peptide-yy and Pancreatitis

Peptide YY (PYY) orchestrates function of the gut and pancreas by regulating growth, digestion and absorption. In addition to its physiological role, PYY exhibits immune and antitrophic properties in the pancreas by decreasing cytokine and amylase release. Although the exact mechanism(s) of action are still not fully understood, PYY interacts at the acinar level with numerous intracellular transcription factors. In addition to ameliorating pancreatic inflammation, novel synthetic analogs of PYY have been developed that are potent inhibitors in the proliferation of pancreatic cancer. The present paper reviews our current findings with PYY and examines the therapeutic implications of its utility in treating inflammation and cancer.

Topics: Animals; Cell Division; Humans; Pancreatic Neoplasms; Pancreatitis; Peptide YY

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.. 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.. 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.. 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.

Topics: Acute Disease; Adult; Aged; Cytokines; Fasting; Female; Follow-Up Studies; Humans; Immunity, Innate; Male; Middle Aged; Neuropeptide Y; Pancreatic Polypeptide; Pancreatitis; Peptide YY

To investigate the factors associated with the circulating levels of oxyntomodulin in healthy individuals and individuals after an episode of acute pancreatitis (AP).. Blood samples were collected from all participants after an overnight fast and analyzed for 28 biomarkers. Participants also underwent comprehensive body composition analysis on a 3-T magnetic resonance imaging scanner. Regression analyses were done to investigate the associations between oxyntomodulin and the studied factors.. The study included 105 individuals who had a primary diagnosis of AP and 58 healthy individuals. Peptide YY (B coefficient, 0.094; 95% confidence interval [95% CI], 0.164-0.123), pancreatic polypeptide (0.048; 95% CI, 0.030-0.066), and leptin (0.394; 95% CI, 0.128-0.661) had significant associations with oxyntomodulin in healthy individuals. Peptide YY was the most prominent factor associated with oxyntomodulin, explaining 60% of its variance in health. Cholecystokinin (0.014; 95% CI, 0.010-0.018), amylin (-0.107; 95% CI, -0.192 to -0.021), and glycated hemoglobin (-0.761; 95% CI, -1.249 to -0.273) had significant associations with oxyntomodulin in individuals after AP. Cholecystokinin was the most prominent factor associated with oxyntomodulin, explaining 44% of its variance after AP.. Factors affecting the circulating levels of oxyntomodulin are different in health and after AP. These insights will enable the determination of populations that benefit from oxyntomodulin therapeutics in the future.

Topics: Acute Disease; Cholecystokinin; Humans; Oxyntomodulin; Pancreatitis; Peptide YY

The study was aimed to investigate gut hormone responses to mixed meal test in individuals with new-onset prediabetes or diabetes after acute pancreatitis (cases) compared with healthy controls, and the effect of body fat parameters. A total of 29 cases and 29 age- and sex-matched healthy controls were recruited. All participants were given standard mixed meal drink and blood samples were collected to measure dipeptidyl peptidase IV, gastric inhibitory peptide, glucagon like peptide-1, insulin, oxyntomodulin, and peptide YY. Body fat parameters were measured using magnetic resonance imaging. Repeated measures and linear regression analyses were conducted in unadjusted and adjusted models. Gastric inhibitory peptide levels were significantly higher whereas oxyntomodulin levels were significantly lower in cases compared with controls in both the unadjusted (p<0.001 and p<0.001, respectively) and adjusted (p<0.001 and p<0.001, respectively) models. In cases, liver fat % contributed up to 13.4% (vs. 2.9% in controls) to variance in circulating levels of gastric inhibitory peptide whereas body mass index - up to 20.8% (vs. 9.9% in controls) in circulating levels of oxyntomodulin. New-onset prediabetes/diabetes after acute pancreatitis is characterised by increased levels of gastric inhibitory peptide and decreased levels of oxyntomodulin. Further, liver fat % and body mass index appear to be the body fat parameters that contribute most significantly to gastric inhibitory peptide and oxyntomodulin levels, respectively.

