Des-acyl Ghrelin Research Articles

サケ・マグロ胃抽出グレリンおよびデスアシルグレリンを利用した抗がん剤による心毒性緩和薬の開発を目指して

サケ・マグロ胃抽出グレリンおよびデスアシルグレリンを利用した抗がん剤による心毒性緩和薬の開発を目指して

Effectiveness of Tongue cleaning as a component of Oral care on the fasting Plasma Desacyl Ghrelin concentration in very elderly individuals: Six-Week Randomized controlled trial

To investigate whether tongue cleaning as a component of oral care affects the fasting plasma desacyl ghrelin concentrations in elderly people with the peak expiratory flow (PEF) as the measure of coughing ability. This randomized controlled trial was conducted in Kitakyushu, Japan from July 2017 to November 2018. We randomly assigned 52 enrolled Japanese subjects from three nursing care facilities to a routine oral care group (control group) and an oral care with twice-daily tongue cleaning group (intervention group). Before and after 6 weeks of each version of oral care, the PEF of each subject was measured and blood was collected. A final total of 48 subjects (39 females, 9 males, mean ± SD age 88.4 ± 7.5 years) was analyzed. The PEF increased significantly in the intervention group (1.62 ± 0.89 L/s to 2.07 ± 1.09 L/s) but not in the control group (1.76 ± 1.05 L/s to 1.53 ± 0.67 L/s). The fasting plasma desacyl ghrelin concentrations in the intervention group did not change significantly (181 ± 102 fmol/mL to 175 ± 98 fmol/mL) whereas those in the control group decreased significantly (168 ± 114 fmol/mL to 142 ± 72 fmol/mL). The change of the plasma desacyl ghrelin concentration was significantly correlated with the change in albumin (correlation coefficient = 0.292, p<0.05), but not with that in PEF. Tongue cleaning accompanied by improved coughing ability seemed to help prevent the decrease in the fasting plasma desacyl ghrelin concentration in very elderly individuals.

Systemic acyl-ghrelin increases tail skin temperature in rats without affecting their thermoregulatory behavior in a cold environment

Fasting increases ghrelin that is a peptide hormone with two circulating isoforms, acyl and des-acyl ghrelin. We reported that fasting or des-acyl ghrelin facilitates behavioral thermoregulation in the cold in rats assessed by tail-hiding behavior that was the indicator of rats’ thermoregulatory behavior in the cold; however, the effect of acyl-ghrelin on the same process remains to be elucidated. We investigated the effect of acyl-ghrelin on thermoregulatory behavior in the cold in rats. The animals received an intraperitoneal saline or 24 μg acyl-ghrelin injection and were exposed to 27 °C or 15 °C for 2 h, while their body temperature, tail skin temperature, and tail-hiding behavior were constantly monitored. cFos immunoreactive (cFos-IR) cells in the median preoptic area, medial preoptic area, paraventricular nucleus (PVN), and arcuate nucleus were counted. Body temperature and the duration of thermoregulatory behavior did not show a significant difference between the acyl-ghrelin-treated and control groups at 15 °C; however, tail skin temperature in the acyl-ghrelin-treated group was higher than that in the control group. The number of cFos-IR cells in the PVN was greater in the control group than that in the acyl-ghrelin-treated group at 27 °C. These results indicate that acyl-ghrelin did not affect behavioral thermoregulation but might affect tail skin temperature in rats in the cold.

Dietary macronutrient regulation of acyl and desacyl ghrelin concentrations in children with Prader-Willi syndrome (PWS).

