are stimulated during meal intake by the presence of nutrients in the small intestine, especially fat, whereas ghrelin is inhibited by eating. The sequence of events (fat intake followed by fat hydrolysis and CCK release) suggests that this process is crucial for triggering the effects. The aim of this study was therefore to investigate whether CCK mediated the effect of intraduodenal (ID) fat on ghrelin secretion and PYY release via CCK-1 receptors. Thirty-six male volunteers were studied in three consecutive, randomized, double-blind, cross-over studies: 1) 12 subjects received an ID fat infusion with or without 120 mg orlistat, an irreversible inhibitor of gastrointestinal lipases, compared with vehicle; 2) 12 subjects received ID long-chain fatty acids (LCF), ID medium-chain fatty acids (MCF), or ID vehicle; and 3) 12 subjects received ID LCF with and without the CCK-1 receptor antagonist dexloxiglumide (Dexlox) or ID vehicle plus intravenous saline (placebo). ID infusions were given for 180 min. The effects of these treatments on ghrelin concentrations and PYY release were quantified. Plasma hormone concentrations were measured in regular intervals by specific RIA systems. We found the following results. 1) ID fat induced a significant inhibition in ghrelin levels (P < 0.01) and a significant increase in PYY concentrations (P < 0.004). Inhibition of fat hydrolysis by orlistat abolished both effects. 2) LCF significantly inhibited ghrelin levels (P < 0.02) and stimulated PYY release (P < 0.008), whereas MCF were ineffective compared with controls. 3) Dexlox administration abolished the effect of LCF on ghrelin and on PYY. ID fat or LCF significantly stimulated plasma CCK (P < 0.006 and P < 0.004) compared with saline. MCF did not stimulate plasma CCK release. In summary, fat hydrolysis is essential to induce effects on ghrelin and PYY through the generation of LCF, whereas MCF are ineffective. Furthermore, LCF stimulated plasma CCK release, suggesting that peripheral CCK is the mediator of these actions. The CCK-1 receptor antagonist Dexlox abolished the effect of ID LCF, on both ghrelin and PYY. Generation of LCF through hydrolysis of fat is a critical step for fat-induced inhibition of ghrelin and stimulation of PYY in humans; the signal is mediated via CCK release and CCK-1 receptors.     

Glucagon-like peptide 1 (GLP-1) secretion and plasma dipeptidyl peptidase IV (DPP-IV) activity in morbidly obese patients undergoing biliopancreatic diversion.

BACKGROUND: The physiological inhibitory control of glucagon-like Peptide 1 (GLP-1) on gastric emptying and the contribution of this peptide in the regulation of food intake as a satiety factor suggest that impaired secretion and/or activity of GLP-1 may be involved in the pathogenesis of obesity. We investigated food-mediated GLP-1 secretion as well as plasma activity of dipeptidyl-peptidase IV (DPP-IV), the enzyme responsible for rapid inactivation of the circulating peptide, in morbidly obese patients, before and after weight loss resulting from biliopancreatic diversion. METHODS: Twenty-two morbidly obese non-diabetic patients (BMI = 47.5 +/- 1.8) and 9 age-matched healthy volunteers were studied. A mixed meal (700 kcal) was administered to all subjects and blood samples were collected at 0, 15, 30, 60, 120 min for the determination of circulating glucose, insulin, GLP-1 (7 - 36 amide) concentrations and plasma DPP-IV activity. The patients repeated the test meal after 50 % overweight reduction resulting from surgical treatment (BMI = 33.8 +/- 1.1). RESULTS: While nutrient ingestion significantly increased plasma GLP-1 levels in the control group (30', 60': p < 0.01), the test-meal failed to modify basal peptide values in the obese patients, and an overall reduction in circulating GLP-1 occurred during the observation period (p < 0.001). Plasma DPP-IV activity in the same patients resulted as being significantly higher than controls, both at fasting and in response to the meal (p < 0.05). With respect to preoperative values, an overall increase in circulating GLP-1 levels occurred in all patients following biliopancreatic diversion (p < 0.001). Plasma DPP-IV activity, on the other hand, continued to be abnormally increased, even after considerable weight loss (p < 0.05 vs. controls). CONCLUSIONS: First: In morbid obesity, the accelerated inactivation of circulating GLP-1 could at least partially account for plasma peptide levels lower than normal, the defective availability of such a satiety factor possibly contributing to eating behaviour abnormalities; Second: plasma DPP-IV hyperactivity in the obese did not seem to be affected by the overweight degree, the increase in postoperative GLP-1 levels mainly resulting from hyperstimulation of GLP-1 secretory cells due to surgical manipulation of gastrointestinal tract. If the abnormally accelerated degradation of GLP-1 in obesity is confirmed, selective DPP-IV inhibitors could actually represent an ideal approach to obesity management.     

