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Diabetes mellitus affects 537 million adults around the world. Adropin is expressed in different cell types. Our aim was to investigate the cellular localization in the endocrine pancreas and its effect on modulating pancreatic endocrine hormone release in streptozotocin (STZ)-induced diabetic rats. Adropin expression in the pancreas was investigated in normal and diabetic rats using immunohistochemistry and immunoelectron microscopy. Serum levels of insulin, glucagon pancreatic polypeptide (PP), and somatostatin were measured using a Luminex ® χMAP (Magpix ® ) analyzer. Pancreatic endocrine hormone levels in INS-1 832/3 rat insulinoma cells, as well as pancreatic tissue fragments of normal and diabetic rats treated with different concentrations of adropin (10 -6 , 10 -9 , and 10 -12 M), were measured using ELISA. Adropin was colocalized with cells producing either insulin, glucagon, or PP. Adropin treatment reduced the number of glucagon-secreting alpha cells and suppressed glucagon release from the pancreas. The serum levels of GLP-1 and amylin were significantly increased after treatment with adropin. Our study indicates a potential role of adropin in modulating glucagon secretion in animal models of diabetes mellitus.

Background: Gastrointestinal hormones (GIHs) are crucial for the regulation of a variety of physiological functions and have been linked to hunger, satiety, and appetite control. Thus, they might constitute meaningful biomarkers in longitudinal and interventional studies on eating behavior and body weight control. However, little is known about the physiological levels of GIHs, their intra-individual stability over time, and their interaction with other metabolic and lifestyle-related parameters. Therefore, the aim of this pilot study is to investigate the intra-individual stability of GIHs in normal-weight adults over time. Methods: Plasma concentrations of ghrelin, leptin, GLP-1 (glucagon-like-peptide), and PP (pancreatic polypeptide) were assessed by enzyme-linked immunosorbent assay (ELISA) in 17 normal-weight, healthy adults in a longitudinal design at baseline and at follow-up six months later. The reliability of the measurements was estimated using intra-class correlation (ICC). In a second step, we considered the stability of GIH levels after controlling for changes in blood glucose and hemoglobin A1 (HbA1c) as well as self-reported physical activity and dietary habits. Results: We found excellent reliability for ghrelin, good reliability for GLP1 and PP, and moderate reliability for leptin. After considering glucose, HbA1c, physical activity, and dietary habits as co-variates, the reliability of ghrelin, GLP1, and PP did not change significantly; the reliability of leptin changed to poor reliability. Conclusions: The GIHs ghrelin, GLP1, and PP demonstrated good to excellent test-retest reliability in healthy individuals, a finding that was not modified after adjusting for glucose control, physical activity, or dietary habits. Leptin showed only moderate to poor reliability, which might be linked to weight fluctuations, albeit small, between baseline and follow-up assessment in our study sample. Together, these findings support that ghrelin, GLP1, and PP might be further examined as biomarkers in studies on weight control, with GLP1 and PP serving as anorexic markers and ghrelin as an orexigenic marker. Additional reliability studies in obese individuals are necessary to verify or refute our findings for this cohort.

Pancreatic polypeptide (PP) is known to affect food intake. In this exploratory study, we set out to investigate its supraphysiological effect on food tolerance, gastric accommodation, and emptying. In 12 healthy volunteers, 0, 3, or 10 pmol*kg -1 *min -1 PP was administered intravenously (PP0, PP3 or PP10). Thirty minutes thereafter, nutrient drink infusion (60 ml*min -1 ) through a nasogastric feeding tube was started until maximum satiation. Gastric accommodation was assessed by measuring the intragastric pressure (IGP; nasogastric manometry). In a separate test, the effect of PP0 or PP10 on gastric emptying was tested in 10 healthy volunteers and assessed using the 13 C breath test. Results are presented as mean ± SEM, and p < 0.05 was considered significant. For the IGP test, PP increased ingested nutrient volume: 886 ± 93, 1059 ± 124, and 1025 ± 125 ml for PP0, PP3, and PP10, respectively (p = 0.048). In all groups, Nadir IGP values were reached upon food intake (transformed values: 1.5 ± 0.2, 1.7 ± 0.3, and 1.6 ± 0.3 mmHg for PP0, PP3, and PP10, respectively; NS) to return to baseline thereafter. For the gastric emptying study, volunteers ingested a similar nutrient volume: 802 ± 119 and 1089 ± 128 ml (p = 0.016), and gastric half-emptying time was 281 ± 52 and 249 ± 37 min for PP0 and PP10, respectively (NS). No significant correlation between tolerated nutrient volume and IGP drop (R² < 0.01; p = 0.88 for PP0 vs. PP3 and R² =0.07; p = 0.40 for PP0 vs. PP10, respectively) or gastric half-emptying time (R² = 0.12; p = 0.32) was found. A supraphysiological PP dose enhances food tolerance; however, this effect is not mediated through gastric motility. CLINICAL TRIAL REGISTRY NUMBER: NCT03854708 is obtained from clinicaltrials.gov., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Background: Dopamine, a key neurotransmitter in the autonomic nervous system participating in the homeostatic balance between sympathetic and parasympathetic divisions, is involved in food intake regulation. Objective: We investigated whether dopamine is altered by acute fasting or overfeeding diets with varying macronutrient content. Design: Ninety-nine healthy subjects underwent 24-h dietary interventions including eucaloric feeding, fasting, and five different overfeeding diets in a crossover design. Overfeeding diets (200% of eucaloric requirements) included one diet with 3%-protein (low-protein high-fat overfeeding-LPF: 46%-fat), three diets with 20%-protein, and a diet with 30%-protein (44%-fat). Urine was collected for 24 h and urinary dopamine concentration was quantified by high-performance liquid chromatography. Plasma pancreatic polypeptide (PP) concentration, an indirect marker of parasympathetic activity, was measured prior to and after each diet after an overnight fast. Results: During 24-h of fasting, dopamine decreased on average by ~14% compared to eucaloric conditions, whereas PP increased by two-fold (both p < 0.001). Lower dopamine during 24-h fasting correlated with increased PP (r = -0.40, p < 0.001). Similarly, on average urinary dopamine decreased during LPF by 14% ( p < 0.001) and lower dopamine correlated with increased PP (r = -0.31, p = 0.01). No changes in dopamine and PP concentrations were observed during other overfeeding diets (all p > 0.05). Conclusions: Dopamine concentrations decrease during short-term fasting and overfeeding with a low-protein diet. As both dietary conditions have in common protein deficit, the correlation between dopamine and PP suggests a compensatory mechanism underlying the shift from sympathetic to parasympathetic drive during dietary protein deprivation.

Physical exercise is known to influence hormonal mediators of appetite, but the effect of short-term maximal intensity exercise on plasma levels of appetite hormones and cytokines has been little studied. We investigated the effect of a 30 s Wingate Test, followed by a postprandial period, on appetite sensations, food intake, and appetite hormones. Twenty-six physically active young males rated their subjective feelings of hunger, prospective food consumption, and fatigue on visual analogue scales at baseline, after exercise was completed, and during the postprandial period. Blood samples were obtained for the measurement of nesfatin-1, ghrelin, leptin, insulin, pancreatic polypeptide (PP), human growth factor (hGH) and cytokine interleukin-6 (IL-6), irisin and plasma lactate concentrations, at 30 min before exercise, immediately (210 s) after exercise, and 30 min following a meal and at corresponding times in control sedentary males without ad libitum meal intake, respectively. Appetite perceptions and food intake were decreased in response to exercise. Plasma levels of irisin, IL-6, lactate, nesfatin-1 and ghrelin was increased after exercise and then it was returned to postprandial/control period in both groups. A significant rise in plasma insulin, hGH and PP levels after exercise was observed while meal intake potentiated this response. In conclusion, an acute short-term fatiguing exercise can transiently suppress hunger sensations and food intake in humans. We postulate that this physiological response involves exercise-induced alterations in plasma hormones and the release of myokines such as irisin and IL-6, and supports the notion of existence of the skeletal muscle-brain-gut axis. Nevertheless, the detailed relationship between acute exercise releasing myokines, appetite sensations and impairment of this axis leading to several diseases should be further examined.

To explore plasma protein panels as potential biomarkers to screen for mild cognitive impairment (MCI) among elderly Chinese individuals with different educational backgrounds. Forty-four illiterate, 36 lower education (1-6 years), and 55 higher education (7 years or more) elderly individuals were included in the present study. Among all subjects, 67 were healthy individuals and 68 were diagnosed with MCI. Fifty plasma proteins in blood samples collected from these subjects were analyzed via the Luminex assay. Binary logistic regression was utilized to explore diagnostic models for MCI among the three educational subgroups. Then, receiver operating characteristic (ROC) curves were conducted for the clinical validity of the MCI models. Among the analyzed proteins, clusterin was used in the model of MCI among the total sample with a sensitivity (se) of 67.6%, a specificity (sp) of 59.7%, and a classification rate of 63.68%. The MCI model for the illiterate group included cystatin C, plasminogen activator inhibitor-1, and apolipoprotein A-I (se: 71.4%, sp.: 82.6%, accuracy: 77.25%). The sensitivity, specificity, and classification rate of the diagnostic model of MCI in elderly adults with lower education (human serum albumin) were each 75.0%. Additionally, the sensitivity, specificity, and accuracy rate of the diagnostic model for MCI elderly individuals with higher education (alpha-acid glycoprotein + soluble intercellular adhesion molecule-1 + pancreatic polypeptide) were 77.8%, 89.3%, and 83.60%, respectively. The performance of diagnostic models for MCI based on different educational levels is superior to that of diagnostic models for MCI without grouping by educational level.