The effects of dietary macronutrients on orexigenic and anorexigenic hormones in children are poorly understood. To explore effects of varying dietary macronutrients on appetite-regulating hormones [acyl ghrelin (AG) and desacyl ghrelin (DAG), glucagon-like peptide 1 (GLP-1), peptide tyrosine tyrosine (PYY) and insulin] in children with PWS and healthy children (HC). Randomized, cross-over experiments compared two test diets [high protein-low carbohydrate (HP-LC) and high protein-low fat (HP-LF)] to a STANDARD meal (55% carbohydrate, 30% fat, 15% protein). Experiment 1 included ten children with PWS (median age 6.63years; BMI z 1.05); experiment 2 had seven HC (median age 12.54years; BMI z 0.95). Blood samples were collected at baseline and at 60-minute intervals for 4hours. Independent linear mixed models were adjusted for age, sex and BMI z-score. Fasting and post-prandial AG and DAG concentrations are elevated in PWS children; the ratio of AG/DAG is normal. Food consumption reduced AG and DAG concentrations in both PWS and HC. GLP-1 levels were higher in PWS after the HP-LC and HP-LF meals than the STANDARD meal (P=.02-0.04). The fasting proinsulin to insulin ratio (0.08 vs 0.05) was higher in children with PWS (P=.05) than in HC. Average appetite scores in HC declined after all three meals (P=.02) but were lower after the HP-LC and HP-LF meals than the STANDARD meal. Altered processing of proinsulin and increased GLP-1 secretion in children with PWS after a high protein meal intake might enhance satiety and reduce energy intake.

Metabolic state and value-based decision-making in acute and recovered female patients with anorexia nervosa

Patients with anorexia nervosa forgo eating despite emaciation and severe health consequences. Such dysfunctional decision-making might be explained by an excessive level of self-control, alterations in homeostatic and hedonic regulation, or an interplay between these processes. We aimed to understand value-based decision-making in anorexia nervosa and its association with the gut hormone ghrelin. Besides its homeostatic function, ghrelin has been implicated in the hedonic regulation of appetite and reward via the modulation of phasic dopamine signalling. In a cross-sectional design, we studied acutely underweight (n = 94) and recovered (n = 37) patients with anorexia nervosa of the restrictive subtype, as well as healthy control participants (n = 119). We assessed plasma concentrations of desacyl ghrelin and parameters of delay discounting, probability discounting for gains and losses, and loss aversion. Recovered patients displayed higher risk aversion for gains, but we observed no group differences for the remaining decision-making parameters. Desacyl ghrelin was higher in acutely underweight and recovered participants with anorexia nervosa relative to healthy controls. Moreover, we found a significant group × desacyl ghrelin interaction in delay discounting, indicating that in contrast to healthy controls, acutely underweight patients with anorexia nervosa who had high desacyl ghrelin concentrations preferably chose the delayed reward option. We probed decision-making using monetary rewards, but patients with anorexia nervosa may react differently to disorder-relevant stimuli. Furthermore, in contrast to acyl ghrelin, the functions of desacyl ghrelin are unclear. Therefore, the interpretation of the results is preliminary. The propensity for risk aversion as found in recovered patients with anorexia nervosa could help them successfully complete therapy, or it could reflect sequelae of the disorder. Conversely, ghrelin findings might be related to a mechanism contributing to disease maintenance; that is, in acutely underweight anorexia nervosa, a hungry state may facilitate the ability to forgo an immediate reward to achieve a (dysfunctional) long-term goal.

Influence of endurance training-induced weight loss on the levels of ghrelin and obestatin of obese women with polycystic ovary syndrome

Polycystic ovary syndrome is an observed plurimetabolic syndrome associated with central obesity and insulin resistance. The purpose of the present study was to investigate the effects of 12-week training program on weight loss, serum ghrelin, acylated ghrelin, des-acylated ghrelin, and obestatin levels in obese sedentary women with polycystic ovary syndrome (PCOS). To this end, thirty sedentary obese women with PCOS (mean age 31.07 ± 2.49 years, height 162.23 ± 2.39 cm, weight: 87.23 ± 4.48 kg, BMI 33.12 ± 0.92) were recruited from a multidisciplinary PCOS specialty clinic in Tabriz city in 2017 and evaluated before and after a 12-week training program, including 45 min per session of aerobic training at an intensity of 60–75% of age-predicted maximum heart rate (300 kcal/day). After the exercise program, body weight, waist circumference, and percentage body fat mass were decreased. Also, fasting glucose, insulin, and serum acylated ghrelin levels were significantly decreased (P 0.05). The moderate aerobic exercise training is associated with improvements in obestatin and health profiles of obese women with PCOS without associated structured energy restriction.

