Effect of low-GDP bicarbonate-lactate-buffered peritoneal dialysis solutions on plasma levels of adipokines and gut appetite-regulatory peptides. A randomized crossover study.

BACKGROUND: Malnutrition is common in patients treated with peritoneal dialysis (PD). Previous studies have disclosed disturbances in the hormonal axes regulating appetite in these patients. The effect of newer biocompatible PD solutions on these disorders is undetermined. METHODS: Using a crossover randomized design, 21 patients stable on PD underwent 5 weeks of therapy with each of classic glucose degradation product (GDP)-rich lactate-buffered PD solutions (L) and newer low-GDP bicarbonate-lactate-buffered PD solutions (BL). At the end of each phase, we scrutinized patients for adequacy markers, peritoneal transport (peritoneal equilibration test with 3.86% glucose-based solutions), general biochemical markers and, more specifically, cytokines, adipokines (leptin and adiponectin) and selected gastrointestinal peptides which regulate appetite in the short term [ghrelin, peptide YY, cholecystokinin, glucagon-like peptide 1 (GLP1)]. For plasma GLP1 levels, we analysed a group of healthy, sex-, age- and body mass index-matched controls. RESULTS: Use of BL solutions was associated with higher plasma levels of acylated (but not total) ghrelin (median 243 BL versus 141 pg/mL L, P = 0.05), adiponectin (median 20.2 BL versus 17.6 mcg/mL L, P = 0.008) and growth hormone (median 1.8 BL versus 1.0 ng/mL L, P = 0.013), without significant differences for the other cytokines, leptin or gut peptides scrutinized. We did not observe significant differences between L and BL solutions concerning estimations of adequacy, peritoneal transport or general biochemical markers. CONCLUSIONS: Use of GDP-free, neutral-pH, bicarbonate-lactate-buffered PD solutions is associated with higher plasma levels of acylated ghrelin and adiponectin than classic solutions. These findings may contribute to explaining improved appetite scores and overall survival rates reported with the use of so-called biocompatible PD solutions.

The decreased growth hormone response to growth hormone releasing hormone in obesity is associated to cardiometabolic risk factors.

The aim of the present study was to evaluate the relationship between GHRH-induced GH secretion in obese premenopausal women and cardiovascular risk markers or insulin resistance. Premenopausal obese women, aged 35-52 years, were studied. GH secretion, IGF-I, serum cardiovascular risk markers, insulin, leptin, mid-waist and hip circumference, total body fat, and truncal fat were measured. Subjects were classified as meeting the criteria for GH deficiency (GHD) when peak GH after stimulation with GHRH was

Short-term regulation of peptide YY secretion by a mixed meal or peritoneal glucose-based dialysate in patients with chronic renal failure.

BACKGROUND: Malnutrition is very prevalent among patients with chronic renal failure. The role of derangements in the gut-brain axis for regulation of appetite in the genesis of anorexia of these patients has not been adequately investigated. Design. Following a randomized, crossover design, we analysed plasma levels of peptide YY (PYY)(1-36) and PYY(3-36) both fasting and after a standardized oral mixed meal or intraperitoneal glucose infusion in 10 stable uraemic patients undergoing peritoneal dialysis and 8 healthy controls, matched for age, gender and body mass index. Main results. Median baseline plasma levels of PYY(1-36) in the different provocation tests oscillated between 406 and 460 pg/mL in patients, as compared with 73 and 100 pg/mL in controls (P < 0.001). Corresponding values for PYY(3-36) oscillated between 235 and 267 pg/mL in patients, versus 56 and 70 pg/mL in controls (P < 0.001). The association of high levels of PYY(3-36) and normal levels of acylated ghrelin (when compared with healthy controls) configurated a markedly pro-anorexigenic pattern in patients. Neither oral intake nor intraperitoneal glucose resulted in significant changes in plasma levels of PYY(1-36) or PYY(3-36) in subjects with renal failure, in contrast with the expected postprandial rise observed in healthy controls (41% for PYY(1-36), P = 0.04 and 32% for PYY(3-36), P = 0.02, median values). CONCLUSIONS: Baseline plasma levels of PYY(1-36) or PYY(3-36) are markedly elevated in patients with renal failure undergoing peritoneal dialysis. Provocation studies disclose a marked disregulation in the postprandial secretion of these anorexigenic peptides, when compared with healthy controls. These findings may contribute to clarify the complex pathogenesis of anorexia of chronic renal failure.

PYY(1-36) and PYY(3-36) secretory response after a mixed meal in healthy individuals.