Background: Vagal nerve stimulation has been reported to treat inflammation with promising results. The aims of our study were to optimize sacral nerve stimulation (SNS) methodologies for colonic inflammation in a rodent model of colitis and to investigate autonomic and cytokine mechanisms., Methods: Three major efforts were made in optimizing SNS: (a) to determine the best stimulation duration: SNS-0.5h daily, SNS-1h daily, and SNS-3h daily with the parameters set at 5 Hz, 10 seconds on, 90 seconds off; (b) to determine the best stimulation position: bilateral, bipolar, and unipolar stimulation; (c) to determine the best stimulation parameters: our 5 Hz intermittent stimulation vs 14 Hz-210 μs continuous stimulation. Inflammatory responses were assessed by the disease activity index (DAI), histological analyses, and the myeloperoxidase (MPO) activity. Levels of inflammatory cytokines, norepinephrine (NE), and pancreatic polypeptide (PP) in both plasma and colon tissues were assessed., Key Results: Both SNS-1h and SNS-3h significantly ameliorated intestinal inflammation; SNS-1h was superior to SNS-3h. Bipolar but not bilateral or unipolar stimulation improved the inflammation in colitis. SNS with 5 Hz intermittent stimulation but not the 14 Hz continuous SNS was better for treating colitis in rats. SNS with the optimized stimulation parameters increased vagal activity and decreased sympathetic activity. CONCLUSION & INFERENCES: Bipolar stimulation for 1 hour daily using intermittent 5 Hz parameters is most effective in improving colonic inflammation in TNBS-treated rats by inhibiting pro-inflammatory cytokines and increasing anti-inflammatory cytokines via the modulation of the autonomic function., (© 2020 John Wiley & Sons Ltd.)

Background: Pancreatic polypeptide (PP) hormone is a 36-amino-acid peptide released from the pancreas, the serum levels of which have been shown to rise upon food intake. The underlying mechanism for metabolic surgery in the treatment of patients with type 2 diabetes mellitus (T2DM) remains intriguing. We compared post-oral glucose challenge PP levels between patients undergoing laparoscopic gastric bypass (GB) and sleeve gastrectomy (SG) at 1 year after surgery., Methods: This hospital-based, prospective study followed up a total of 12 laparoscopic GB and 12 laparoscopic SG patients and evaluated their glucose homeostasis. One year after metabolic surgery, 75-g oral glucose tolerance tests (OGTTs) were performed in the patients in the GB and SG groups and the blood levels of PP were evaluated., Results: The laparoscopic GB group had stable serum PP levels within 120 min after OGTT; however, the levels were significantly higher in the laparoscopic SG group at 30 min after OGTT. The patients with complete T2DM remission did not exhibit significantly different PP levels at fasting and post-OGTT than those in patients without remission after GB. Similarly, after SG, patients with T2DM remission did not show significantly different PP levels at fasting and post-OGTT than those in patients without T2DM remission., Conclusions: No significant difference was found in plasma PP levels after OGTT in T2DM patients that received either GB or SG, or in T2DM remitters or non-remitters 1 year after metabolic surgery., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: The relationship between cardiovascular and gastrointestinal (ie, plasma pancreatic polypeptide [PP] response to modified sham feeding [MSF]) indices of vagal function is unclear. Hyperglycemia inhibits PP secretion via vagally mediated mechanisms. Our aims were to (a) compare the PP response, (b) its relationship with glycemia, and (c) the relationship between PP response to MSF, gastric emptying (GE) of solids, and symptoms during GE study in healthy controls, patients with diabetic gastroenteropathy (DM), and non-ulcer dyspepsia (NUD)., Methods: In 24 healthy controls, 40 DM, and 40 NUD patients, we measured plasma PP concentrations during MSF, cardiovagal functions, GE, and symptoms during a GE study., Key Results: Baseline PP concentrations were higher in DM than in controls and NUD (P = .01), and in type 2 than in type 1 DM patients (P < .01). The PP increment during MSF was normal (≥20 pg/mL) in 70% of controls, 54% of DM, and 47% of NUD patients. Overall, the PP response and cardiovagal tests were concordant (P = .01). Among patients with a reduced PP increment with MSF, 7/10 of T1DM and 1/7 of T2DM patients had moderate or severe cardiovagal dysfunctions (P < .05). The PP response to MSF was not associated with GE., Conclusions & Inferences: Up to 30% of healthy controls have a reduced PP increment during MSF, limiting the utility of this test to detect vagal injury. The PP response is more useful when it is normal than abnormal. A reduced PP response is more likely to be associated with cardiovagal dysfunctions in T1DM than in T2DM., (© 2019 John Wiley & Sons Ltd.)

Little is known about how dairy products with different nutrient contents and food matrices affect appetite sensation and gut hormone secretion. The objective of this study was to investigate how appetite sensation and gut hormone secretion in healthy adults are affected by meals with the same amount of fat but from different dairy products. Forty-seven healthy adults (70% women) were recruited to a randomized controlled crossover study with 4 dairy meals consisting of butter, cheese, whipped cream, or sour cream, corresponding to 45 g (approximately 60 energy percent) of fat. Plasma samples were collected for analysis of cholecystokinin (CCK), pancreatic polypeptide (PP), peptide YY (PYY), and ghrelin concentrations at 0, 2, 4, and 6 h after the meals and analyzed as the incremental area under the curve (iAUC 0-6h ) in a mixed model. Hunger, satiety, and appetite sensations were measured with a visual analog scale (VAS) immediately after finishing the meals and at 4 and 6 h postprandially. Intake of cheese induced a higher level of plasma PP-iAUC 0-6h compared with butter or whipped cream, and a higher level of plasma CCK-iAUC 0-6h compared with whipped cream. Intake of whipped cream increased VAS appetite at 4 h compared with cheese or sour cream, and at 6 h compared with cheese or butter. No significant meal effect was found for hunger, satiety, plasma PYY, or plasma ghrelin concentration. Intake of cheese increased postprandial plasma PP and CCK concentrations and decreased appetite compared with whipped cream but not with sour cream. These findings encourage further investigations of how different dairy products affect gut hormone secretion and appetite sensation., (Copyright © 2020 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Although sacral nerve stimulation (SNS) has been applied for treating constipation, its parameters were adopted from SNS for fecal incontinence, its effects are limited, and mechanisms are largely unknown. We investigated the effects and mechanism of SNS with appropriate parameters on constipation in rats treated with loperamide. First, using rectal compliance as an outcome measure, an experiment was performed to derive effective SNS parameters. Then, a 7-day SNS was performed in rats with constipation induced by loperamide. Autonomic functions were assessed by spectral analysis of heart rate variability (HRV) derived from an electrocardiogram. Serum levels of pancreatic polypeptide (PP), norepinephrine (NE), and acetylcholine (ACh) in colon were assessed. 1 ) Acute SNS at 5 Hz, 100 µs was found effective in enhancing rectal compliance and accelerating distal colon transit ( P < 0.05 vs. sham SNS). 2 ) The 7-day SNS normalized loperamide-induced constipation, assessed by the number, weight, and water content of fecal pellets, and accelerated the distal colon transit (29.4 ± 3.7 min with sham SNS vs. 16.4 ± 5.3 min with SNS but not gastric emptying or intestinal transit. 3 ) SNS significantly increased vagal activity ( P = 0.035) and decreased sympathetic activity ( P = 0.012), assessed by spectral analysis of HRV as well as by the serum PP. 4 ) SNS increased ACh in the colon tissue; atropine blocked the accelerative effect of SNS on distal colon transit. We concluded that SNS with appropriate parameters improves constipation induced by loperamide by accelerating distal colon motility, mediated via the autonomic-cholinergic function. NEW & NOTEWORTHY Although sacral nerve stimulation (SNS) has been applied for treating constipation, its parameters were adopted from SNS for fecal incontinence, effects are limited, and mechanisms are largely unknown. This paper shows that SNS with appropriate parameters improves constipation induced by loperamide by accelerating distal colon motility mediated via the autonomic-cholinergic function.

C-peptide, insulin, leptin, and other metabolic hormones are assumed to play roles in breast cancer development; though, results are inconsistent. In this prospective case-control study nested within the Mano a Mano Cohort Study, we assessed the risk of breast cancer with regard to plasma levels of c-peptide, gastric inhibitory polypeptide, insulin, leptin, monocyte chemoattractant protein-1, pancreatic polypeptide, and peptide YY. Among women followed for a median of 8.5 years, 109 breast cancer cases were identified and frequency-matched to 327 controls at a ratio of 1:3. Overall, only c-peptide was observed significantly associated with breast cancer risk. High c-peptide levels (≥ the median level of controls) were significantly associated with increased breast cancer risk (odds ratio [OR] = 1.39, 95% confidence interval [CI]: 1.01, 2.44). In an analysis of participants stratified by age, the significant association between c-peptide levels and breast cancer risk was evident in only women age ≥51 years (OR = 1.53, 95% CI: 1.02, 3.27). Among women age <51 years, high leptin levels were significantly associated with decreased breast cancer risk (OR = 0.49, 95% CI: 0.24, 0.82). Our findings suggest that selected metabolic hormones are associated with breast cancer development in Mexican American women.