MON-603 GPR142 Expression Levels Were Correlated with Plasma Ghrelin Levels and Heights in Morbidly Obese Patients

Recently, aromatic amino acids, especially tryptophan were discovered to be the strongest ligands for GPR142, which was previously known as an orphan GPCR. GPR142 is expressed in the digestive tract and pancreas in mice and human. Previously we found that GPR142 is highly expressed in the ghrelin-producing cell line, MGN3-1 cells, and that tryptophan strongly stimulated ghrelin secretion in vitro.In this study, we measured the mRNA expression levels of GPR142 in the gastric samples of 6 morbid obese patients undergone laparoscopic sleeve gastrectomy and compared its level with their clinical parameters. GPR142 expression levels were negatively correlated with plasma desacyl ghrelin levels (p=0.011) and positively correlated with heights (p=0.08).The current results that GPR142 expression levels were correlated with plasma desacyl ghrelin levels may confirm the link between GPR142 signal and regulation of ghrelin secretion demonstrated in our in vitro study. Regarding to the correlation with heights, there are some reports that plasma ghrelin levels were inversely correlated with heights in children[1-3], although, as far as we know, there are no reports demonstrating the relationship between plasma ghrelin levels and heights in adults. Considering that ghrelin strongly stimulates growth hormone secretion, GPR142 signaling may have influence on height through regulating ghrelin-growth hormone axis.ConclusionGPR142 mRNA expression levels were negatively and positively correlated with plasma desacyl ghrelin levels and heights in morbid obese adults undergone bariatric surgery. Current results may help understanding the pathophysiological role of GPR142 in the regulation of ghrelin secretion and heights.

Association between des-acyl ghrelin at fasting and predictive index of muscle derangement, metabolic markers and eating disorders: a cross-sectional study in overweight and obese adults

ABSTRACT Background: This study aimed to analyse the impact of des-acyl and acyl ghrelin (AG) on a wide range of muscular and metabolic markers and in order to discover the possible relationships and interactions of des-acylated ghrelin (DAG) on eating disorders. Materials & Methods: A total of 88 subjects (64 women and 24 men, with a mean age of 43 years and a mean body mass index (BMI) of 30.20 ± 3.27 kg/m2) were enrolled in the cross-sectional study. Results: The findings showed that for each unit of increase of free fat mass index (FFMI), levels of DAG decreased by −41.11 pg/mL (p < 0.05). Moreover, similar associations with DAG were found for insulin (β = −30.67; p < 0.001), leptin (β = −0.64; p < 0.05), body weight (β = −14.36; p < 0.001), and free fat mass (FFM) (β = −30.67; p < 0.001). In addition, associations were found between DAG and resting energy expenditure (REE) (β = −0.84; p = 0.05) and the binge eating scale (BES) in which a unit increase of the BES score Q3 (depression) correlated with a decrease of DAG levels (β = −9.98; p = 0.08). Further, a unit increase of AG/DAG ratio correspond with an increase in body weight (β = 12.20; p < 0.05), BMI (β = 4.70; p < 0.05) and fat mass (β = 7.30; p < 0.05). However, the AG/DAG ratio was not associated with FFMI (β = 2.61; p = 0.165) and FFML/BMI (β = −0,064; p = 0.625). Conclusion: This study suggests that higher levels of DAG at fasting are indices of poor muscle mass, insulin resistance and depression.

Effect of desacyl-ghrelin on food anticipatory activity in a mouse model of chronic food restriction