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Female; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin; Magnetic Resonance Imaging; Male; Meals; Middle Aged; Oxyntomodulin; Pancreatitis; Peptide YY; Postprandial Period; Prediabetic State; Subcutaneous Fat

Pro-inflammatory cytokines, such as interleukin (IL)-6, tumour necrosis factor (TNF)α, and monocyte chemoattractant protein (MCP)-1, are often elevated in individuals after acute pancreatitis but what determines their levels is poorly understood. Gut hormones have emerged as possible modulators of inflammatory response. The aim was to investigate the associations between pro-inflammatory cytokines and a comprehensive panel of gut hormones after an episode of acute pancreatitis.. Fasting blood samples were collected to measure cytokines (IL-6, TNFα, and MCP-1) and gut hormones (cholecystokinin, gastric inhibitory peptide (GIP), ghrelin, glicentin, glucagon-like peptide-1, oxyntomodulin, peptide YY, secretin, and vasoactive intestinal peptide). A series of linear regression analyses was conducted and four statistical models were used to adjust for patient- and pancreatitis-related covariates.. A total of 83 individuals were recruited. GIP and peptide YY were significantly (p < 0.001) associated with IL-6, TNFα, MCP-1, consistently in all the four models. Every 1 ng/mL change in GIP resulted in a 16.2, 3.2, and 50.8% increase in IL-6, TNFα, and MCP-1, respectively, in the most adjusted model. Every 1 ng/mL change in peptide YY resulted in a 7.0, 2.4, and 32.1% increase in IL-6, TNFα, and MCP-1, respectively, in the most adjusted model. GIP independently contributed 29.0-36.5% and peptide YY - 17.4-48.9% to circulating levels of the studied pro-inflammatory cytokines. The other seven studied gut hormones did not show consistently significant associations with pro-inflammatory cytokines.. GIP and peptide YY appear to be involved in perpetuation of subclinical inflammation following an episode of acute pancreatitis, which is known to play an important role in the pathogenesis of blood glucose derangements. These findings advance the understanding of mechanisms underlying diabetes of the exocrine pancreas and have translational implications.

Topics: Acute Disease; Adult; Aged; Chemokine CCL2; Cross-Sectional Studies; Fasting; Female; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Humans; Hyperglycemia; Interleukin-6; Male; Middle Aged; Pancreatitis; Peptide YY; Pregnancy; Tumor Necrosis Factor-alpha

Peptide YY (PYY) orchestrates the functions of the gut and the pancreas by regulating growth, digestion and absorption. In addition to its physiological role, PYY exhibits immune and antitrophic properties in the pancreas by decreasing cytokine and amylase release. Although the exact mechanism(s) of action are still incompletely understood, PYY interacts at the acinar level with numerous intracellular transcription factors. In addition to ameliorating pancreatic inflammation, novel synthetic analogs of PYY have been developed that are potent inhibitors of pancreatic cancer proliferation, in vitro and in vivo. Additionally, PYY and its analogs have been shown to inhibit the growth of breast, esophagus, and gastric cancer in vitro. We, herein, plan to review some of the methods employed in the laboratory while investigating the utility of PYY in the treatment of inflammation and cancer.

Topics: Apoptosis; Blotting, Western; Cell Proliferation; Enzyme-Linked Immunosorbent Assay; Gene Expression Profiling; Humans; Oligonucleotide Array Sequence Analysis; Pancreatic Neoplasms; Pancreatitis; Peptide YY; Tumor Cells, Cultured