Eccentric exercise has been suggested to improve muscle atrophy, muscle function, and insulin sensitivity. The aim of this study was to examine the effect of acute eccentric exercise on appetite-related hormones, food preferences, and food intake. Fourteen moderately active men were recruited to participate in this study (age 24.2 ± 5.5 years; BMI 23.4 ± 3.3 kg/m 2 ; VO 2max 48.9 ± 3.1 ml/kg/min). Three different conditions were implemented; no exercise, flat running "inclination 0" and downhill running "inclination -12%." Appetite-related hormones, subjective appetite sensations, food preference and reward, and ad libitum food intake were measured at pre-, immediately post-, and 24 h post exercise. There were no significant median changes in total ghrelin or pancreatic peptide concentrations between conditions. There were also no median differences in subjective appetite ratings or energy intake between conditions, but the median change in explicit liking of sweet versus savory foods differed significantly between pre-exercise and 24 h post exercise ( p = .013). Post-hoc analysis observed a significant difference in the pre-exercise to 24 h post exercise change between front running and downhill running ( p = .023), and indicated greater liking of savory foods over sweet foods in downhill running than front running. However, no further differences were seen between conditions for the remaining food preference parameters, suggesting there were no systematic trends in these data. In conclusion, there was no effect of front and downhill running on eating behavior as compared to a nonexercise control condition, but these data need to be replicated in a larger and more heterogeneous sample.

Background: Acid exposure time (AET) prolongation plays an important role in the pathogenesis of gastroesophageal reflux disease (GERD). Gastric inhibitory polypeptide (GIP) and pancreatic polypeptide (PP) participate in the regulation of gastric acid secretion, blood glucose and lipid levels, and food intake. In this study, we evaluated the serum GIP and PP levels in refractory GERD patients and analyzed their metabolic and motility characteristics., Methods: Seventy-three refractory GERD patients were enrolled in this study from September 2015 to September 2017. We investigated the clinical characteristics, severity, and duration of GERD symptoms. High-resolution manometry and 24 hours impedance-pH monitoring were performed to assess esophageal motility and reflux parameters. The patients were divided into the AET- group (AET <4.2%) and AET+ group (AET >4.2%). GIP and PP levels were determined in all subjects and their associations with other parameters evaluated., Results: Age and GERDQ score were significantly higher (P < .05) and acid reflux and heartburn more frequent in the AET+ group than in the AET- group. The contraction front velocity was increased in the AET- group, while there was no significant difference in the distal contraction integral, peristalsis interruption, distal latency, or resting pressures of the lower and upper esophageal sphincters between the 2 groups (P > .05). The serum levels of GIP (P = .003) and PP (P = .012) were significantly increased in the AET+ group. Increased GIP and PP levels were associated with abnormal upright AET (correlation coefficients 0.307 and 0.233, P = .008 and P = .047). There was a positive correlation between GIP and triglyceride levels (correlation coefficient 0.279, P = .017)., Conclusion: The serum levels of GIP and PP in refractory GERD patients with prolongation of AET are significantly elevated, mainly in the upright position.

Diabetes of the exocrine pancreas (DEP) is a form of diabetes that occurs due to pancreatic disease. It is far more common than has been previously considered, with a recent study showing 1.8% of adults with new-onset diabetes should have been classified as DEP. The majority is misdiagnosed as type 2 diabetes mellitus (T2DM). Patients with DEP exhibit varying degrees of exocrine and endocrine dysfunction. Damage to the islet of Langerhans effects the secretion of hormones from the β, α, and pancreatic polypeptide cells; the combination of low insulin, glucagon, and pancreatic polypeptide contributes to rapid fluctuations in glucose levels. This form of "brittle diabetes" may result in the poorer glycemic control observed in patients with DEP, when compared with those with T2DM. Diabetes of the exocrine pancreas has a different natural history to other forms of diabetes; patients are more likely to require early insulin initiation compared with those with T2DM. Therefore, individuals with DEP should be advised about the symptoms of decompensated hyperglycemia, although they are less likely to develop ketoacidosis. Clinicians should screen for DEP in patients with acute or chronic pancreatitis, following pancreatic resection, or with co-existing cystic fibrosis or hemochromatosis. Incident diabetes may herald the onset of pancreatic ductal carcinoma in a small subset of patients. Once identified, patients with DEP can benefit from specific lifestyle advice, pancreatic enzyme replacement therapy, metformin treatment, appropriate insulin dosing, and monitoring. Further research is needed to establish the ideal treatment regimens to provide optimal clinical outcomes for this unique form of diabetes., (© 2018 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Introduction: Proteins, particularly whey proteins, represent the most satiating macronutrient in animals and humans. A dietetic regimen based on proteins enriched preload before eating might be a strategy to counteract obesity., Aims and Methods: The aim of the present study was to evaluate the effects of an isocaloric drink containing whey proteins or maltodextrins (preload) on appetite (satiety/hunger measured by a visual analogue scale or VAS), glucometabolic control (blood glucose/insulin), and anorexigenic gastrointestinal peptides (pancreatic polypeptide or PP, glucagon-like peptide 1 or GLP-1 and peptide YY or PYY) in a cohort of obese young women ( n = 9; age: 18.1 ± 3.0 years; body mass index, BMI: 38.8 ± 4.5 kg/m²). After two and a half hours, they were administered with a mixed meal at a fixed dose; satiety and hunger were measured by VAS., Results: Each drink significantly augmented satiety and reduced hunger, and the effects were more evident with whey proteins than maltodextrins. Similarly, there were significant increases in GLP-1 and PYY levels (but not PP) after the ingestion of each drink; these anorexigenic responses were higher with whey proteins than maltodextrins. While insulinemia identically increased after each drink, whey proteins induced a lower glycemic response than maltodextrins. No differences in satiety and hunger were found after the meal, which is presumably due to the late administration of the meal test, when the hypophagic effect of whey proteins was disappearing., Conclusions: While whey proteins actually reduce appetite, stimulate anorexigenic gastrointestinal peptides, and improve glucometabolic homeostasis in young obese women, further additional studies are mandatory to demonstrate their hypophagic effects in obese subjects, when administered as preload before eating., Competing Interests: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

The consumption of blueberries, as well as the phenolic compounds they contain, may alter metabolic processes related to type 2 diabetes. The study investigated the effects of adding 140 g of blueberries to a higher-carbohydrate breakfast meal on postprandial glucose metabolism, gastrointestinal hormone response, and perceived appetite. As part of a randomized crossover design study, 17 healthy adults consumed a standardized higher-carbohydrate breakfast along with 2 treatments: (1) 140 g (1 cup) of whole blueberries and (2) a placebo gel (matched for calories, sugars, and fiber of the whole blueberries). Each subject participated in two 2-h meal tests on separate visits ≥8 days apart. Venous blood samples and perceived appetite ratings using visual analog scales were obtained prior to and at 30, 60, 90, and 120 min after consuming the breakfast meals. Results show that glucose metabolism, several gastrointestinal hormones, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), peptide YY (PYY) concentrations and perceived appetite did not change significantly with blueberry consumption. However, pancreatic polypeptide (PP) concentrations were statistically significantly higher ( p = 0.0367), and the concentrations were higher during 30, 60, 90, and 120 min after consumption of the blueberry breakfast meal than the placebo breakfast meal. Additional research is needed to determine whether blueberries and other flavonoid-rich foods reduce type 2 diabetes risk by modifying gastrointestinal hormones and perceived appetite.

Neuroendocrine tumours (NETs) are neoplasms that arise from neuroendocrine cells. Neuroendocrine cells and their tumours can secrete a wide range of amines and polypeptide hormones into the systemic circulation. This feature has triggered widespread investigation into circulating biomarkers for the diagnosis of NETs as well as for the prediction of the biological behaviour of tumour cells. Classic examples of circulating biomarkers for gastroenteropancreatic NETs include chromogranin A, neuron-specific enolase and pancreatic polypeptide as well as hormones that elicit clinical syndromes, such as serotonin and its metabolites, insulin, glucagon and gastrin. Biomarker metrics of general markers for diagnosing all gastroenteropancreatic NET subtypes are limited, but specific hormonal measurements can be of diagnostic value in select cases. In the past decade, methods for detecting circulating transcripts and tumour cells have been developed to improve the diagnosis of patients with NETs. Concurrently, modern scanning techniques and superior radiotracers for functional imaging have markedly expanded the options for clinicians dealing with NETs. Here, we review the latest research on biomarkers in the NET field to provide clinicians with a comprehensive overview of relevant diagnostic biomarkers that can be implemented in dedicated situations.