Background The physiological mechanisms involved in the adaptation to chronic food restriction are largely unknown. Anorexia nervosa (AN) is characterized by elevated plasma concentrations of ghrelin, a gut orexigenic hormone. AN patients maintain a restricted feeding behavior, usually associated with elevated physical activity in meal anticipation called food anticipatory activity (FAA). Ghrelin exists in two forms: acylghrelin (AG), carrying an octanoyl group, and des-acylghrelin (DAG) which predominates in plasma and having an opposite action on energy homeostasis. The respective role of AG and DAG in the initiation of FAA remains unknown. Objectives We used a mouse model, which combined chronic food restriction and voluntary activity mimicking most of the alterations of AN1. We evaluated: – the change in plasma AG and/or DAG concentrations in relation with FAA; – determine whether injections of AG and/or DAG elicit FAA and interact on hypothalamic (ARC: energy homeostasis) and mesolimbic (VTA: reward/motivation) neurons. Methods Eight-week old female mice were placed in a cage containing a running wheel in free access for 20 days. Mice were exposed to a progressive food restriction (FRW, n = 24) compared to ad libitum fed condition (ALW, n = 24). On D10, blood samples were collected before the onset of FAA (9 a.m.) and during FAA (5 p.m). AG and DAG were measured with selective immunoassays. On D20, AG (10 nmol/10 g BW), DAG (10 nmol/10 g BW), AG + DAG (respectively 10 and 20 nmol/10 g BW), or saline solution were injected subcutaneously both in ALW and FRW mice (n = 6/group); followed by 2 h of the evaluation of physical activity. Immunocytochemical detection of c-Fos protein, a marker of neuronal activation, was obtained in the ARC and VTA. Data were analyzed with a One-Way ANOVA test (Statview software, P Results FRW mice displayed a stable FAA from D6 of restriction. Plasma concentrations of AG and DAG significantly increased between 9 a.m and 5 p.m in FRW mice compared to ALW mice. AG and DAG concentrations were the highest in mice displaying the highest FAA. Interestingly, only the injection of DAG was able to elicit: – an increase in physical activity (P = 0.06) associated with significant neuronal activation in the VTA (P – to decrease glycemia (P = 0.06) and low neuronal activation in the ARC contrary to AG (P Conclusion These results suggest that DAG might have an unexpected function in the induction of physical activity in meal anticipation.

Effects of Testosterone Supplementation on Ghrelin and Appetite During and After Severe Energy Deficit in Healthy Men.

Severe energy deficits cause interrelated reductions in testosterone and fat free mass. Testosterone supplementation may mitigate those decrements, but could also reduce circulating concentrations of the orexigenic hormone ghrelin, thereby exacerbating energy deficit by suppressing appetite. To determine whether testosterone supplementation during severe energy deficit influences fasting and postprandial ghrelin concentrations and appetite. Secondary analysis of a randomized, double-blind trial that determined the effects of testosterone supplementation on body composition changes during and following severe energy deficit in nonobese, eugonadal men. Phase 1 (PRE-ED): 14-day run-in; phase 2: 28 days, 55% energy deficit with 200 mg testosterone enanthate weekly (TEST; n = 24) or placebo (PLA; n = 26); phase 3: free-living until body mass recovered (end-of-study; EOS). Fasting and postprandial acyl ghrelin and des-acyl ghrelin concentrations and appetite were secondary outcomes measured during the final week of each phase. Fasting acyl ghrelin concentrations, and postprandial acyl and des-acyl ghrelin concentrations increased in PLA during energy deficit then returned to PRE-ED values by EOS, but did not change in TEST (phase-by-group, P < 0.05). Correlations between changes in free testosterone and changes in fasting acyl ghrelin concentrations during energy deficit (ρ = -0.42, P = 0.003) and body mass recovery (ρ = -0.38; P = 0.01) were not mediated by changes in body mass or body composition. Transient increases in appetite during energy deficit were not affected by testosterone treatment. Testosterone supplementation during short-term, severe energy deficit in healthy men prevents deficit-induced increases in circulating ghrelin without blunting concomitant increases in appetite. www.clinicaltrials.gov NCT02734238 (registered 12 April 2016).

Plasma Peptide Concentrations and Peptide-Reactive Immunoglobulins in Patients with Eating Disorders at Inclusion in the French EDILS Cohort (Eating Disorders Inventory and Longitudinal Survey).

Eating disorders (EDs) are increasingly frequent. Their pathophysiology involves disturbance of peptide signaling and the microbiota–gut–brain axis. This study analyzed peptides and corresponding immunoglobulin (Ig) concentrations in groups of ED. In 120 patients with restrictive (R), bulimic (B), and compulsive (C) ED, the plasma concentrations of leptin, glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and insulin were analyzed by Milliplex and those of acyl ghrelin (AG), des-acyl ghrelin (DAG), and α-melanocyte-stimulating hormone (α-MSH) by ELISA kits. Immunoglobulin G (in response to an antigen) concentrations were analyzed by ELISA, and their affinity for the respective peptide was measured by surface plasmon resonance. The concentrations of leptin, insulin, GLP-1, and PYY were higher in C patients than in R patients. On the contrary, α-MSH, DAG, and AG concentrations were higher in R than in C patients. After adjustment for body mass index (BMI), differences among peptide concentrations were no longer different. No difference in the concentrations of the IgG was found, but the IgG concentrations were correlated with each other. Although differences of peptide concentrations exist among ED subtypes, they may be due to differences in BMI. Changes in the concentration and/or affinity of several anti-peptide IgG may contribute to the physiopathology of ED or may be related to fat mass.

