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Interaction of GLP-1 and Ghrelin on Glucose Tolerance in Healthy Humans.
Page, LC, Gastaldelli, A, Gray, SM, D'Alessio, DA, Tong, J
Diabetes. 2018;(10):1976-1985
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Abstract
Emerging evidence supports the importance of ghrelin to defend against starvation-induced hypoglycemia. This effect may be mediated by inhibition of glucose-stimulated insulin secretion as well as reduced insulin sensitivity. However, administration of ghrelin during meal consumption also stimulates the release of glucagon-like peptide 1 (GLP-1), an incretin important in nutrient disposition. The objective of this study was to evaluate the interaction between ghrelin and GLP-1 on parameters of glucose tolerance following a mixed-nutrient meal. Fifteen healthy men and women completed the study. Each consumed a standard meal on four separate occasions with a superimposed infusion of 1) saline, 2) ghrelin, 3) the GLP-1 receptor antagonist exendin(9-39) (Ex9), or 4) combined ghrelin and Ex9. Similar to previous studies, infusion of ghrelin caused glucose intolerance, whereas Ex9 had a minimal effect. However, combined ghrelin and Ex9 resulted in greater postprandial glycemia than either alone, and this effect was associated with impaired β-cell function and decreased glucose clearance. These findings suggest that in the fed state, stimulation of GLP-1 mitigates some of the effect of ghrelin on glucose tolerance. This novel interaction between gastrointestinal hormones suggests a system that balances insulin secretion and glucose disposal in the fed and fasting states.
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Acute administration of acyl, but not desacyl ghrelin, decreases blood pressure in healthy humans.
Zhang, CJ, Bidlingmaier, M, Altaye, M, Page, LC, D'Alessio, D, Tschöp, MH, Tong, J
European journal of endocrinology. 2017;(2):123-132
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Abstract
OBJECTIVE To compare the effects of acyl ghrelin (AG) and desacyl ghrelin (DAG) on blood pressure (BP), heart rate (HR) and other autonomic parameters in healthy humans and to elucidate the hormonal mechanisms through which AG could exert its cardiovascular effects. DESIGN Seventeen healthy participants underwent frequent monitoring of systolic (sBP) and diastolic blood pressure (dBP), HR, respiratory rate (RR) and body surface temperature (Temp) during continuous infusion of AG, DAG, combined AG + DAG or saline control before and during an IV glucose tolerance test on 4 separate days. Plasma catecholamines, renin and aldosterone levels were also measured. Differences in outcome measures between treatment groups were assessed using mixed-model analysis. RESULTS Compared to the saline control, AG and combined AG + DAG infusions decreased sBP, dBP, mean arterial blood pressure (MAP), HR and Temp. In contrast, DAG infusion did not alter BP, RR or Temp, but did decrease HR. The AG and AG + DAG infusions also raised plasma aldosterone levels compared to saline (P < 0.001) without affecting renin or catecholamine levels. CONCLUSIONS The decrease in BP, HR, RR and Temp with AG infusion suggests mediation through the autonomic nervous system. The lack of response to DAG suggests that these autonomic effects require activation of the ghrelin receptor.
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Elevation of Fasting Ghrelin in Healthy Human Subjects Consuming a High-Salt Diet: A Novel Mechanism of Obesity?
Zhang, Y, Li, F, Liu, FQ, Chu, C, Wang, Y, Wang, D, Guo, TS, Wang, JK, Guan, GC, Ren, KY, et al
Nutrients. 2016;(6)
Abstract
Overweight/obesity is a chronic disease that carries an increased risk of hypertension, diabetes mellitus, and premature death. Several epidemiological studies have demonstrated a clear relationship between salt intake and obesity, but the pathophysiologic mechanisms remain unknown. We hypothesized that ghrelin, which regulates appetite, food intake, and fat deposition, becomes elevated when one consumes a high-salt diet, contributing to the progression of obesity. We, therefore, investigated fasting ghrelin concentrations during a high-salt diet. Thirty-eight non-obese and normotensive subjects (aged 25 to 50 years) were selected from a rural community in Northern China. They were sequentially maintained on a normal diet for three days at baseline, a low-salt diet for seven days (3 g/day, NaCl), then a high-salt diet for seven days (18 g/day). The concentration of plasma ghrelin was measured using an immunoenzyme method (ELISA). High-salt intake significantly increased fasting ghrelin levels, which were higher during the high-salt diet (320.7 ± 30.6 pg/mL) than during the low-salt diet (172.9 ± 8.9 pg/mL). The comparison of ghrelin levels between the different salt diets was statistically-significantly different (p < 0.01). A positive correlation between 24-h urinary sodium excretion and fasting ghrelin levels was demonstrated. Our data indicate that a high-salt diet elevates fasting ghrelin in healthy human subjects, which may be a novel underlying mechanism of obesity.