Objectives: Human pancreatic polypeptide (HPP) is a hormone secreted by the ventral pancreas. While postprandial HPP levels have been studied in chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC), there are limited data on fasting HPP in these diseases., Methods: Fasting serum HPP was measured in the following groups of patients: CP with diabetes mellitus (DM) (n = 16), CP without DM (n = 34), PDAC with new-onset DM (n = 50), PDAC without DM (n = 49), new-onset type 2 DM (n = 50), and controls without DM (n = 49). Sixty-six had type 3c DM (CP with DM, n = 16; PDAC with new-onset DM, n = 50)., Results: Median fasting HPP levels (in picograms per milliliter) were similar among all groups. Median (interquartile range) HPP levels in new-onset type 2 DM (n = 50; 288.3 [80.1-1072.1]) were similar to those in type 3c DM (n = 66; 242.3 [64.9-890.9]) (P = 0.71). In PDAC (n = 99), HPP values were similar in pancreatic head (n = 75) versus body/tail (n = 24) tumors (245.3 [64.3-1091.3] vs 334.7 [136.1-841.5]; P = 0.95), regardless of DM., Conclusions: Fasting HPP levels are similar in CP, PDAC, and controls regardless of glycemic status.

The aim of this study was to review the diagnostic significance of pancreatic polypeptide (PP) in pancreatic diseases. PP may play a significant role in monitoring the development of the disease and the patient's healing process, particularly after the removal of a portion of the pancreas. Determining PP in acute pancreatitis is quite controversial. At the 1st stage of severe pancreatic damage, there is excessive PP release followed by its fall. In patients with chronic pancreatitis, a significant decrease in PP secretion was found in the presence of a food stimulant. In this case, PP could be a good marker for determining the stage of pancreatitis. Pancreatic polypeptide also functions as a hepatic glucose regulator. PP increases hepatic insulin sensitivity, resulting in reduced hepatic glucose production. Therefore, impaired hepatic insulin sensitivity in chronic pancreatitis is abrogated after the PP administration. Endocrine pancreatic tumors initially grow without specific symptoms. In contrast, they are almost always correlated with elevated serum pancreatic polypeptide. Therefore, the level of PP may be a good diagnostic parameter confirming the presence of pancreatic cancer. Depending on the type of disease, the polypeptide concentration can be increased or decreased, evidencing the disease progress or regression.

Phenylephrine increases mean arterial pressure (MAP) by enhanced total peripheral resistance (TPR) but near-infrared spectroscopy (NIRS) determined muscle oxygenation (S m O 2 ) increases. We addressed that apparent paradox during supine rest and head-up tilt (HUT). Variables were determined ± phenylephrine in males during supine rest (n = 17) and 40° HUT (n = 7). MAP, stroke volume (SV), heart rate (HR), and TPR were derived by Modelflow ® and NIRS determined biceps S m O 2 and (tibial) bone oxygenation (S tibial O 2 ). For ten subjects, cardiac filling and the diameter of the inferior caval vein (ICV collapsibility index: ((ICV expiration  - ICV inspiration )/ICV expiration ) × 100) were assessed by ultrasound. Pancreatic polypeptide (PP) and atrial natriuretic peptide (proANP) in plasma were determined by immunoassay. Brachial artery blood flow was assessed by ultrasound and skin oxygenation (S skin O 2 ) monitored by white light spectroscopy. Phenylephrine increased MAP by 34% and TPR (62%; P < 0.001) during supine rest. The ICV collapsibility index decreased (24%; P < 0.001) indicating augmented cardiac preload although volume of the left atrium and ventricle did not change. SV increased (18%; P < 0.001) as HR decreased (24%; P < 0.001). ProANP increased by 9% (P = 0.002) with unaffected PP. Brachial artery blood flow tended to decrease while S skin O 2 together with S tibial O 2 decreased by 11% (P = 0.026) and 20% (P < 0.001), respectively. Conversely, phenylephrine increased S m O 2 (9%) and restored the HUT elicited decrease in S m O 2 (by 19%) along with SV (P = 0.02). Phenylephrine reduces skin and bone oxygenation and tends to reduce arm blood flow, suggesting that the increase in S m O 2 reflects veno-constriction with consequent centralization of the blood volume.

Background: Inadequate protein intake (PI), containing a sub-optimal source of essential amino acids (EAAs), and reduced appetite are contributing factors to age-related sarcopenia. The satiating effects of dietary protein per se may negatively affect energy intake (EI), thus there is a need to explore alternative strategies to facilitate PI without compromising appetite and subsequent EI., Methods: Older women completed two experiments (EXP1 and EXP2) where they consumed either a Bar (565 kJ), a Gel (477 kJ), both rich in EAAs (7.5 g, 40% L-leucine), or nothing (Control). In EXP1, participants (n = 10, 68 ± 5 years, mean ± SD) consumed Bar, Gel or Control with appetite sensations and appetite-related hormonal responses monitored for one hour, followed by consumption of an ad libitum breakfast (ALB). In EXP2, participants (n = 11, 69 ± 5 years) ingested Bar, Gel or Control alongside an ALB., Results: In EXP1, EI at ALB was not different (P = 0.674) between conditions (1179 ± 566, 1254 ± 511, 1206 ± 550 kJ for the Control, Bar, and Gel respectively). However, total EI was significantly higher in the Bar and Gel compared to the Control after accounting for the energy content of the supplements (P < 0.0005). Analysis revealed significantly higher appetite Area under the Curve (AUC) (P < 0.007), a tendency for higher acylated ghrelin AUC (P = 0.087), and significantly lower pancreatic polypeptide AUC (P = 0.02) in the Control compared with the Bar and Gel. In EXP2, EI at ALB was significantly higher (P = 0.028) in the Control (1282 ± 513 kJ) compared to the Bar (1026 ± 565 kJ) and Gel (1064 ± 495 kJ). However, total EI was significantly higher in the Bar and Gel after accounting for the energy content of the supplements (P < 0.007)., Conclusions: Supplementation with either the Bar or Gel increased total energy intake whether consumed one hour before or during breakfast. This may represent an effective nutritional means for addressing protein and total energy deficiencies in older women., Trial Registration: Clinical trial register: retrospectively registered, ISRCTN12977929 on.

Aerobic exercise (AE) and strength exercise (SE) are reported to induce discrete and specific appetite-related responses; however, the effect of combining AE and SE (i.e., combined exercise; CE) remains relatively unknown. Twelve inactive overweight men (age: 48 ± 5 y; BMI: 29.9 ± 1.9 kg∙m 2 ) completed four conditions in a random order: 1) nonexercise control (CON) (50 min seated rest); 2) AE (50 min cycling; 75% VO 2peak ); 3) SE (10 × 8 leg extensions; 75% 1RM); and 4) CE (50% SE + 50% AE). Perceived appetite, and appetiterelated peptides and metabolites were assessed before and up to 2 h postcondition (0P, 30P, 60P, 90P, 120P). Perceived appetite did not differ between trials (p < .05). Acylated ghrelin was lower at 0P in AE compared with CON (p = .039), while pancreatic polypeptide (PP) was elevated following AE compared with CON and CE. Glucose-dependent insulinotropic peptide (GIP total ) was greater following all exercise conditions compared with CON, as was glucagon, although concentrations were generally highest in AE (p < .05). Glucose was acutely increased with SE and AE (p < .05), while insulin and C-peptide were higher after SE compared with all other conditions (p < .05). In inactive, middle-aged men AE, SE and CE each have their own distinct effects on circulating appetite-related peptides and metabolites. Despite these differential exercise-induced hormone responses, exercise mode appears to have little effect on perceived appetite compared with a resting control in this population.

Background: Electrical stimulation of the cervical vagus nerve (VNS) prevents postoperative ileus (POI) in mice. As this approach requires an additional cervical procedure, we explored the possibility of peroperative abdominal VNS in mice and human., Methods: The effect of cervical and abdominal VNS was studied in a murine model of POI and lipopolysaccharide (LPS)-induced sepsis. Postoperative ileus was quantified by assessment of intestinal transit of fluorescent dextran expressed as geometric center (GC). Next, the effect of cervical and abdominal VNS on heart rate was determined in eight Landrace pigs to select the optimal electrode for VNS in human. Finally, the effect of sham or abdominal VNS on LPS-induced cytokine production of whole blood was studied in patients undergoing colorectal surgery., Key Results: Similar to cervical VNS, abdominal VNS significantly decreased LPS-induced serum tumor necrosis factor-α (TNFα) levels (abdominal VNS: 366±33 pg/mL vs sham: 822±105 pg/mL; P<.01). In line, in a murine model of POI, abdominal VNS significantly improved intestinal transit (GC: sham 5.1±0.2 vs abdominal VNS: 7.8±0.6; P<.01) and reduced intestinal inflammation (abdominal VNS: 35±7 vs sham: 80±8 myeloperoxidase positive cells/field; P<.05). In pigs, heart rate was reduced by cervical VNS but not by abdominal VNS. In humans, abdominal VNS significantly reduced LPS-induced IL8 and IL6 production by whole blood., Conclusions & Inferences: Abdominal VNS is feasible and safe in humans and has anti-inflammatory properties. As abdominal VNS improves POI similar to cervical VNS in mice, our data indicate that peroperative abdominal VNS may represent a novel approach to shorten POI in man., (© 2017 John Wiley & Sons Ltd.)