Plasma levels of ghrelin, des-acyl ghrelin and LEAP2 in children with obesity: correlation with age and insulin resistance.

The octanoylated peptide hormone ghrelin regulates appetite and glycaemic control. Des-acyl ghrelin abolishes some effects of ghrelin, but does not bind to ghrelin receptor. LEAP2 is a novel ligand for ghrelin receptor that blocks the effects of ghrelin. Some evidences show that plasma levels of these peptides are altered in adults with obesity, but their levels in childhood obesity remain poorly studied. Therefore, the objective of this study was to assess fasting plasma levels of ghrelin, des-acyl ghrelin and LEAP2 in children with normoweight, overweight/obesity and their association with different anthropometric and metabolic variables. A total of 42 females and 40 males, ages 3-12 years old were enrolled as a cross-sectional cohort. Plasma levels of des-acyl ghrelin and LEAP2 (but not ghrelin) were lower and ghrelin/des-acyl ghrelin ratio was higher in children with overweight/obesity. Des-acyl ghrelin negatively correlated with age, BMI z-score, insulin and HOMA index, and the correlations were stronger in children with overweight/obesity. LEAP2 levels negatively correlated with BMI z-score. No gender differences were found. Our findings suggest that ghrelin tone is increased in childhood obesity, due to a decrease on plasma levels of des-acyl ghrelin and LEAP2, and that des-acyl ghrelin is associated to insulin resistance, particularly in children with overweight/obesity.

Alteration of saliva and blood ghrelin, obestatin, leptin and weight based on adjuvant chemotherapy treatment in early-stage operated breast cancer patients

Aim: To evaluate the weight change and ghrelin, obestatin and leptin levels in operated early stage breast cancer patients receiving adjuvant chemotherapy. Material and Methods: This study was conducted with 22 operated breast cancer patients (examined before and after adjuvant chemotherapy) and 33 BMI-matched two different healthy controls (of 33 healthy controls, 17 BMI-matched control was used to compare before adjuvant chemotherapy, 16 BMI-matched control was used to compare after adjuvant chemotherapy). Age, anthropometric measurements (weight, BMI, waist circumference), and blood biochemistry were recorded. Blood and salivary total ghrelin, obestatin and leptin levels are measured by using ELISA.Results: The mean ± SD weight (67.2 ± 12.3 and 72.9 ± 11.8 kg., p0.001), BMI (27.3 ± 4.7 and 29.61 ± 4.4 kg/m2, p0.001) and waist circumference (88.6 ± 10.8 and after adjuvant chemotherapy, (93.4 ± 11.0 cm., p0.05) values increased significantly when compared to pre-treatment values. Acyl ghrelin (74.05 ± 50.85 and 186.47 ± 89.61 pg/ml., p0.001 and 59.28 ± 45.74 and 151.74 ± 94.88 pg/ml., p0.01) and des-acyl ghrelin (347.59 ± 241.95 and 936.76 ± 446.93 pg/ml., p0.001 and 295.40 ± 241.44 and 765.38 ± 471.74 pg/ml., p0.01) serum levels were significantly lower in breast cancer patients compared to the control group in both pre-treatment and post-treatment periods.Conclusion: In conclusion, our study confirms that adjuvant chemotherapy causes significant weight gain in early stage breast cancer patients but does not indicate a concomitant treatment related change in ghrelin, leptin or obestatin levels. The fact that serum ghrelin levels were lower in breast cancer patients compared to BMI-matched control group, independent from treatment, might indicate that ghrelin-specific weight or adjuvant chemotherapy may be a regulatory mechanism for cancer etiopathology in breast cancer patients.