Cytokine activation in the pancreatitis induces local and systemic cellular damage. Transcription factors interferon regulatory factor-1 (IRF-1) and the tumor suppressor gene p53 collaborate to enhance p21 related cell cycle regulation during pathological disease progression. However, little is known about their role in the pancreas after cytokine challenge. Our laboratory has previously shown that TNF-alpha induces the binding of many transcription factors, including NF-kappa B, and treatment with the gut hormone, Peptide YY (PYY), ameliorates the effects. We hypothesized that TNF-alpha would induce IRF-1 and p53 protein binding in pancreatic acinar cells and that PYY would attenuate the effect.. Rat pancreatic acinar AR42J cells were treated with rat recombinant TNF-alpha (200 ng/ml). To verify that our model was inducing pancreatitis, alpha-amylase activity was measured in the cell culture supernatant by fluorescence spectroscopy. PYY [3-36] was added at 500 pM 30 min post-TNF treatment; cells were harvested at 2 h for extraction of nuclear protein. Transcription factor binding of IRF-1 and p53 were determined by protein/DNA array analysis using chemiluminescence detection, and relative spot densities were measured by densitometry. A two-fold increase or decrease in density was considered significant.. Amylase enzyme activity was significantly (P < 0.05) elevated in the TNF-alpha-treated cells by 2 h. Protein/DNA array analysis revealed significant up-regulation of both IRF-1 and p53 protein in nuclear extracts. Induction by TNF-alpha increased IRF-1 protein binding 3.5-fold, while binding levels of p53 protein increased six-fold. The addition of PYY to TNF-treated cells reduced IRF-1 and p53 binding to control levels.. We have shown for the first time that short-term exposure to TNF-alpha induces the binding activity of transcription factors IRF-1 and p53 in rat pancreatic acinar cells, and that addition of PYY reduces it. Regulation of transcription factor activity by PYY may have therapeutic potential in altering the progression of pancreatitis.

Topics: Acute Disease; Amylases; Animals; Cell Line; Interferon Regulatory Factor-1; Oligonucleotide Array Sequence Analysis; Pancreas, Exocrine; Pancreatitis; Peptide YY; Protein Binding; Rats; Transcription Factors; Tumor Necrosis Factor-alpha; Tumor Suppressor Protein p53

Acute pancreatitis (AP) is a disease characterized by inflammation. Nuclear factor (NF)-kappaB, Smad proteins, and the steroid hormone family peroxisome proliferator-activated receptors (PPARs) are involved in regulation of gene transcription during the disease process. Peptide YY (PYY), a gastrointestinal hormone, inhibits NF-kappaB translocation to acinar nuclei in tumor necrosis factor (TNF)-alpha-induced AP. We investigated TNF-alpha induction of Smad proteins, PPARalpha/gamma, and NF-kappaB by TNF-alpha, and hypothesized that PYY would attenuate this effect.. Rat acinar cells were treated with recombinant TNF-alpha (200 ng/mL). PYY (3 to 36) was added at 500 pM at 30 minutes after TNF-alpha treatment until cell harvest at 2 hours. Western blot analysis and intracellular staining of the p65 subunit of NF-kappaB were performed. NF-kappaB, Smad3/4, and PPARalpha/gamma binding activities were determined by protein/DNA array analysis and verified by electrophoretic-mobility shift assay and densitometry.. Cellular localization of NF-kappaB p65 showed nuclear staining within 2 hours, with controls stained in the cytoplasm. With PYY, p65 stained in the cytoplasm. Nuclear p65 was increased significantly (p < 0.05) by TNF-alpha at 2 hours and PYY reduced it. Array analysis revealed upregulation of NF-kappaB, PPARalpha/gamma, and Smad3/4 with TNF-alpha. TNF-alpha stimulated NF-kappaB activation sevenfold, and binding was enhanced (p < 0.05). PYY reduced NF-kappaB binding to control levels. PPAR binding increased 51% after TNF-alpha treatment and was reduced to 33% with PYY. Smad3/4 binding was increased (p < 0.05) above controls with TNF-alpha and PYY reduced it by 40%.. TNF-alpha increases early nuclear translocation of the p65 subunit of NF-kappaB in acinar cells. Exposure to TNF-alpha activates transcription factors NF-kappaB, Smad3/4, and PPARalpha/gamma. PYY reduces this activation. Treatment with PYY may have therapeutic potential in improving AP.