Aims: Ghrelin is a gastric-derived hormone that stimulates growth hormone (GH) secretion and has a multi-faceted role in the regulation of energy homeostasis, including glucose metabolism. Circulating ghrelin concentrations are modulated in response to nutritional status, but responses to ghrelin in altered metabolic states are poorly understood. We investigated the metabolic effects of ghrelin in obesity and early after Roux-en-Y gastric bypass (RYGB)., Materials and Methods: We assessed central and peripheral metabolic responses to acyl ghrelin infusion (1 pmol kg -1  min -1 ) in healthy, lean subjects (n = 9) and non-diabetic, obese subjects (n = 9) before and 2 weeks after RYGB. Central responses were assessed by GH and pancreatic polypeptide (surrogate for vagal activity) secretion. Peripheral responses were assessed by hepatic and skeletal muscle insulin sensitivity during a hyperinsulinaemic-euglycaemic clamp., Results: Ghrelin-stimulated GH secretion was attenuated in obese subjects, but was restored by RYGB to a response similar to that of lean subjects. The heightened pancreatic polypeptide response to ghrelin infusion in the obese was attenuated after RYGB. Hepatic glucose production and hepatic insulin sensitivity were not altered by ghrelin infusion in RYGB subjects. Skeletal muscle insulin sensitivity was impaired to a similar degree in lean, obese and post-RYGB individuals in response to ghrelin infusion., Conclusions: These data suggest that obesity is characterized by abnormal central, but not peripheral, responsiveness to ghrelin that can be restored early after RYGB before significant weight loss. Further work is necessary to fully elucidate the role of ghrelin in the metabolic changes that occur in obesity and following RYGB., (© 2017 John Wiley & Sons Ltd.)

Introduction: Body composition in early life influences development of obesity during childhood and beyond. Appetite-regulating hormones (ARH) play a role in regulation of food intake and might thus influence body composition in later life. Studies on associations between ARH and body composition in early life are limited., Methods: In 197 healthy term infants, we measured serum fasting levels of ghrelin, leptin, insulin, glucose-dependent insulinotropic peptide (GIP), pancreatic polypeptide (PP) and peptide YY (PYY) at 3 months and in 41 infants also at 6 months and their associations with type of feeding and longitudinal fat mass percentage (FM%) measured by air displacement plethysmography at 1, 3 and 6 months and abdominal visceral and subcutaneous fat, measured by ultrasound, at 3 and 6 months., Results: Infants with formula feeding for 3 months had significantly higher serum levels of ghrelin, leptin, insulin, GIP and PP (p = 0.026, p = 0.018, p = 0.002, p < 0.001, resp.) and lower serum levels of PYY (p = 0.002) at 3 months than breastfed infants. Leptin and ghrelin correlated positively with FM% at 3 months and insulin with change in FM% between 1 and 3 months (r = 0.40, p < 0.001, r = 0.23, p < 0.05, r = 0.22, p < 0.01, resp.). Leptin at 3 months correlated with subcutaneous fat at 3 months (r = 0.23, p < 0.001), but not with visceral fat. Other ARH did not correlate with body composition., Conclusion: Formula-fed infants had a different profile of ARH than breastfed infants, suggesting that lower levels of ghrelin, leptin and insulin in breastfed infants contribute to the protective role of breastfeeding against obesity development. Leptin, ghrelin and insulin were associated with fat mass percentage or its changes.

Pancreatic polypeptide (PP) is a gut hormone that acts on Y4 receptors to reduce appetite. Obese humans display a reduced postprandial increase in PP and remain fully sensitive to the anorectic effects of exogenous PP. The utility of PP as an anti-obesity treatment is limited by its short circulating half-life. Insight into the mechanisms by which PP is degraded could aid in the design of long-acting PP analogs. We investigated the role of peptidases in PP degradation to determine whether inhibition of these enzymes enhanced PP plasma levels and bioactivity in vivo. Dipeptidyl peptidase IV (DPPIV) and neprilysin (NEP) were two peptidase found to cleave PP. Limiting the effect of both peptidases improved the in vivo anorectic effect of PP and PP-based analogs. These findings suggest that inhibiting the degradation of PP using specific inhibitors and/or the design of analogs resistant to cleavage by DPPIV and NEP might be useful in the development of PP as an anti-obesity pharmacotherapy.

Acute exposure to high altitude (>3500 m) is associated with marked changes in appetite regulation and substrate oxidation but the effects of lower altitudes are unclear. This study examined appetite, gut hormone, energy intake and substrate oxidation responses to breakfast ingestion and exercise at simulated moderate and severe altitudes compared with sea-level. Twelve healthy males (mean ± SD; age 30 ± 9years, body mass index 24.4 ± 2.7 kg·m -2 ) completed in a randomised crossover order three, 305 min experimental trials at a simulated altitude of 0 m, 2150 m (∼15.8% O 2 ) and 4300 m (∼11.7% O 2 ) in a normobaric chamber. Participants entered the chamber at 8am following a 12 h fast. A standardised breakfast was consumed inside the chamber at 1 h. One hour after breakfast, participants performed a 60 min treadmill walk at 50% of relative V˙O 2max . An ad-libitum buffet meal was consumed 1.5 h after exercise. Blood samples were collected prior to altitude exposure and at 60, 135, 195, 240 and 285 min. No trial based differences were observed in any appetite related measure before exercise. Post-exercise area under the curve values for acylated ghrelin, pancreatic polypeptide and composite appetite score were lower (all P < 0.05) at 4300 m compared with sea-level and 2150 m. There were no differences in glucagon-like peptide-1 between conditions (P = 0.895). Mean energy intake was lower at 4300 m (3728 ± 3179 kJ) compared with sea-level (7358 ± 1789 kJ; P = 0.007) and 2150 m (7390 ± 1226 kJ; P = 0.004). Proportional reliance on carbohydrate as a fuel was higher (P = 0.01) before breakfast but lower during (P = 0.02) and after exercise (P = 0.01) at 4300 m compared with sea-level. This study suggests that altitude-induced anorexia and a subsequent reduction in energy intake occurs after exercise during exposure to severe but not moderate simulated altitude. Acylated ghrelin concentrations may contribute to this effect., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Appetite and gastrointestinal hormones (GIHs) participate in energy homeostasis, feeding behavior and regulation of body weight. We demonstrated previously the superior effect of a hypocaloric diet regimen with lower meal frequency (B2) on body weight, hepatic fat content, insulin sensitivity and feelings of hunger compared to the same diet divided into six smaller meals a day (A6). Studies with isoenergetic diet regimens indicate that lower meal frequency should also have an effect on fasting and postprandial responses of GIHs. The aim of this secondary analysis was to explore the effect of two hypocaloric diet regimens on fasting levels of appetite and GIHs and on their postprandial responses after a standard meal. It was hypothesized that lower meal frequency in a reduced-energy regimen leading to greater body weight reduction and reduced hunger would be associated with decreased plasma concentrations of GIHs: gastric inhibitory peptide (GIP), glucagon-like peptide-1(GLP-1), peptide YY(PYY), pancreatic polypeptide (PP) and leptin and increased plasma concentration of ghrelin. The postprandial response of satiety hormones (GLP-1, PYY and PP) and postprandial suppression of ghrelin will be improved., Methods: In a randomized crossover study, 54 patients suffering from type 2 diabetes (T2D) underwent both regimens. The concentrations of GLP-1, GIP, PP, PYY, amylin, leptin and ghrelin were determined using multiplex immunoanalyses., Results: Fasting leptin and GIP decreased in response to both regimens with no difference between the treatments (p = 0.37 and p = 0.83, respectively). Fasting ghrelin decreased in A6 and increased in B2 (with difference between regimens p = 0.023). Fasting PP increased in B2with no significant difference between regimens (p = 0.17). Neither GLP-1 nor PYY did change in either regimen. The decrease in body weight correlated negatively with changes in fasting ghrelin (r = -0.4, p<0.043) and the postprandial reduction of ghrelin correlated positively with its fasting level (r = 0.9, p<0.001). The postprandial responses of GIHs and appetite hormones were similar after both diet regimens., Conclusions: Both hypocaloric diet regimens reduced fasting leptin and GIP and postprandial response of GIP comparably. The postprandial responses of GIHs and appetite hormones were similar after both diet regimens. Eating only breakfast and lunch increased fasting plasma ghrelin more than the same caloric restriction split into six meals. The changes in fasting ghrelin correlated negatively with the decrease in body weight. These results suggest that for type 2 diabetic patients on a hypocaloric diet, eating larger breakfast and lunch may be more efficient than six smaller meals during the day.

Gastroenteropancreatic neuroendocrine neoplam (GEP-NEN) is a rare group of tumors with its incidence rising significantly in recent decades. Because of the late presentation of the disease and limitations in conventional biomarkers, about 50% of GEP-NEN patients manifests advanced disease when diagnosed. Therefore, it is vital to identify circulating biomarkers which can not only be used for early diagnosis but also accurately evaluating the biological behavior of GEP-NEN. This review summarizes the advances of circulating biomarkers in diagnosing and evaluating efficacy of treatment in GEP-NEN. Well-known circulating biomarkers include chromogranin A (CgA), pancreastatin (PST), chromogranin B (CgB), neuron-specific enolase (NSE) and pancreatic peptide(PP). Novel biomarkers including circulating tumor cell(CTC), microRNA and NETest are promising biomarkers with potential clinical benefit, but further researches are needed before their clinical applications.