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Exenatide Treatment Causes Suppression of Serum Ghrelin Levels following Mixed Meal Test in Obese Diabetic Women.
Topyildiz, F, Kiyici, S, Gul, Z, Sigirli, D, Guclu, M, Kisakol, G, Cavun, S
Journal of diabetes research. 2016;:1309502
Abstract
AIM: To investigate the effect of exenatide treatment on serum ghrelin levels in obese female patients with type 2 diabetes mellitus. METHODS Fourteen female patients with type 2 diabetes mellitus being treated with metformin and exenatide were enrolled. A mixed meal test was applied to the patients while continuing with their daily medications. Blood samples were taken before and at 60, 120, and 180 minutes following mixed meal test to measure serum total ghrelin, glucose, and insulin levels. The following week, exenatide treatment of the patients was paused for 24 hours and the same experimental procedures were repeated. RESULTS Serum ghrelin levels were suppressed significantly at 180 minutes with exenatide treatment compared with baseline (294.4 ± 57.5 versus 234.5 ± 59.4 pg/mL) (p < 0.001). Serum ghrelin levels at 180 minutes were statistically different when percentage change in serum ghrelin levels after mixed meal tests with and without exenatide usage were compared (p = 0.001). Estimated total area under the curve values for serum ghrelin concentrations was also significantly lower with exenatide compared with omitted treatment (p = 0.035). CONCLUSION These results suggest that the effect of exenatide on weight loss may be related with the suppression of serum ghrelin levels, which is an orexigenic peptide.
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Improvement of cisplatin-related renal dysfunction by synthetic ghrelin: a prospective randomised phase II trial.
Yanagimoto, Y, Takiguchi, S, Miyazaki, Y, Makino, T, Takahashi, T, Kurokawa, Y, Yamasaki, M, Miyata, H, Nakajima, K, Hosoda, H, et al
British journal of cancer. 2016;(12):1318-25
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BACKGROUND Ghrelin, a 28-amino acid peptide predominantly produced by the stomach, exerts powerful renal protective effects by increasing levels of insulin-like growth factor-1 (IGF-1). The aim of this study was to evaluate the effects of ghrelin on the incidence of renal dysfunction in patients receiving cisplatin-based chemotherapy. METHODS Forty patients with oesophageal cancer receiving cisplatin-based chemotherapy were assigned to either the ghrelin group (n=20), which received ghrelin (0.5 μg kg(-1) h(-1)) for 5 days, or a placebo group (n=20). The primary endpoint was serum creatinine. Secondary endpoints were serum cystatin C, chemotherapy-related adverse events, changes in serum ghrelin-related hormone levels, correlation between markers of renal injury and hormone concentrations, and effects on the second cycle of chemotherapy. RESULTS Blood acyl ghrelin, total ghrelin, and IGF-1 concentrations on day 4 were significantly higher in the ghrelin group. The renal dysfunction, serum creatinine and cystatin C levels, dose reduction, and delay in the initiation of the second cycle of chemotherapy were lower in the ghrelin group than in the control group. Serum creatinine levels were significantly correlated with serum IGF-1 levels. CONCLUSION Continuous synthetic ghrelin administration during cisplatin-based chemotherapy attenuated renal dysfunction and harmful effects on subsequent chemotherapy, possibly by increasing IGF-1 levels.
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Effect of oral glucose administration on rebound growth hormone release in normal and obese women: the role of adiposity, insulin sensitivity and ghrelin.