Effects of exogenous ghrelin on muscle atrophy in elderly mice

Objective To investigate the effects of acylated ghrelin and des-acylated ghrelin on skeletal muscle atrophy in elderly mice. Methods Eighteen-month-old wild type(WT)mice and ghrelin-/- mice were selected to perform body composition analysis and wheel-running test under conditions of feeding versus fasting.The gene expressions of myogenic regulatory factors including muscle differentiation factor MyoD, myogenin, atrogin-1, muscle-specific RING finger protein 1(muRF-1), and insulin growth factor 1(IGF-1)in mice gastrocnemius muscle were detected by realtime polymerase chain reaction(PCR). Results The locomotor activity during the wheel-running test were significantly lower in elderly ghrelin-/- mice than in elderly WT mice(3 929±263 times/h vs.5359±601 times/h, t=4.87, P 0.05). After 48 h fasting, the decrements of body weight, fat and muscle weight were more in ghrelin-/- mice than in WT mice(P<0.05). In fasting old ghrelin-/- mice, the gene expressions of MyoD and myogenin were increased(improved)(t=232.00 and 121.00, P<0.05), and the gene expressions of atrogin-1 and muRF-1 were decreased(improved)(t=30.40 and 54.00, P<0.05)after treatment with both acylated ghrelin and desacylated ghrelin. Conclusions The acylated ghrelin and desacylated ghrelin may play protective roles in age-related muscle atrophy. Key words: Ghrelin; Muscular atrophy

Relationship between metabolic syndrome and acylated/desacylated ghrelin ratio in patients with schizophrenia under olanzapine medication.

Ghrelin is a peptide hormone that mediates glucose homeostasis and lipid metabolism. Acylated ghrelin (AG) and desacylated ghrelin (DAG) are the two main forms of ghrelin, which have opposing roles in energy homeostasis. The AG/DAG ratio has been proposed to be associated with metabolic syndrome (MetS) in the general population. This study compared the relationships between MetS and ghrelin parameters in patients with schizophrenia. Patients diagnosed with schizophrenia and under olanzapine monotherapy were recruited. Fasting blood samples were collected for the analyses of metabolic and ghrelin parameters. The serum levels of total ghrelin and AG were measured by enzyme-linked immunosorbent assay kits. DAG level was calculated by subtracting the AG level from the total ghrelin level. We recruited 151 subjects with schizophrenia, and classified them into those with MetS (n = 41) and those without MetS (n = 110). Subjects with MetS had a significantly higher AG/DAG ratio, as well as lower total ghrelin and DAG levels. There were no sex differences in ghrelin parameters. The AG/DAG ratio was significantly and positively correlated with weight, body mass index, waist circumference, insulin level, homeostasis model assessment of insulin resistance and number of MetS components. Multiple linear regression analysis indicated that the number of MetS components remained significantly associated with the AG/DAG ratio. Our results revealed that lower AG/DAG ratios were associated with better metabolic profiles in olanzapine-treated patients with schizophrenia. These observations suggest that the balance between AG and DAG plays a crucial role in the metabolic homeostasis among patients with schizophrenia.

A randomized crossover trial assessing the effects of acute exercise on appetite, circulating ghrelin concentrations, and butyrylcholinesterase activity in normal-weight males with variants of the obesity-linked FTO rs9939609 polymorphism

The fat mass and obesity-associated gene (FTO) rs9939609 A-allele is associated with higher acyl-ghrelin (AG) concentrations, higher energy intake, and obesity, although exercise may mitigate rs9939609 A-allele-linked obesity risk. Butyrylcholinesterase (BChE) hydrolyzes AG to des-acyl-ghrelin (DAG), potentially decreasing appetite. However, the effects of the FTO rs9939609 genotype and exercise on BChE activity, AG, DAG, and energy intake are unknown. We hypothesized that individuals homozygous for the obesity-risk A-allele (AAs) would exhibit higher postprandial AG and energy intake than individuals homozygous for the low obesity-risk T-allele (TTs), but that exercise would increase BChE activity and diminish these differences. Twelve AA and 12 TT normal-weight males completed a control (8 h rest) and an exercise (1 h of exercise at 70% peak oxygen uptake, 7 h rest) trial in a randomized crossover design. A fixed meal was consumed at 1.5 h and an ad libitum buffet meal at 6.5 h. Appetite, appetite-related hormones, BChE activity, and energy intake were assessed. AAs displayed lower baseline BChE activity, higher baseline AG:DAG ratio, attenuated AG suppression after a fixed meal, and higher ad libitum energy intake compared with TTs [effect sizes (ESs)≥0.72, P≤0.049]. Exercise increased Δ BChE activity in both genotypes (ESs=0.37, P=0.004); however, exercise lowered AG and the AG:DAG ratio to a greater extent in AAs (P≤0.023), offsetting the higher AG profile observed in AAs during the control trial (ESs≥1.25, P≤0.048). Exercise did not elevate energy intake in either genotype (P=0.282). Exercise increases BChE activity, suppresses AG and the AG:DAG ratio, and corrects the higher AG profile observed in obesity-risk AA individuals. These findings suggest that exercise or other methods targeting BChE activity may offer a preventative and/or therapeutic strategy for AA individuals. This trial was registered at clinicaltrials.gov as NCT03025347.