Glucagon-like peptide-1 (GLP-1, GLP-1 7-36amide ) and its sister peptide glucagon-like peptide 2 (GLP-2) influence numerous intestinal functions and GLP-2 greatly increases intestinal blood flow. We hypothesized that GLP-1 also stimulates intestinal blood flow and that this would impact on the overall digestive and cardiovascular effects of the hormone. To investigate the influence of GLP-1 receptor agonism on mesenteric and renal blood flow and cardiovascular parameters, we carried out a double-blinded randomized clinical trial. A total of eight healthy volunteers received high physiological subcutaneous injections of GLP-1, GLP-1 9-36 amide (bioactive metabolite), exenatide (stable GLP-1 agonist), or saline on four separate days. Blood flow in mesenteric, celiac, and renal arteries was measured by Doppler ultrasound. Blood pressure, heart rate, cardiac output, and stroke volume were measured continuously using an integrated system. Plasma was analyzed for glucose, GLP-1 (intact and total), exenatide and Pancreatic polypeptide (PP), and serum for insulin and C-peptide. Neither GLP-1, GLP-1 9-36 amide , exenatide nor saline elicited any changes in blood flow parameters in the mesenteric or renal arteries. GLP-1 significantly increased heart rate (two-way ANOVA, injection [ P  = 0.0162], time [ P  = 0.0038], and injection × time [ P  = 0.082]; Tukey post hoc GLP-1 vs. saline and GLP-1 9-36amide [ P  < 0.011]), and tended to increase cardiac output and decrease stroke volume compared to GLP-1 9-36 amide and saline. Blood pressures were not affected. As expected, glucose levels fell and insulin secretion increased after infusion of both GLP-1 and exenatide., (© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Background and Aim: Low-grade inflammation persists in patients with acute pancreatitis (AP) after hospital discharge, and is linked to metabolic disorders. Neuropeptide Y (NPY) is well recognized as an important mediator of inflammation in these patients but the role of the other two structurally similar peptides, pancreatic polypeptide (PP) and peptide YY (PYY), in inflammation has been sparsely investigated. The aim was to investigate the association between PYY, PP, NPY and circulating levels of innate cytokines in patients after AP., Methods: Fasting blood samples were collected to measure PYY (ng/mL), PP (ng/mL), NPY (pg/mL), interleukin-6 (IL-6) (ng/mL), monocyte chemoattractant protein (MCP) 1 (ng/mL), and tumour necrosis factor (TNF) α (ng/mL). Modified Poisson regression analysis and linear regression analyses were conducted. Age, sex, ethnicity, obesity, diabetes, aetiology, time from 1st attack of AP, recurrence, severity, physical activity, and smoking were adjusted for in several statistical models. P<0.05 was considered statistically significant., Results: A total of 93 patients were recruited. Peptide YY was significantly associated (p<0.001) with IL-6, MCP-1, and TNFα in the unadjusted and all adjusted models. Pancreatic polypeptide was significantly associated (p<0.001) with IL-6, MCP-1, and TNFα in the unadjusted and at least one adjusted model. Peptide YY and PP together contributed 22.2%, 72.7%, and 34.6% to the variance of IL-6, MCP-1, and TNFα, respectively. Neuropeptide Y was not significantly associated with any of the three cytokines., Conclusions: Peptide YY and PP are associated with circulating innate pro-inflammatory cytokines in patients after AP and cumulatively contribute to nearly half of the variance of IL-6, MCP-1, and TNFα. Future research is warranted to investigate the signaling pathways that underlie these associations., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: The changes in gastrointestinal hormones associated with pancreatic ductal adenocarcinoma (PDAC) in patients with impaired glucoregulation have yet to be evaluated. The aim of this study was to determine plasma concentrations of selected gastrointestinal hormones in PDAC patients with and without diabetes and to compare them with levels found in Type 2 diabetic patients without cancer., Methods: In this study we examined plasma concentrations of glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide 1 (GLP-1), pancreatic polypeptide (PP), peptide YY (PYY) and neuropeptide Y (NPY), and cytokines leptin and adiponectin in 94 patients with histologically confirmed PDAC. Thirty-nine patients with Type 2 diabetes without PDAC and 29 healthy individuals with no evidence of acute or chronic diseases were examined as controls., Results: Significantly lower plasma concentrations of GIP were found in PDAC patients with new-onset diabetes/prediabetes (n = 76), or in those with normal glucose regulation (n = 18), compared to patients with Type 2 diabetes without PDAC and controls (15.5 (3.7-64.5) or 6.5 (1.7-24.5) vs. 39.8 (15.1-104.7) and 28.8 (7.4-112.2) ng/L, p < 0.001); the same relationship was observed for PP (38.9 (10.2-147.9) or 28.1 (7.9-100.0) vs 89.1 (38.0-208.9) and 75.8 (30.1-190.6) ng/L, p < 0.01), respectively. The lowest levels of GIP and PP concentrations were found in PDAC patients with new-onset diabetes/prediabetes and weight loss > 2 kg (p < 0.001)., Conclusions: We conclude that GIP and PP plasma concentrations are lower in pancreatic cancer irrespective of the degree of glucose intolerance as compared to Type 2 diabetic patients and healthy controls. In new onset diabetes especially if associated with weight loss, these changes may represent a new clue for the diagnosis of PDAC., (Copyright © 2016 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Gastrointestinal (GI) hormonal peptides play a role in the development of gastrointestinal malignancies, and their abnormal levels may contribute to dysmotility. The aim of this study was to analyze plasma concentrations of enterohormones (motilin, ghrelin, gastrin and pancreatic polypeptide) and to verify if their abnormal levels may contribute to the severity of dyspeptic symptoms in colorectal cancer patients. The study included 60 patients with colorectal malignancies (22 men and 38 women), among them 30 individuals with colon cancers (group A) and 30 subjects with rectal tumors (group B). Fasting plasma levels of pancreatic polypeptide (PP), motilin, gastrin and ghrelin were determined by means of ELISA. The results were compared with the respective parameters of healthy volunteers. Colon cancer patients presented with significantly lower concentrations of ghrelin than the subjects with rectal tumors and healthy controls (156.8±86.7 vs. 260.2±87.6 vs. 258.4±94.2 pg/ml, p=0.02), as well as with significantly higher levels of PP (265.5±66.3 vs. 154.1±54.6 vs. 148.3±64.3 pg/ml, p=0.005). Also the levels of motilin turned out to be lower in colon cancer patients than in the subjects with rectal malignancies and healthy controls. No statistically significant intergroups differences were found in plasma levels of gastrin (388.2±98.6 vs. 475.6±88.7 vs. 428.2±91.2 pg/ml, p>0.05). Epigastric bloating was the most frequent dyspeptic symptom, reported by 63.3% and 40% of patients with colon and rectal tumors, respectively. Our findings imply that colon cancer patients may present with abnormal plasma levels of enterohormones significantly more often than individuals with rectal malignancies. Dysmotility observed in colon cancer patients may result not only from anticancer surgery, but also from abnormal release of enterohormones, induced either by neoplastic process or by changes within the autonomic nervous system.

Background and Objectives: Parkinson's disease (PD) patients experience several non-motor symptoms from the gastrointestinal tract that may partly be caused by parasympathetic deficiency. The pancreas is densely innervated by the vagus nerve, which mediates early meal-induced secretion of pancreatic polypeptide (PP). Early secretion after sham feeding has been validated as a marker of vagal integrity. Thus, the aim was to evaluate the ratio of increased PP plasma levels after sham feeding in PD and correlate findings with gastrointestinal transit time (GITT)., Methods: Twenty-five PD patients and 17 controls were included. PP, insulin, and blood glucose levels were measured before, during, and after sham feeding with white bread and chocolate spread. GITT was measured using radiopaque markers. Furthermore, faeces samples were analyzed for pancreatic elastase enzyme as a marker of exocrine pancreatic function., Results: PD patients showed significantly lower PP ratio levels after sham feeding, which was most pronounced at 10 minutes. No significant association was seen between attenuated PP response and GITT in PD patients. No between-group differences were seen in glucose or insulin levels over time, but PD patients showed generally lower insulin levels compared to controls. No difference was found in faeces pancreatic elastase., Conclusions: Early-to-moderate stage PD patients demonstrated significantly decreased PP response after sham feeding suggestive of vagal denervation.

Objective: The effect of physical activity on food intake regulation may be moderated by environmental temperature. The aim of the study was to determine the single and combined effects of metabolic activity and temperature on energy intake and its hormonal regulation., Methods: A randomized crossover study was conducted in the laboratory. Ten healthy and physically active young Afro-Caribbean men participated in four experimental sessions (rest at 22°C and 31°C and cycling at 60% of their maximal oxygen uptake at 22°C and 31°C, all for 40 min). Each test period was followed by a 30-min recovery period and then an ad libitum meal. The main outcome measures were energy balance, subjective appetite, and plasma pancreatic polypeptide (PP), cholecystokinin (CCK) and ghrelin concentrations., Results: Relative energy intake was significantly decreased whereas plasma PP was increased in the exercise conditions (p=0.004 and p=0.002, respectively). Postprandial levels of CCK were elevated only in the rest conditions. Exposure to heat induced a decrease in plasma ghrelin (p=0.031)., Conclusions: Exercise induced a short-term energy deficit. However, modifications in the hormonal regulation of food intake in response to short-term heat or heat and exercise exposure seem to be minor and did not induce changes in energy intake. This trial was registered at clinicaltrials.gov as NCT02157233., (Copyright © 2016. Published by Elsevier Inc.)