Pena-Bello, L, Pertega-Diaz, S, Outeiriño-Blanco, E, Garcia-Buela, J, Tovar, S, Sangiao-Alvarellos, S, Dieguez, C, Cordido, F
PloS one. 2015;(3):e0121087
Abstract
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.
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Appetite and gut hormone responses to moderate-intensity continuous exercise versus high-intensity interval exercise, in normoxic and hypoxic conditions.
Bailey, DP, Smith, LR, Chrismas, BC, Taylor, L, Stensel, DJ, Deighton, K, Douglas, JA, Kerr, CJ
Appetite. 2015;:237-45
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Abstract
This study investigated the effects of continuous moderate-intensity exercise (MIE) and high-intensity interval exercise (HIIE) in combination with short exposure to hypoxia on appetite and plasma concentrations of acylated ghrelin, peptide YY (PYY), and glucagon-like peptide-1 (GLP-1). Twelve healthy males completed four, 2.6 h trials in a random order: (1) MIE-normoxia, (2) MIE-hypoxia, (3) HIIE-normoxia, and (4) HIIE-hypoxia. Exercise took place in an environmental chamber. During MIE, participants ran for 50 min at 70% of altitude-specific maximal oxygen uptake (V˙O2max) and during HIIE performed 6 × 3 min running at 90% V˙O2max interspersed with 6 × 3 min active recovery at 50% V˙O2max with a 7 min warm-up and cool-down at 70% V˙O2max (50 min total). In hypoxic trials, exercise was performed at a simulated altitude of 2980 m (14.5% O2). Exercise was completed after a standardised breakfast. A second meal standardised to 30% of participants' daily energy requirements was provided 45 min after exercise. Appetite was suppressed more in hypoxia than normoxia during exercise, post-exercise, and for the full 2.6 h trial period (linear mixed modelling, p <0.05). Plasma acylated ghrelin concentrations were lower in hypoxia than normoxia post-exercise and for the full 2.6 h trial period (p <0.05). PYY concentrations were higher in HIIE than MIE under hypoxic conditions during exercise (p = 0.042). No differences in GLP-1 were observed between conditions (p > 0.05). These findings demonstrate that short exposure to hypoxia causes suppressions in appetite and plasma acylated ghrelin concentrations. Furthermore, appetite responses to exercise do not appear to be influenced by exercise modality.
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Four-hour infusion of hydrocortisone does not suppress the nocturnal increase of circulating acyl- or desacyl-ghrelin concentrations in healthy young adults.
Nass, R, Liu, J, Patrie, J, Pezzoli, SS, Farhy, LS, Gaylinn, BD, Thorner, MO
The Journal of clinical endocrinology and metabolism. 2014;(9):E1696-700
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BACKGROUND Ghrelin is a 28-amino acid peptide released from the stomach. Ghrelin is found in the circulation in two forms: acyl- and desacyl-ghrelin. Acyl- and desacyl-ghrelin concentrations increase at night, when cortisol concentrations are low. Acute ghrelin administration increases ACTH and cortisol concentrations and a feedback loop between the ghrelin and ACTH-cortisol axis has been postulated. A previous study showed that exogenously induced hypercortisolism for 5 days decreased plasma ghrelin concentrations. OBJECTIVE The objective of the study was to determine whether a 4-hour infusion of hydrocortisone given at a time of low endogenous cortisol concentrations (11:00 pm to 3:00 am) acutely suppresses acyl- and desacyl-ghrelin. METHODS Eight healthy young men aged (mean ± SD) 21.5 ± 2.7 years with a body mass index of 22.4 ± 2.5 kg/m(2) were studied in a single-blind, placebo-controlled study during two separate overnight admissions on the Clinical Research Unit. The volunteers received either a 4-hour (11:00 pm to 3:00 am) infusion of hydrocortisone or a saline infusion. The hydrocortisone infusion rate was 0.3 mg/kg·h for the initial 3 minutes, 0.24 mg/kg·h for 9 minutes, and then 0.135 mg/kg·h until the end of the infusion. Plasma acyl- and desacyl-ghrelin concentrations (in-house two site sandwich assay) and ACTH, cortisol, insulin, GH, and glucose levels were measured every 10 minutes for 16 hours (5:00 pm to 9:00 am). RESULTS The mean differences (lower 95% limit; upper 95% limit) between the saline infusion and hydrocortisone infusion for acyl- and desacyl-ghrelin concentrations were not significantly different from zero. The infusion period (11:00 pm to 3:00 am) was as follows: acyl-ghrelin, 0.22 (-7.39; 7.83) (P = 1.00); desacyl-ghrelin, -3.36 (-17.66; 10.95) (P = 1.00). The postinfusion period (3:00-7:00 am) was as follows: acyl-ghrelin, 8.68 (1.07; 16.28); (P = .056); desacyl-ghrelin, 8.75 (-5.56; 23.05) (P = .403). CONCLUSIONS A short-term increase in circulating cortisol concentrations by exogenous hydrocortisone infusion does not suppress circulating nocturnal acyl- or desacyl-ghrelin concentrations. Thus, it is likely that the diurnal pattern of ghrelin secretion is under circadian control and not directly regulated by cortisol.