Human atrial natriuretic polypeptide in plasma of patients with anorexia nervosa

To examine the effects of chronic dehydration and starvation on plasma levels of human atrial natriuretic polypeptide (hANP) in human subjects, the basal level and saline-induced rise of plasma hANP in 7 patients with anorexia nervosa were compared with those in age-matched healthy subjects. The unstimulated level of plasma hANP was markedly high in the patients with anorexia nervosa (patients vs. control; 55.4 +/- 9.0 pg/ml vs. 11.4 +/- 6.1 pg/ml, P less than 0.01). However, no significant increase of plasma hANP in the anorectic patients was observed in response to saline-infusion, while a 3-fold increase over the basal level of plasma hANP was noted in the saline-infused normal young subjects. These results show that hANP may be secreted to an inadequate extent, hence the release would be resistant to volume-loading. The pathophysiological meaning of such a high plasma concentrations of hANP in anorexia nervosa is the subject of ongoing studies.     

Plasma adiponectin levels in women with anorexia nervosa.

Adiponectin is a plasma protein exclusively secreted by adipose tissue, which plays a role in modulating lipid and glucose metabolism. The plasma adiponectin concentration shows an inverse correlation with the body mass index in normal and obese individuals, but it has not been investigated in subjects with an extremely low body weight and undernutrition such as anorexia nervosa patients. We investigated plasma adiponectin levels in 21 females with anorexia nervosa. Nineteen healthy females served as the lean control group. The subjects with anorexia nervosa had a significantly lower weight and showed a tendency towards higher adiponectin levels than the control group. No correlation between adiponectin and BMI was found in patients with anorexia nervosa, while a linear negative correlation was seen in lean controls. The patient who showed the lowest adiponectin level reached a life-threatening state and required intravenous feeding in hospital. In association with improved nutrition and weight gain, the adiponectin level increased gradually until the body mass index was about 16 and then decreased subsequently as would be expected in lean normal subjects. These observations suggest that adipose tissue secretes less adiponectin and the adiponectin levels do not show an inverse correlation simply with body mass index in some subjects with severe undernutrition.     

GLP-1 as a satiety factor in children with eating disorders.

GLP-1, with its insulinotropic properties and direct action on satiety center in the brain, may be the main hormone regulating the amount of ingested food. In this study, GLP-1 secretion was investigated in age-matched adolescent girls (14 +/- 2 years): 13 with anorexia nervosa (BMI 14.8 +/- 1.4 kg/m(2)), 13 with simple obesity (BMI 33.0 +/- 3.3 kg/m(2)) and 10 healthy girls as a control group (BMI 21.6 +/- 0.7 kg/m(2)). Each girl was subjected to OGTT and standard meal tests after a 12 h overnight fast. Blood samples were collected before and 15, 30, 60, and 120 min after the stimulation. The mean fasted GLP-1 levels in simple obesity group (1.6 +/- 0.3 pmol/l) and in anorexia nervosa group (1.7 +/- 0.3 pmol/l) were significantly lower than those in the control group (2.6 +/- 0.4 pmol/l) (p < 0.05 in both cases). The highest peak concentration of GLP-1 was observed in the control group after both stimuli. In each group, the mean integrated GLP-1 outputs were almost twice as high after OGTT than after the test meal (p < 0.001 in each case). In our opinion, low secretion of GLP-1 in girls with simple obesity may seriously and negatively influence the course of this disease. On the other hand, low GLP-1 levels in girls with anorexia nervosa are beneficial and promote appetite.     

Orlistat reduces gallbladder emptying by inhibition of CCK release in response to a test meal

BACKGROUND AND AIMS: Orlistat is a covalent inhibitor of digestive lipase derived from lipstatin, the natural product of Streptomyces toxytricini. By blocking the active site of intestinal lipase, orlistat inhibits hydrolysis of dietary triglycerides and thus reduces the intestinal lipid absorption. It is uncertain whether intestinal inhibition of lipase by orlistat also interferes with nutrient-induced CCK release from intestinal I-cells. The aim of the present study was therefore to assess whether oral administration of orlistat inhibits CCK release in response to a test meal and thus causes impaired gallbladder emptying. METHODS: 22 healthy volunteers were given a test meal consisting of 200 ml dairy cream and two teaspoons of chocolate powder (552 kcal=2328 kJ; 56.0 g fat; 5.2 g proteins, 6.6 g carbohydrates), with and without oral application of 120 mg orlistat. Gallbladder volume was determined by ultrasound before and 5, 10, 20, 30 and 40 min after meal ingestion. In parallel, a venous blood sample was collected for the measurement of bioactive CCK. CCK activity was assessed using a bioassay with isolated rat pancreatic acini cells. RESULTS: Oral administration of orlistat significantly impairs gallbladder emptying. After ingestion of the test meal the gallbladder contracted by 78.5% in the control group, whereas the test group with orlistat only showed a contraction of 45.7% (p<0.01). Maximal contraction was reached after 35 to 40 min, the maximal gallbladder emptying was delayed up to 10 min by orlistat. Orlistat induced a significant reduction of bioactive CCK levels in response to a test meal (CCK(max) with orlistat=4.1 pmol/l; CCK(max) without orlistat=7.8 pmol/l). CCK levels were reduced by 47% and the onset of maximal CCK secretion was delayed up to 10 min. CONCLUSION: The inhibition of intestinal lipolytic activity by orlistat results in reduced gallbladder emptying through inhibition of meal-mediated CCK release. We therefore hypothesize that impaired gallbladder motility may represent a risk factor in chronic treatment of severe obesity using orlistat.     