Objective: Pancreatic neuroendocrine tumours (PNETs) are the major source of disease-specific mortality in multiple endocrine neoplasia type 1 (MEN1) patients. Chromogranin A (CgA), pancreatic polypeptide (PP), glucagon and gastrin have some diagnostic value in sporadic PNETs, but there is very little evidence for their efficacy in diagnosing PNETs in MEN1 patients., Design: We performed a retrospective chart review of the existing MEN1 database in our institution., Patients: One hundred and thirteen patients were eligible for diagnostic value analysis of tumour markers. Patients were excluded if measurement of tumour markers was missing, either 3 months prior to PNET diagnosis (PNET patients) or prior to abdominal imaging (non-PNET patients)., Measurements: Clinicopathologic characteristics and of tumour marker measurements were analysed., Results: Of 293 confirmed MEN1 cases, 55 PNETs and 58 non-PNETs met inclusion criteria. The area under the curve (AUC) for CgA, PP, glucagon and gastrin in MEN1 cases was 59·5%, 64·1%, 77·0% and 75·9%, respectively. The AUC for the combination of CgA, PP and gastrin was 59·6%. PP, but not CgA, glucagon or gastrin was significantly associated with both age and PNET functional status (P = 0·0485 and 0·0188, respectively). No markers were significantly associated with sex, PNET size, tumour number, tumour location, American Joint Committee on Cancer (AJCC) stage, presence of lymph node metastasis, lymphovascular invasion or overall survival. CgA values were not significantly lower following PNET resection than pre-operatively (P = 0·554)., Conclusions: The value of blood markers for diagnosing PNETs in MEN1 patients is relatively low, even when used in combination., (© 2016 John Wiley & Sons Ltd.)

Abnormal glucose metabolism is present in almost 40% of patients after acute pancreatitis, but its pathophysiology has been poorly investigated. Pancreatic hormone derangements have been sparingly studied to date, and their relationship with abnormal glucose metabolism is largely unknown. The aim was to investigate the associations between pancreatic hormones and glucose metabolism after acute pancreatitis, including the effect of potential confounders. This was a cross-sectional study of 83 adult patients after acute pancreatitis. Fasting venous blood was collected from all patients and used for analysis of insulin, glucagon, pancreatic polypeptide, amylin, somatostatin, C-peptide, glucose, and hemoglobin A1c. Statistical analyses were conducted using the modified Poisson regression, multivariable linear regression, and Spearman's correlation. Age, sex, body mass index, recurrence of acute pancreatitis, duration from first attack, severity, and etiology were adjusted for. Increased insulin was significantly associated with abnormal glucose metabolism after acute pancreatitis, in both unadjusted (P = 0.038) and adjusted (P = 0.001) analyses. Patients with abnormal glucose metabolism also had significantly decreased pancreatic polypeptide (P = 0.001) and increased amylin (P = 0.047) in adjusted analyses. Somatostatin, C-peptide, and glucagon were not changed significantly in both unadjusted and adjusted analyses. Increased insulin resistance and reduced insulin clearance may be important components of hyperinsulinemic compensation in patients after acute pancreatitis. Increased amylin and reduced pancreatic polypeptide fasting levels characterize impaired glucose homeostasis. Clinical studies investigating islet-cell hormonal responses to mixed-nutrient meal testing and euglycemic-hyperinsulinemic clamps are now warranted for further insights into the role of pancreatic hormones in glucose metabolism derangements secondary to pancreatic diseases., (Copyright © 2016 the American Physiological Society.)

Unlabelled: Peripheral muscarinic acetylcholine receptors regulate insulin and glucagon release in rodents but their importance for similar roles in humans is unclear. Bethanechol, an acetylcholine analogue that does not cross the blood-brain barrier, was used to examine the role of peripheral muscarinic signaling on glucose homeostasis in humans with normal glucose tolerance (NGT; n = 10), impaired glucose tolerance (IGT; n = 11), and type 2 diabetes mellitus (T2DM; n = 9). Subjects received four liquid meal tolerance tests, each with a different dose of oral bethanechol (0, 50, 100, or 150 mg) given 60 min before a meal containing acetaminophen. Plasma pancreatic polypeptide (PP), glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), glucose, glucagon, C-peptide, and acetaminophen concentrations were measured. Insulin secretion rates (ISRs) were calculated from C-peptide levels. Acetaminophen and PP concentrations were surrogate markers for gastric emptying and cholinergic input to islets. The 150 mg dose of bethanechol increased the PP response 2-fold only in the IGT group, amplified GLP-1 release in the IGT and T2DM groups, and augmented the GIP response only in the NGT group. However, bethanechol did not alter ISRs or plasma glucose, glucagon, or acetaminophen concentrations in any group. Prior studies showed infusion of xenin-25, an intestinal peptide, delays gastric emptying and reduces GLP-1 release but not ISRs when normalized to plasma glucose levels. Analysis of archived plasma samples from this study showed xenin-25 amplified postprandial PP responses ~4-fold in subjects with NGT, IGT, and T2DM. Thus, increasing postprandial cholinergic input to islets augments insulin secretion in mice but not humans., Trial Registration: ClinicalTrials.gov NCT01434901.

The physiological control of appetite regulation involves circulating hormones with orexigenic (appetite-stimulating) and anorexigenic (appetite-inhibiting) properties that induce alterations in energy intake via perceptions of hunger and satiety. As the effectiveness of exercise to induce weight loss is a controversial topic, there is considerable interest in the effect of exercise on the appetite-regulating hormones such as acylated ghrelin, peptide YY (PYY), glucagon-like peptide-1 (GLP-1), and pancreatic polypeptide (PP). Research to date suggests short-term appetite regulation following a single exercise session is likely affected by decreases in acylated ghrelin and increases in PYY, GLP-1, and PP. Further, this exercise-induced response may be intensity-dependent. In an effort to guide future research, it is important to consider how exercise alters the circulating concentrations of these appetite-regulating hormones. Potential mechanisms include blood redistribution, sympathetic nervous system activity, gastrointestinal motility, cytokine release, free fatty acid concentrations, lactate production, and changes in plasma glucose and insulin concentrations. This review of relevant research suggests blood redistribution during exercise may be important for suppressing ghrelin, while other mechanisms involving cytokine release, changes in plasma glucose and insulin concentrations, SNS activity, and muscle metabolism likely mediate changes in the anorexigenic signals PYY and GLP-1. Overall, changes in appetite-regulating hormones following acute exercise appear to be intensity-dependent, with increasing intensity leading to a greater suppression of orexigenic signals and greater stimulation of anorexigenic signals. However, there is less research on how exercise-induced responses in appetite-regulating hormones differ between sexes or different age groups. A better understanding of how exercise intensity and workload affect appetite across the sexes and life stages will be a powerful tool in developing more successful strategies for managing weight., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Purpose: Gastro-entero-pancreatic neuroendocrine tumors (GEPNETs) are increasing in incidence, and accurate staging is important for selecting the appropriate treatment. (68)Ga-DOTATATE imaging is a promising approach for detecting GEPNETs and could help in selecting optimal therapeutic strategies. The aim of this study was to prospectively determine the clinical utility of (68)Ga-DOTATATE positron emission tomography (PET)/computed tomography (CT) in detecting unknown primary and metastatic GEPNETs., Patients and Methods: One hundred thirty-one patients were enrolled in a prospective study of patients undergoing (68)Ga-DOTATATE PET/CT, (111)In-pentetreotide single-photon emission computed tomography (SPECT)/CT and multiphasic CT scan, and/or magnetic resonance imaging in a blinded fashion with comprehensive biochemical testing. The primary outcome measure was the detection of lesions by each imaging study., Results: (68)Ga-DOTATATE PET/CT imaging detected 95.1% of lesions (95% CI, 92.4% to 96.8%) with an average maximum standardized uptake value of 65.4 ± 47 (range, 6.9 to 244), anatomic imaging detected 45.3% of lesions (95% CI, 37.9% to 52.9%), and (111)In-pentetreotide SPECT/CT detected 30.9% of lesions (95% CI, 25.0% to 37.5%), with a significant difference between imaging modalities (P < .001). In four of 14 patients (28.6%), (68)Ga-DOTATATE PET/CT found a previously unknown primary tumor, and detected primary GEPNET, lymph node, and distant metastases correctly in 72 of 113 lesions (63.7%) when compared with histopathology, with 22.1% and 38.9% detected by using (111)In-pentetreotide SPECT/CT and anatomic imaging, respectively. On the basis of findings with (68)Ga-DOTATATE PET/CT, 43 of 131 patients (32.8%) had a change in management recommendation. In patients with carcinoid symptoms but negative biochemical testing, (68)Ga-DOTATATE PET/CT detected lesions in 65.2% of patients, 40% of which were detected neither by anatomic imaging nor by (111)In-pentetreotide SPECT/CT., Conclusion: (68)Ga-DOTATATE PET/CT imaging provides important information for accurate staging of GEPNETs and selection of appropriate treatment interventions even in the absence of biochemical evidence of disease in symptomatic patients., (© 2015 by American Society of Clinical Oncology.)