Plasma desacyl ghrelin‑to‑acyl ghrelin ratio is a predictor of postoperative complications and prognosis after pancreaticoduodenectomy

The current study aimed to clarify the significance of the preoperative desacyl ghrelin (DG)-to-acyl ghrelin (AG) ratio in patients undergoing pancreaticoduodenectomy (PD). Ghrelin, a peptide hormone mainly produced in the stomach, possesses unique functions. Recently, studies have determined the involvement of plasma gherlin in certain postoperative outcomes, particularly in surgical resections of the stomach. Although PD involves gastric resection, few reports have determined the involvement of ghrelin following PD. From April 2003 to December 2011, 195 patients underwent PD for tumors of the pancreatic head, bile duct and ampulla of Vater at the Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, University of Miyazaki Faculty of Medicine (Miyazaki, Japan). Of these, 83 patients were enrolled into the present study as their plasma gherlin levels were measured. AG, DG, total ghrelin (TG) and the DG-to-AG ratio (D/A) were subsequently assessed. Furthermore, the prognostic nutritional index (PNI) and high-sensitivity modified Glasgow Prognostic Score (HS-mGPS) were determined. Morbidity was examined in all 83 patients, but mortality was only determined in 69 individuals after 14 patients were excluded due to the presence of benign disease. The results revealed that the TG of patients undergoing standard PD (SPD) was significantly lower than that of patients undergoing pylorus-preserving PD or subtotal stomach-preserving PD. It was also determined that TG levels declined significantly in SPD patients at 2 weeks after surgery. Negative associations were identified between plasma ghrelin levels and PNI, and between serum albumin and HS-mGPS. Patient morbidity was determined to be 31.3% and the severe complications exhibited by patients included pancreatic fistula (14.5%), intra-abdominal abscess (15.7%), intra-abdominal bleeding (6.0%) and liver abscess (1.2%). Multivariate analysis revealed that disease location and low D/A were independent risk factors for severe complications. The 5-year overall survival (OS) rate was 41.5%. Multivariate analysis also demonstrated that diabetes mellitus, long postoperative hospital stay and low D/A were independent risk factors for OS. The present study revealed the D/A may serve as a useful predictive factor for postoperative complications and prognosis after PD.

Association of cord blood des-acyl ghrelin with Apgar score and anthropometric measures in relation to its maternal one.

Ghrelin is a pleiotropic hormone that governs eating and energy equilibrium as well as promotes the release of growth hormone release. Although cord blood ghrelin has been correlated to the weight at birth and other anthropometric measures, the implication of des-acyl ghrelin in fetal and postnatal growth still not well understood. The goal of this research was to investigate the concentration of des-acyl ghrelin (DAG) in cord blood of appropriate for gestational age (AGA), small for gestational age (SGA) and large for gestational age (LGA) infants in order to elucidate their correlation with birth weight, anthropometric measures as well as apgar score of the newborn and relating them to maternal DAG levels. Cord blood specimens were procured from 25 SGA, 24 AGA infants and 25 LGA infants. Desacyl ghrelin, was quantified by ELIZA. A significant negative correlation has been found between cord ghrelin and neonatal anrthropometric measures( neonatal weight, height, head circumference, mean arm circumference) As well, a significant negative correlation has been detected between cord ghrelin and apgar score at 1 and 5 min. The current results shed the light on the critical role of DAG in the growth during the intrauterine period. Further studies are necessary to identify the exact mechanisms underlying the contribution of DAG in the growth of the fetus.