BACKGROUND: Peptide YY (PYY) is a 36 amino acid peptide synthesized mostly by intestinal L cells. This peptide reaches its nadir during fasting and increases immediately after meals. After food intake, two molecular forms are released, PYY(1-36) and PYY(3-36). PYY(3-36) reduces food intake in both humans and rodents. There is scarce information about plasmatic concentrations of PYY, especially of PYY(3-36), after food ingestion, and their relationship to ghrelin. OBJECTIVES: To study PYY(1-36) and PYY(3-36) secretory response after a mixed meal, and its relationship to total and acylated ghrelin secretion in healthy subjects. SUBJECTS AND METHOD: We studied eight healthy subjects, 4 women and 4 men, with a median age of 53 (range, 36-59) years. After an overnight fast, the subjects received either a mixed standard meal (400ml Isosource Energy® [159kcal/100ml]) or placebo (400ml of water) orally in random order on two different days. Blood samples were obtained at 0, 30, 45, 60 and 120 min for measurement of PYY(1-36), PYY(3-36), total ghrelin and acylated ghrelin. Comparisons were made by Wilcoxon's test. Numerical correlations were performed using Spearman's test. P-values ≤ 0.05 were considered significant. RESULTS: After a mixed meal, PYY(1-36) reached a peak of (median [range]) 141.5 (81-198) pg/ml. There was no response to placebo, with a peak of 92.5 (46-219) pg/ml (p=0.04). The area under the curve (AUC) of PYY(1-36) levels after a mixed meal were 14,865 (8,032-19,822) pg/ml/min and after placebo were 8,992 (4,455-21,382) pg/ml/min (p=0.06). After ingestion of a mixed meal, PYY(3-36) reached a peak of 92.5 (59-135) pg/ml, with no response to placebo (46.5 [30-66] pg/ml) (p = 0.02). The AUC of PYY(3-36) levels after a mixed meal were 9,086 (6,412-14,970) pg/ml/min, and after placebo were 4,984 (3,142-6,772) pg/ml/min (p=0.012). The quotient between nadir total ghrelin/peak PYY(1-36) was markedly diminished after food ingestion, with preprandial values of 7.44 (3.64-14.56) and postprandial values of 3.55 (1.64-7.16) (p=0.03). The former quotient was unmodified by placebo. The quotient between nadir acylated ghrelin/peak PYY(3-36) was markedly diminished after ingestion of a mixed meal, with preprandial values of 2.03 (0.92-3) and postprandial values of 0.73 (0.26-1.27) (p=0.02). This quotient was unmodified by placebo. CONCLUSIONS: In healthy subjects, blood levels of both PYY(1-36) and PYY(3-36) increase after ingestion of a mixed meal. Simultaneously, total and acylated ghrelin levels diminish. The quotient between nadir acylated ghrelin/peak PYY(3-36) diminishes after a mixed meal. All these data suggest the possible contribution of these peptides to appetite regulation after ingestion.

Effect of oral glucose on acylated and total ghrelin secretion in acromegalic patients.

OBJECTIVE: The pathophysiology of ghrelin secretion in acromegaly is unclear. Our aim was to study circulating fasting ghrelin levels and their response to oral glucose in acromegalic patients and normal control subjects. DESIGN AND PATIENTS: 9 acromegalic patients (4 male, 5 female; 59.4+/-3.6 years; 28.6+/-1.0 kg/m2) and 9 age and BMI matched healthy control subjects (4 male, 5 female; 59.1+/-1.4 years; 26.5+/-0.8 kg/m2) were included. We obtained blood samples for glucose, insulin, GH, total ghrelin and acylated ghrelin at times 0, 30, 60, 90 and 120 minutes after 75 g of oral glucose. RESULTS: Fasting GH and IGF-I were statistically different between patients and controls: GH (microg/l): 6.7+/-1.4 vs. 0.8+/-0.4, p<0.01; IGF-I (ng/ml): 414+/-75 vs. 86+/-6, p<0.01. Fasting total ghrelin (pg/ml) were similar in the patient and in the control group, 916+/-132 vs. 844+/-169, p=ns. In both groups total ghrelin levels decreased during oral glucose, and nadir total ghrelin was lower than fasting ghrelin: patients: 916+/-132 vs. 747+/-95, p<0.05; controls: 844+/-169 vs. 625+/-90, p<0.05). The AUCs of total ghrelin (pg/ml*min) were not different between the two groups: 98953+/-13052 vs. 83773+/-13096, p=ns). Fasting acylated ghrelin (pg/ml) were similar in the patient and the control group 65+/-13 pg/ml vs.74+/-14 pg/ml, p=ns. In both groups acylated ghrelin levels decreased during oral glucose, and nadir acylated ghrelin levels were lower than basal acylated ghrelin levels: patients: 65+/-13 vs. 42+/-6, p<0.05; controls: 74+/-14 pg/ml vs. 37+/-4 pg/ml, p<0.05). The AUCs of acylated ghrelin (pg/ml*min) were not different between the two groups: patients: 6173+/-992 vs. controls 8648+/-2742, p=ns). In acromegalic patients there was a negative correlation between fasting, both total and acylated, ghrelin and both fasting and post oral glucose insulin levels. CONCLUSIONS: These data suggest that circulating total and acylated ghrelin in acromegaly is regulated by insulin and not by GH hypersecretion.