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Circulating ghrelin and GLP-1 are not affected by habitual diet.
Ellis, AC, Chandler-Laney, P, Casazza, K, Goree, LL, McGwin, G, Gower, BA
Regulatory peptides. 2012;(1-3):1-5
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BACKGROUND Ghrelin and glucagon-like peptide-1 (GLP-1) are gut hormones known to induce hunger and satiety, respectively. Current knowledge about the effects of different macronutrients on circulating ghrelin and GLP-1 comes mainly from acute test meals, whereas little is known about the effects of chronic dietary intake on gut hormone secretion. This study was designed to examine whether 8-week habituation to diets with different percentages of carbohydrate and fat would affect serum ghrelin, GLP-1, and subjective hunger in a postabsorptive state and in response to a standard liquid mixed meal. METHODS Sixty-one overweight men and women were provided all food for 8 weeks of either a higher-carbohydrate/lower-fat diet (High-CHO/Low-FAT; 55% CHO, 18% PRO, 27% FAT) or a lower-carbohydrate/higher-fat diet (Low-CHO/High-FAT; 43% CHO, 18% PRO, 39% FAT). After overnight fasts at baseline and week 8, participants consumed a standard liquid meal (7 kcals/kg, 58.6% CHO, 17.4% PRO, 24% FAT). Blood was sampled before the meal and at 15, 60, 90, 120, 180, and 240 min to determine total serum ghrelin and active GLP-1. Hunger was assessed by a visual analog scale. Mixed models were used to evaluate whether the temporal patterns of total serum ghrelin and active GLP-1 differed with diet. RESULTS Although both diet groups reported greater hunger after 8 weeks (p=0.03), circulating ghrelin and GLP-1 were not affected by acclimation to different macronutrients. CONCLUSION Habituation to different diets does not appear to influence fasting ghrelin, fasting GLP-1, or responses of these gut hormones to a standard meal.
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Higher postprandial serum ghrelin among African-American girls before puberty.
Ellis, AC, Casazza, K, Chandler-Laney, P, Gower, BA
Journal of pediatric endocrinology & metabolism : JPEM. 2012;(7-8):691-6
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OBJECTIVE Recent reports suggest that ghrelin regulation may differ by ethnicity and age. This study was designed to examine circulating ghrelin among overweight female African Americans across different age groups. METHODS Eleven overweight peripubertal girls, 17 overweight pubertal girls, and a control group of 18 overweight African-American premenopausal women ingested a standard liquid meal after an overnight fast. Blood samples were obtained before the meal and for 4 h postchallenge. Participants rated appetite by a visual analog scale. RESULTS Peripubertal girls demonstrated higher postprandial ghrelin and lesser ghrelin suppression compared with adults (p < 0.05), corresponding with greater desire to eat across the test period (p = 0.017). Fasting ghrelin tended to be inversely related to fasting estradiol (r = -0.264, p = 0.076). CONCLUSION Compared with overweight African-American women, peripubertal girls had higher ghrelin as well as greater appetite after a standard meal. These results may suggest a dysregulation in ghrelin reflective of demands of growth.