Role of ghrelin isoforms in the mitigation of hepatic inflammation, mitochondrial dysfunction, and endoplasmic reticulum stress after bariatric surgery in rats.

Bariatric surgery improves nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), but the underlying mechanisms remain elusive. We evaluated the potential role of ghrelin isoforms in the amelioration of hepatic inflammation after sleeve gastrectomy and Roux-en-Y gastric bypass (RYGB). Plasma ghrelin isoforms were measured in male Wistar rats (n = 129) subjected to surgical (sham operation, sleeve gastrectomy, or RYGB) or dietary interventions [fed ad libitum a normal (ND) or a high-fat diet (HFD) or pair-fed diet]. The effect of acylated and desacyl ghrelin on markers of inflammation, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress in primary rat hepatocytes under palmitate-induced lipotoxic conditions was assessed. Plasma desacyl ghrelin was decreased after sleeve gastrectomy and RYGB, whereas the acylated/desacyl ghrelin ratio was augmented. Both surgeries diminished obesity-associated hepatic steatosis, CD68+- and apoptotic cells, proinflammatory JNK activation, and Crp, Tnf, and Il6 transcripts. Moreover, a postsurgical amelioration in the mitochondrial DNA content, oxidative phosphorylation (OXPHOS) complexes I and II, and ER stress markers was observed. Specifically, following bariatric surgery GRP78, spliced XBP-1, ATF4, and CHOP levels were reduced, as were phosphorylated eIF2α. Interestingly, acylated and desacyl ghrelin inhibited steatosis and inflammation of palmitate-treated hepatocytes in parallel to an upregulation of OXPHOS complexes II, III, and V, and a downregulation of ER stress transducers IRE1α, PERK, ATF6, their downstream effectors, ATF4 and CHOP, as well as chaperone GRP78. Our data suggest that the increased relative acylated ghrelin levels after bariatric surgery might contribute to mitigate obesity-associated hepatic inflammation, mitochondrial dysfunction, and ER stress.

Concurrent Use of Teneligliptin and Canagliflozin Improves Glycemic Control with Beneficial Effects on Plasma Glucagon and Glucagon-Like Peptide-1: A Single-Arm Study.

IntroductionWe investigated the mechanisms of the glucose-lowering effects of teneligliptin and canagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, by monitoring several gastrointestinal peptides using the most appropriate measuring methods during multiple meal tolerance tests (MTTs) and flash glucose monitoring.MethodsTwelve Japanese patients with type 2 diabetes were enrolled in the 14-day study. Subjects were treated with teneligliptin 20 mg/day from day 4, followed by a combination tablet of teneligliptin 20 mg and canagliflozin 100 mg (T/C) per day from day 11. MTTs were conducted on days 3 (premedication; Pre), 10 (teneligliptin; T) and 13 (T/C) to evaluate plasma glucose, C-peptide, glucagon, active glucagon-like peptide-1 (GLP-1), active gastric inhibitory polypeptide (GIP), ghrelin and des-acyl ghrelin.ResultsPlasma glucose was significantly decreased with the progress of treatment intervention, and C-peptide was significantly decreased in T/C compared to the others. Plasma postprandial glucagon was increased for 90 min from fasting in Pre, but only for 30 min in T and T/C. Plasma postprandial active GLP-1 was significantly increased in T compared to Pre, and that of T/C was significantly higher than T. Plasma postprandial active GIP was increased in T and T/C compared to Pre. Plasma ghrelin and des-acyl ghrelin levels did not change during the treatment.ConclusionTeneligliptin increased incretin hormones and suppressed postprandial glucagon secretion as expected. Concurrent use of canagliflozin and teneligliptin improved glycemic control without increasing postprandial glucagon secretion, and increased postprandial GLP-1 secretion and decreased the required amount of postprandial insulin secretion. The underlying mechanisms may involve canagliflozin’s inhibitory activity against not only SGLT2 but also SGLT1.Trial RegistrationUMIN identifier, UMIN000030043.FundingMitsubishi Tanabe Pharma Corporation and a Grant for Clinical Research from Miyazaki University Hospital.Electronic supplementary materialThe online version of this article (10.1007/s13300-019-0666-7) contains supplementary material, which is available to authorized users.