Effect of oral glucose administration on rebound growth hormone release in normal and obese women: the role of adiposity, insulin sensitivity and ghrelin.

CONTEXT: Metabolic substrates and nutritional status play a major role in growth hormone (GH) secretion. Uncovering the mechanisms involved in GH secretion following oral glucose (OG) administration in normal and obese patients is a pending issue. OBJECTIVE: The aim of this study was to investigate GH after OG in relation with adiposity, insulin secretion and action, and ghrelin secretion in obese and healthy women, to further elucidate the mechanism of GH secretion after OG and the altered GH secretion in obesity. PARTICIPANTS AND METHODS: We included 64 healthy and obese women. After an overnight fast, 75 g of OG were administered; GH, glucose, insulin and ghrelin were obtained during 300 minutes. Insulin secretion and action indices and the area under the curve (AUC) were calculated for GH, glucose, insulin and ghrelin. Univariate and multivariate linear regression analyses were employed. RESULTS: The AUC of GH (µg/L•min) was lower in obese (249.8±41.8) than in healthy women (490.4±74.6), P=0.001. The AUC of total ghrelin (pg/mL•min) was lower in obese (240995.5±11094.2) than in healthy women (340797.5±37757.5), P=0.042. There were significant correlations between GH secretion and the different adiposity, insulin secretion and action, and ghrelin secretion indices. After multivariate analysis only ghrelin AUC remained a significant predictor for fasting and peak GH.

Altered fasting and postprandial plasma ghrelin levels in patients with liver failure are normalized after liver transplantation.

CONTEXT: Anorexia is a problem of paramount importance in patients with advanced liver failure. Ghrelin has important actions on feeding and weight homeostasis. Experimental data exist, which suggest that ghrelin could protect hepatic tissue. Both fasting and post-oral glucose tolerance test (OGTT) ghrelin concentrations are controversial in liver cirrhosis and are unknown after liver transplantation. OBJECTIVE: Our aim was to study fasting ghrelin concentrations and their response to an OGTT in liver failure patients before and after liver transplantation. DESIGN AND METHODS: We included 21 patients with severe liver failure studied before (pretransplantation, PreT) and 6 months after liver transplantation (posttransplantation, PostT), and 10 age- and body mass index-matched healthy or overweight subjects as the control group (Cont). After an overnight fast, 75 g of oral glucose were administered; glucose, insulin, and ghrelin were obtained at baseline and at times 30, 60, 90, and 120 min. RESULTS: Fasting ghrelin (median and range, pg/ml) levels were lower in PreT: 539 (309-1262) than in Cont: 643 (523-2163), P=0.045. Fasting ghrelin levels increased after liver transplantation, 539 (309-1262) vs 910 (426-3305), for PreT and PostT respectively, P=0.001. The area under the curve (AUC) of ghrelin (pg/ml min) was lower in PreT: 63,900 (37,260-148,410) than in Cont: 76,560 (56,160-206,385), P=0.027. The AUC of ghrelin increased in PostT, 63,900 (37,260-148,410) vs 107,595 (59,535-357,465), for PreT and PostT respectively, P=0.001. Fasting levels and the AUC of ghrelin were similar in PosT and Cont. CONCLUSIONS: Decreased fasting and post-OGTT ghrelin levels in liver failure patients were normalized after liver transplantation.

Fasting and postprandial plasma ghrelin levels are decreased in patients with liver failure previous to liver transplantation.