Purpose: Exercise improves appetite regulation, but it is not known if premeal or postmeal exercise more effectively improves appetite regulation in individuals with type 2 diabetes. For the first time, this study compared how premeal and postmeal exercise alters appetite regulation in individuals with type 2 diabetes., Methods: Twelve obese individuals with type 2 diabetes performed 3 different trials, all in a random order, in which they consumed a dinner meal with the following: no resistance exercise (RE), premeal RE, or postmeal RE beginning 45 min after dinner. A visual analog scale was used to assess perceived hunger and fullness, and frequent blood samples were drawn for determination of acylated ghrelin, pancreatic polypeptide (PP), and peptide tyrosine tyrosine (PYY) concentrations., Results: Premeal RE increased premeal perceived fullness, reduced perceived hunger, and reduced acylated ghrelin concentrations compared with the no RE and postmeal RE trial (P < 0.05). In the postprandial period, both premeal and postmeal RE reduced perceived hunger compared with no RE, whereas only postmeal RE reduced postprandial perceived fullness (P < 0.05) compared with no RE. Premeal or postmeal RE did not alter PYY concentrations. In both the premeal and postprandial period, RE reduced PP concentrations compared with no RE (P < 0.05), but upon cessation of RE, PP concentrations rebounded to concentrations that were similar to no RE., Conclusions: Both premeal and postmeal RE reduced perceived hunger and increased perceived fullness, effects that may help control food intake and aid in weight management efforts in individuals with type 2 diabetes.

Calorie restriction is a common strategy for weight loss and management. Consumption of food and nutrients stimulates diet-induced thermogenesis (DIT), as well as pancreatic and gastrointestinal hormone secretion that may regulate energy metabolism. Yet, little is known about the impact of hypocaloric diets on energy metabolism-related parameters. In this study, we assessed the effects of hypocaloric diets on hormonal variance in relation to DIT in healthy adults. Ten healthy male adults were enrolled in a randomized crossover study comprising three meal trials. Each subject was given a meal of 200 (extremely hypocaloric), 400 (moderately hypocaloric), or 800 kcal (normocaloric). Postprandial blood variables and energy expenditure were measured for 4 h (after the 200- and 400-kcal meals) or 6 h (after the 800-kcal meal). DIT and postprandial changes in blood pancreatic peptide and ghrelin were significantly smaller after the extremely or moderately hypocaloric diet than after the normocaloric diet but were similar between the hypocaloric diets. Postprandial blood insulin, amylin, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide type-1 (GLP-1) increased in a calorie-dependent manner. Thermogenic efficiency (DIT per energy intake) was negatively correlated with the maximum blood level (Cmax) (p=0.01) and incremental area under the curve (p=0.01) of the blood GIP response. Calorie restriction thus leads to hormonal responses and lower DIT in healthy adults. Extreme calorie restriction, however, led to greater thermogenic efficiency compared with moderate calorie restriction. The postprandial GIP response may be a good predictor of postprandial thermogenic efficiency.

Neuroendocrine tumours (NETs) are rare tumours with an annual incidence in the population in a range of 2-5 new cases per 100,000 inhabitants. NETs are widely variable in terms of anatomical location, hormone production, clinical behaviour and syndromes they can cause. This article reviews the many localizations and clinical presentations of NETs with a main focus on clinical biomarkers and their use in medical practice., (© 2016 European Society of Endocrinology.)

Enteropancreatic hormone secretion is thought to include a cephalic phase, but the evidence in humans is ambiguous. We studied vagally induced gut hormone responses with and without muscarinic blockade in 10 glucose-clamped healthy men (age: 24.5 ± 0.6 yr, means ± SE; body mass index: 24.0 ± 0.5 kg/m(2); HbA1c: 5.1 ± 0.1%/31.4 ± 0.5 mmol/mol). Cephalic activation was elicited by modified sham feeding (MSF, aka "chew and spit") with or without atropine (1 mg bolus 45 min before MSF + 80 ng·kg(-1)·min(-1) for 2 h). To mimic incipient prandial glucose excursions, glucose levels were clamped at 6 mmol/l on all days. The meal stimulus for the MSF consisted of an appetizing breakfast. Participants (9/10) also had a 6 mmol/l glucose clamp without MSF. Pancreatic polypeptide (PP) levels rose from 6.3 ± 1.1 to 19.9 ± 6.8 pmol/l (means ± SE) in response to MSF and atropine lowered basal PP levels and abolished the MSF response. Neither insulin, C-peptide, glucose-dependent insulinotropic polypeptide (GIP), nor glucagon-like peptide-1 (GLP-1) levels changed in response to MSF or atropine. Glucagon and ghrelin levels were markedly attenuated by atropine prior to and during the clamp: at t = 105 min on the atropine (ATR) + clamp (CLA) + MSF compared with the saline (SAL) + CLA and SAL + CLA + MSF days; baseline-subtracted glucagon levels were -10.7 ± 1.1 vs. -4.0 ± 1.1 and -4.7 ± 1.9 pmol/l (means ± SE), P < 0.0001, respectively; corresponding baseline-subtracted ghrelin levels were 303 ± 36 vs. 39 ± 38 and 3.7 ± 21 pg/ml (means ± SE), P < 0.0001. Glucagon and ghrelin levels were unaffected by MSF. Despite adequate PP responses, a cephalic phase response was absent for insulin, glucagon, GLP-1, GIP, and ghrelin., (Copyright © 2016 the American Physiological Society.)

Background/aims: The aim of the study was to analyze the effect of celiac disease(CED) on the upper-gut motility and release of enteral hormones (ghrelin and pancreatic peptide (PP))., Materials and Methods: the study included 25 patients diagnosed with CED and 30 healthy controls. Gastric myoelectric activities (EGG) in a fasted and fed state were recorded. The plasma concentrations of ghrelin and PP were determined. R e s u l t s: CED patients presented in a fasted state a decreased percentage of normogastria 54.8 ± 24.5 vs. 86 ± 12.3%, p = 0.02 and slow wave coupling (SWC) 52.7 ± 13.4 vs. 77.4 ± 11.9%; p = 0.00001 with increased dominant power (DP) 11.6 ± 1.5 vs. 11.1 ± 1.1. Contrary to the controls, they did not show an improvement in the percentage of normogastria, DP and SWC when examined in a fed state (p 〈0.05). Furthermore, CED patients presented with significantly lower fasting plasma concentrations of ghrelin 156.8 ± 86.7 vs. 260.2 ± 87.6 pg/ml, p = 0.0002 and significantly higher fasting PP levels than did the controls 265.2 ± 306.3 vs. 54.1 ± 54.6 pg/ml, p = 0.0005. C o n c l u s i o n: CED affects gastric myoelectric activity (decreasing normogastria and coupling) and causes changes in fasting concentrations of enteral hormones (decrease in ghrelin and an increase in PP). Gastric myoelectric response to food is abolished in CED patients, probably due to the neurohormonal changes induced by primary inflammation associated with this disease.

Aliquots of serum or plasma samples are combined with stable isotope labeled internal standard. Pancreatic polypeptide (PP) and its truncated variant PP3-36 are enriched by incubation with anti-PP antibody conjugated to magnetic beads. Peptides are eluted from beads in acidic buffer and the samples analyzed using liquid chromatography coupled with tandem mass spectrometry. Instrumental analysis of PP and PP3-36 is performed using electrospray ionization ESI in positive ion mode and multiple reaction monitoring (MRM) acquisition.

Unlabelled: Hyperemesis gravidarum (HG) is described as unexplained excessive nausea and vomiting during pregnancy. Some gut hormones that regulate appetite may have important role in etiopathogenesis of HG and weight changes during pregnancy. In this study, levels of gut satiety hormones were evaluated in pregnant women with HG., Methods: This prospective case-control study was conducted in 30 women with HG and 30 healthy pregnant women without symptoms of HG. Fasting venous blood samples were taken from all subjects for measurement of plasma gut hormone levels; obestatin (pg/mL), peptide YY (PYY), pancreatic polypeptide (PP) and cholecystokinin (CCK)., Results: Plasma PYY and PP levels were significantly higher in HG group. The most important parameter in diagnosis of HG was plasma PP level. Simple use of PP level led to the diagnosis 91.1 % of HG cases correctly. The single most important parameter in the prediction of HG was also PP level., Conclusion: Anorexigenic gut hormones might have important role in etiopathogenesis of hyperemesis gravidarum and weight changes during pregnancy.

Obesity may protect against the nutritional consequences of short bowel syndrome. We hypothesized that rats preconditioned with an obesogenic diet would have better outcomes after surgical induction of short bowel syndrome compared to rats on regular chow. Rats were fed a high-fat diet or regular rat chow for six months, and then underwent 50% proximal, 50% distal, or sham enterectomy. Food intake, weight, and body composition were monitored before and for 4 weeks after surgery. The high-fat diet consistently produced obesity (>25% body fat). All procedures induced weight loss, but there was no discernable difference between resection vs. sham resection. Rats on the high-fat diet had a greater post-resection loss of body fat compared to rats on chow (36 vs. 26 g, respectively). There was a nonsignificant trend of less lean mass loss in the former compared to the latter rats (16 vs. 33 g, respectively). Enterectomy moderated serum ghrelin, GIP, PPY, insulin, and leptin. Intestinal adaptation was not different between obese vs. non-obese rats. Rats preconditioned with the high-fat diet may have had better retention of lean body mass after a surgical procedure compared to rats on chow. The effect of 50% enterectomy was less than expected.