In vitro, release of cholecystokinin from hypothalamus and frontal cortex of Sprague-Dawley, Zucker lean (Fa/-) and obese (fa/fa) rats

Cholecystokinin (CCK) has been suggested as a putative satiety factor, whose site of action is in the hypothalamus. The genetically obese (fa/fa) Zucker rat has been proposed as a model of human obesity. Though hypothalamic tissue levels of CCK did not vary between the fa/fa rat and age-matched lean littermates (25.5 +/- 5.7 vs. 27.6 +/- 5.2 pmoles/g tissue) we sought to determine if the releasability of hypothalamic and cortical CCK was the same in lean and obese rats. The in vitro superfusion paradigm was used to study the release of CCK and substance P (sP) from hypothalamus, and CCK and vasoactive intestinal polypeptide (VIP) from frontal cortex. The potassium stimulated release of CCK from obese rat hypothalamic tissue was significantly higher than from lean rat hypothalamus (3.62 +/- 0.3 vs. 1.91 +/- 0.3 fmole equivalents CCK-8/mg tissue/10 min). Similarly, sP release was exaggerated in obese rats in a parallel fashion (5.56 +/- 0.44 vs. 2.761 +/- 0.46 fmoles/mg tissue/10 min). However, the potassium stimulated release of CCK and VIP from cortical tissue was the same in all three groups of rats. The obese Zucker rat thus, may have an anomalous release of CCK and sP from the hypothalamus, but not from the frontal cortex, an area not presumably associated with satiety.     

Peptide histidine methionine (PHM) increases ileostomy output

The human vasoactive intestinal peptide (VIP) gene also encodes peptides histidine methionine (PHM) which has substantial sequence homology with VIP. Both are present in nerve fibers in the human ileum and circulate in greatly increased concentrations in patients with the watery diarrhoea syndrome. We have infused PHM (23 pmol/kg/min) into 5 patients with ileostomies to determine the effect of PHM on human ileal output. Plasma PHM levels rose from 22 +/- 6 to 6013 +/- 874 pM (mean +/- S.E.M.) during PHM infusions and ileal output rose from 16 +/- 3 to 177 +/- 27 g/30 min (P less than 0.0001). PHM infusions also produced a significant fall in the percentage of solid material and a rise in the concentration of chloride in the ileal effluent. Mean plasma PHM concentrations during PHM infusions were equal to the highest levels seen in patients with the watery diarrhoea syndrome, so PHM may contribute to diarrhoea in this condition. Neuronal PHM may exert physiological control over ileal transport of water and electrolytes.     

The role of leptin and orexins in the dysfunction of hypothalamo-pituitary-gonadal regulation and in the mechanism of hyperactivity in patients with anorexia nervosa

Anorexia nervosa (AN) belongs to a group of eating disorders and is characterized by extreme body weight loss. AN patients show combination of physical, psychological and behavioral disturbances. Neuropeptides partly control energy homeostasis and modulate hormone release. Leptin, a peptide secreted by adipocytes, may influence the interactions between central and peripheral signals. Hypoleptinaemia found in AN is connected with disturbed control of appetite and hormonal dysfunction as well as has implications for the hypothalamo-pituitary-gonadal axis, bone mineral density and physical hyperactivity. Low leptin levels are increased with refeeding. However, the prolonged hypoleptinaemia in weight recovered AN patients may result in persistent hypothalamic amenorrhoea. The hyperactivity has been observed in 31-80 % of AN cases. The mechanisms underlying the hyperactivity found in patients with anorexia nervosa seem to be more complicated as many factors including neuropeptides may be involved. Orexins may affect not only appetite but also behavior and psychophysical activity as they may regulate reproductive and stress hormone secretion, stimulate a variety of stereotypic behaviors including eating and stress reaction, and affect the hypothalamo-pituitary-adrenal (HPA) axis, alter glucocorticoid and catecholamine secretion and activate the sympathetic nervous system. Orexins influence the mechanism regulating arousal and sleep, cardiovascular function, temperature, metabolic rate and locomotive activity. It is worth considering how abnormal activity of hypothalamic neuropeptides or their receptors may play a role in the mechanisms of hyperactivity, disturbed control of appetite and hormonal dysfunction in patients with anorexia nervosa.