UNLABELLED: Anorexia is a problem of paramount importance in patients with advanced liver failure. Ghrelin has important actions on feeding and weight homeostasis. Concentrations of ghrelin are controversial in liver cirrhosis. Our aim was to study fasting ghrelin and their response to an oral glucose tolerance test (OGTT) in liver failure patients and normal subjects. METHODS: We included 16 patients with severe liver failure prior to liver transplantation. As a control group we included 10 age- and BMI-matched healthy subjects. After an overnight fast, 75 g of oral glucose were administered; glucose, insulin, and ghrelin were obtained at baseline and at times 30, 60, 90, and 120 min, respectively. RESULTS: Fasting ghrelin (median and range) were statistically significantly lower for patients compared to the controls, 527 (377-971) pg/ml vs. 643 (523-2163) pg/ml, P = 0.045, for patients and controls, respectively. The area under the curve for total ghrelin post-OGTT were lower in end-stage liver failure patients than in the control group, 58815 (44730-87420) pg/ml min vs. 76560 (56160-206385) pg/ml min, for patients and controls, respectively, P = 0.027. CONCLUSIONS: Ghrelin levels are significantly decreased both fasting and post-OGTT in patients with liver failure candidates for transplantation. Decreased ghrelin levels could contribute to anorexia in patients with cirrhosis.

Acute plasma ghrelin and leptin responses to oral feeding or intraperitoneal hypertonic glucose-based dialysate in patients with chronic renal failure.

BACKGROUND: Chronic renal failure (CRF) is associated with increased plasma levels of ghrelin and leptin, but the regulation of the secretion of these hormones has been insufficiently studied, in this setting. The aim of this study was to analyze the acute effects of oral feeding or intraperitoneal 3.86% glucose-based dialysate infusion on plasma ghrelin and leptin levels in patients with CRF undergoing peritoneal dialysis (PD). METHODS: Following a crossover design, 10 patients and eight healthy controls underwent a standardized oral intake, a 3.86% glucose-based dialysate PD exchange (patients) and placebo oral intake. We scrutinized acute changes in plasma ghrelin, leptin, glucose, insulin, and growth hormone (GH) levels. RESULTS: In patients, total ghrelin decreased modestly immediately after oral feeding (nadir 90.6% of baseline, range 85.1, 94.5, P= 0.03) or the PD exchange test (92.2%, range 58.7, 101.9, P= 0.05) (median). Response to oral feeding was markedly blunted when compared with healthy individuals (73.8%, range 56.1, 89.1, P= 0.007) (P < 0.005 vs. patients). Plasma acyl-ghrelin had a less marked but more persistent decay after the PD exchange test (nadir 80.4%, range 55.1, 96.3, P= 0.02) than after oral intake (64.4%, range 45.6, 82.3, P= 0.005); again, changes were more intense in normal controls (47.4%, range 32.1, 67.3, P= 0.01) (P < 0.05 vs. patients). Leptin levels decreased slightly (P < 0.05) after the PD exchange in patients, but did not respond acutely to oral feeding in patients or controls. CONCLUSION: Ghrelin secretion is partially refractory to the acute inhibitory effect of oral feeding in patients with CRF undergoing PD therapy. A 3.86% glucose-based PD exchange results in a significant decrease of plasma ghrelin levels. Plasma leptin levels are not acutely affected by oral feeding in patients with CRF or healthy individuals.

Plasma ghrelin levels in patients undergoing haemodialysis and peritoneal dialysis.

BACKGROUND: Ghrelin has been characterized as a relevant physiologic regulator of appetite and body weight in humans. However, the potential relationships between ghrelin levels, inflammation and malnutrition in dialysis patients have not been adequately studied. METHODS: We used a cross-sectional design to study 20 haemodialysis (HD) and 21 peritoneal dialysis (PD) patients, and compared their plasma ghrelin (PGhr) levels with that of an age-matched control group. We also explored correlations between ghrelin and selected hormonal, renal adequacy, nutritional and inflammation markers in both groups. RESULTS: PGhr levels were higher in HD (median 119.8 pg/ml, range 71.1-333.7, P = 0.001) and PD (99.3, range 45.8-578.5, P = 0.045) patients than in healthy controls (78, range 29-158) (HD vs PD, not significant). Ghrelin levels were strongly and inversely correlated with age (r = -0.46, P = 0.02 for patients; r = -0.61, P = 0.001 for controls). Except for a positive correlation between ghrelin and growth hormone (r = 0.48, P = 0.002), univariate analysis failed to detect associations between PGhr and the measured hormonal values, renal adequacy, nutritional indicators and markers of inflammation. However, multivariate analysis revealed significant inverse correlations between PGhr levels and nutritional markers, including subjective global assessment (P = 0.013), albumin (P = 0.001), transferrin (P = 0.01) and protein nitrogen appearance (as an estimate of protein intake) (P = 0.035), after controlling for the confounding effect of age. CONCLUSIONS: PGhr levels were moderately and similarly increased in patients undergoing HD and PD. Age was a strong determinant of PGhr levels, both in uraemic patients and in healthy controls. Dialysis adequacy, residual renal function and inflammation did not appear to influence ghrelin levels in these patients. The negative correlation between PGhr and nutritional markers suggests that low dietary intake causes increases in ghrelin secretion in dialysis patients.