Topics: Acute Disease; Animals; Cell Line; DNA-Binding Proteins; Gastrointestinal Hormones; Models, Animal; NF-kappa B; Pancreas; Pancreatitis; Peptide YY; Rats; Receptors, Cytoplasmic and Nuclear; Smad Proteins; Trans-Activators; Transcription Factors; Translocation, Genetic; Tumor Necrosis Factor-alpha

Peptide YY (PYY), a gastrointestinal regulatory peptide, improves survival and histologic parameters in animal models of acute pancreatitis. Its effects on pancreatic cell growth and acute pancreatitis in pancreatic acinar and ductal cells are unknown. We hypothesized that PYY would affect cell growth and attenuate acute pancreatitis in pancreatic acinar and ductal cells in vitro.. Rat pancreatic acinar and ductal cells were cultured in the presence of 1) cerulein, a synthetic cholecystokinin analog that induces pancreatitis, 2) PYY, or 3) a combination group pretreated with PYY prior to addition of cerulein. Cell survival was measured at 48 h using MTT assay. Amylase secretion, as marker for pancreatitis, was measured at 48 h using an amylase activity assay. Statistical significance was calculated using analysis of variance and the Student's t test.. Peptide yy significantly increased cell growth and decreased amylase secretion compared with control and cerulein groups. Pretreatment with PYY significantly protected against the pancreatitis effects of cerulein.. We have shown for the first time that PYY has a mitogenic effect on pancreatic acinar and ductal cells in vitro. In addition, it directly protects against cerulein-induced pancreatitis. Its potential therapeutic benefit in acute pancreatitis would therefore be twofold: amelioration of the inflammatory process, and augmenting growth of normal pancreas to replace necrotic or apoptotic cell loss.

Topics: Acute Disease; Amylases; Animals; Cell Culture Techniques; Cell Division; Cell Survival; Ceruletide; Gastrointestinal Agents; Mitogens; Pancreas; Pancreatitis; Peptide YY; Rats

In patients with chronic pancreatitis (CP) the relation among exocrine pancreatic secretion, gastrointestinal hormone release, and motility is disturbed. We studied digestive and interdigestive antroduodenal motility and postprandial gut hormone release in 26 patients with CP. Fifteen of these patients had pancreatic insufficiency (PI) established by urinary para-aminobenzoic acid test and fecal fat excretion. Antroduodenal motility was recorded after ingestion of a mixed liquid meal. The effect of pancreatic enzyme supplementation was studied in 8 of the 15 CP patients with PI. The duration of the postprandial antroduodenal motor pattern was significantly (P < 0.01) prolonged in CP patients (324 +/- 20 min) compared with controls (215 +/- 19 min). Antral motility indexes in the first hour after meal ingestion were significantly reduced in CP patients. The interdigestive migrating motor complex cycle length was significantly (P < 0.01) shorter in CP patients (90 +/- 8 min) compared with controls (129 +/- 8 min). These abnormalities were more pronounced in CP patients with exocrine PI. After supplementation of pancreatic enzymes, these alterations in motility reverted toward normal. Digestive and interdigestive antroduodenal motility are abnormal in patients with CP but significantly different from controls only in those with exocrine PI. These abnormalities in antroduodenal motility in CP are related to maldigestion.