Marked GH secretion after ghrelin alone or combined with GH-releasing hormone (GHRH) in obese patients.

OBJECTIVES: Ghrelin is a 28-amino-acid peptide, predominantly produced by the stomach. It displays a strong GH-releasing activity mediated by the hypothalamus-pituitary GH secretagogue (GHS)-receptor (GHS-R). There are different studies that suggest the importance of ghrelin in feeding and weight homeostasis. In obesity there is a markedly decreased GH secretion. For both children and adults, the greater the body mass index (BMI), the lower the GH response to provocative stimuli, including the response to GHRH. However, the response to the natural GH secretaogogue ghrelin is unclear at the present time. The aim of the present study was to evaluate the GH response to ghrelin alone or combined with GHRH in a group of obese patients, in order to further understand the deranged GH secretory mechanisms in obesity and to clarify the mechanism of action of ghrelin. PATIENTS AND MEASUREMENTS: Six obese female patients (31 +/- 3.4 years) with a BMI of 36.1 +/- 7.7 kg/m(2) were studied. As a control group, six normal nonobese female subjects of similar age and sex were studied. Four tests were performed: placebo, GHRH [1 micro g/kg, no more than 100 micro g, intravenous (i.v.)], ghrelin (1 micro g/kg, no more than 100 micro g, i.v.) and GHRH (1 micro g/kg, no more than 100 micro g, i.v.) plus ghrelin (1 micro g/kg, no more than 100 micro g, i.v.). Blood samples were taken at appropriate intervals for determination of GH. Statistical analyses were performed by Wilcoxon and by Mann-Whitney tests. RESULTS: After GHRH, the median peak GH secretion in obese patients was 2.4 micro g/l (range 0.9-8.9 micro g/l). Ghrelin-induced GH secretion showed in obese patients a median peak of 24.4 micro g/l (range 7.4-85.0 micro g/l), significantly greater than the response after GHRH (P < 0.05). After the combined administration of GHRH plus ghrelin in obese patients the median peak GH secretion was 39.9 micro g/l (range 19.2-120.0 micro g/l), significantly greater than the response after GHRH (P < 0.05) or ghrelin (P < 0.05). GHRH-induced GH secretion in normal control subjects showed a median peak of 25.0 micro g/l (range 16.5-33.4 micro g/l). Ghrelin-induced GH secretion in normal showed a median peak of 68.5 micro g/l (range 22.5-119.5 micro g/l), significantly greater than the response after GHRH (P < 0.05). After the combined administration of GHRH plus ghrelin, in normal subjects the median peak GH secretion was 117.8 micro g/l (range 77.5-280.1 micro g/l), significantly greater than the response after GHRH or ghrelin alone (P < 0.05). When we compare the response of normal and obese patients, after GHRH alone, it was markedly decreased in obese people when compared with normal patients (P < 0.05) with a median GH peak of 25.0 micro g/l (range 16.5-33.4 micro g/l) and 2.4 micro g/l (range 0.9-8.9 micro g/l) for normal and obese patients, respectively. When we compare the response of normal and obese patients, after ghrelin alone or GHRH plus ghrelin, it was only blunted in obese subjects when compared with normal subjects with a median GH peak of 68.5 micro g/l (range 22.5-119.5 micro g/l) and 24.4 micro g/l (range 7.4-85 micro g/l) for normal and obese subjects, respectively, after ghrelin alone (P < 0.05) and a median GH peak of 117.8 micro g/l (range 77.5-280.1 micro g/l) and 39.9 micro g/l (range 19.2-120.0 micro g/l) for normal and obese patients, respectively, after GHRH plus ghrelin (P < 0.05). CONCLUSIONS: This study has demonstrated a massive GH response to ghrelin alone or combined with GHRH in obese patients, suggesting that altered ghrelin secretion could play a major role in the blunted GH secretion present in obese patients.