Topics: Adult; Aged; Cholecystokinin; Chronic Disease; Diabetes Mellitus, Type 1; Digestion; Duodenum; Eating; Enzymes; Female; Gastrointestinal Motility; Humans; Islets of Langerhans; Male; Middle Aged; Pancreas; Pancreatic Polypeptide; Pancreatitis; Peptide YY

Peptide YY (PYY), a known inhibitor of both pancreatic secretion and the release of cholecystokinin (CCK), may play a role in the pathophysiology of acute pancreatitis (AP). Supramaximal stimulation of the pancreas with CCK, or its analogue cerulein, induces edematous AP. We previously documented significant decreases in plasma PYY in sodium taurocholate-induced AP in the anesthetized pig, with exogenous PYY suppressing plasma amylase activity. We hypothesized that PYY may ameliorate cerulein-induced pancreatic injury in a conscious animal model. Thirty-two male Sprague-Dawley rats underwent chronic cannulation of the jugular vein and carotid artery for drug infusion and blood sampling. The animals were allowed to recover from anesthesia for a minimum of 16 hours, after which they were randomized to one of four (n = 8) treatment groups (cerulein 10 micrograms/kg/h, PYY 400 pmol/kg/h, cerulein+PYY, and control-saline 2 mL/kg/h). All treatments were administered by intravenous infusion over the first 6 hours of the experiment. Blood samples were taken prior to infusion and at 1, 3, 6, 9, and 24 hours into the study; the rats were then killed and the pancreata removed for weighing and histologic examination. All pancreatic specimens were graded in a blinded fashion for vacuolization, edema, inflammation, and necrosis. The mean basal plasma amylase level for all animals was 1,171 +/- 100 U/L and was not significantly different between groups. Infusion of cerulein resulted in significant increases in plasma amylase levels at 3, 6, 9, and 24 hours (4,827 +/- 1,022 U/L at 24 hours). In the group receiving both cerulein and PYY, the hyperamylasemia was attenuated with a return to basal values at 24 hours (1,206 +/- 103 U/L). There was significant pancreatic weight gain (1.99 +/- 0.07 g versus 1.03 +/- 0.07 g) and a worsened histologic picture in cerulein-treated animals compared with control animals (worsened edema, necrosis, and vacuolization). The addition of PYY to cerulein resulted in significantly lower pancreatic weight (1.27 +/- 0.11 g) than in the non-PYY-treated rats receiving cerulein. Pancreatic weight was not significantly different in this group compared with the control group. In addition, pancreatic histologic findings were significantly improved in those rats receiving PYY (decreased vacuolization and necrosis). Amylase levels, pancreatic weight, and morphologic findings were not significantly changed compared with basal values in the control or P

Topics: Amylases; Animals; Ceruletide; Gastrointestinal Hormones; Male; Organ Size; Pancreas; Pancreatitis; Peptide YY; Peptides; Rats; Rats, Sprague-Dawley

Plasma concentrations of peptide YY (PYY), a newly isolated peptide produced by ileal and colonic endocrine cells, were measured in several groups of patients with digestive disorders after a standardized normal breakfast. Peptide YY levels were found to be grossly elevated in patients with steatorrhea due to small intestinal mucosal atrophy (tropical sprue). Basal levels in these patients were 79 +/- 18 pM, which was nearly 10-fold higher than those seen in healthy controls (8.5 +/- 0.8 pM). Patients with steatorrhea due to chronic destructive pancreatitis also had substantially increased basal PYY levels (47.5 +/- 6.3 pM), and their postprandial response was also greater than that of normal subjects. Moderately elevated plasma PYY concentrations were seen in patients with inflammatory bowel disease and patients recovering from acute infective diarrhea. In contrast, patients with diverticular disease, duodenal ulcer, and functional bowel disease had normal PYY responses. These changes in the secretion of PYY responses. These changes in the secretion, may shed light on the physiologic role of this newly discovered peptide and on intestinal adaptation to common digestive disorders.

Topics: Adult; Aged; Celiac Disease; Chromatography, Gel; Colitis, Ulcerative; Colonic Diseases, Functional; Crohn Disease; Diarrhea; Diverticulitis; Duodenal Ulcer; Female; Food; Gastrointestinal Diseases; Gastrointestinal Hormones; Humans; Intestinal Absorption; Male; Middle Aged; Pancreatitis; Peptide YY; Peptides; Radioimmunoassay