Pancreatic Polypeptide Secretion Research Articles

Obesity is associated with impaired postprandial pancreatic polypeptide secretion.

This study aims to compare the levels of serum pancreatic polypeptide (PP), insulin (INS), C-peptide (C-P), and glucagon (GCG) before and after glucose stimulation in type 2 diabetes mellitus (T2DM) patients with different body mass indexes (BMI), analyze the relevant factors associated with PP secretion, and further investigate the role of PP in the development of obesity and diabetes. Data were collected from 83 patients from the hospital. The subjects were divided into normal-weight group, overweight group, and obese group according to their BMI. All subjects were tested with the standard bread meal test (SBMT). PP and relevant parameters were measured, and the area under the curve (AUC) was calculated after 120min of SBMT. AUCpp (AUC of PP) was used as the dependent variable, and the potential influencing factors were used as independent variables for multiple linear regression analysis. The obese and overweight groups had significantly lower PP secretion than the normal-weight group (485.95 pg·h/ml, 95% CI 76.16-895.74, p = 0.021; 664.61 pg·h/ml, 95% CI 285.46-1043.77, p = 0.001) at 60min postprandial. PP secretion in the obese and overweight groups was also significantly lower than that in the normal-weight group (520.07 pg·h/ml, 95% CI 186.58-853.56, p = 0.003; 467.62 pg·h/ml, 95% CI 159.06-776.18, p = 0.003) at 120min postprandial. AUCpp was negatively associated with BMI (r = -0.260, p = 0.017) and positively associated with AUCGCG (r = 0.501, p< 0.001). Multiple linear regression analysis showed that there was a linear correlation between AUCGCG, BMI, and AUCpp (p< 0.001, p = 0.008). The regression equation was calculated as follows: AUCpp = 1772.255-39.65 × BMI + 0.957 × AUCGCG (R2=54.1%, p< 0.001). Compared with normal-weight subjects, overweight and obese subjects had impaired PP secretion after glucose stimulation. In T2DM patients, PP secretion was mainly affected by BMI and GCG. The Ethics Committee of the Affiliated Hospital of Qingdao University. http://www.chictr.org.cn, identifier ChiCTR2100047486.

Establishment of an enzyme-linked immunosorbent assay for mouse pancreatic polypeptide clarifies the regulatory mechanism of its secretion from pancreatic γ cells.

Pancreatic polypeptide (PP), secreted from γ cells of the islets of Langerhans, is a 36 amino-acid peptide encoded by the Ppy gene. Although previous studies have reported that PP causes a decrease in appetite, the molecular mechanism that regulates PP secretion has not been fully elucidated. Lack of understanding of the regulatory mechanism of PP secretion may be partially owing to the lack of assay systems that can specifically detect PP. We recently developed the mouse monoclonal antibody 23-2D3 that specifically recognizes PP. In the present study, we developed a sandwich enzyme-linked immunosorbent assay for the measurement of mouse PP, and directly monitored intracellular Ca2+ concentrations in Ppy-expressing cells from a newly developed reporter mouse. Using these systems, we identified agonists, such as carbachol and glucose-dependent insulinotropic polypeptide (GIP), which stimulate PP secretion. We further demonstrated that, unlike the case of GIP-induced insulin secretion from β cells, there is a unique mechanism by which PP secretion is triggered by an increase in intracellular Ca2+ concentrations via voltage-dependent calcium channels even in low-glucose conditions.

Impaired glucose tolerance is associated with enhanced postprandial pancreatic polypeptide secretion

BackgroundThe purpose of this study is to compare serum pancreatic polypeptide (PP), insulin, C‐peptide, and glucagon in different glucose tolerance stages; analyze the influencing factors of PP secretion; and further explore the role of PP in the pathogenesis of diabetes mellitus.MethodsData were collected from 100 subjects from hospital. According to the results of oral glucose tolerance test (OGTT), the subjects were divided into a normal glucose tolerance (NGT) group, an impaired glucose regulation (IGR) group, and a newly diagnosed type 2 diabetes mellitus (T2DM) group. PP and the related parameters were measured, and the area under the curve (AUC) 120 min after OGTT was calculated. AUCpp (AUC of PP) was used as the dependent variable and the potentially influencing factors were used as the independent variable for multiple linear regression analysis.ResultsPostprandial 60 min PP in the IGR group was higher than those in the NGT group (2973.80 [±547.49] pg·h/mL vs 2663.55 [±594.89] pg·h/mL, p < 0.05). AUCpp was significantly higher in the IGR group (428.76 pg·h/mL, 95% confidence interval [CI] [41.06 –816.46], p = 0.031) and newly diagnosed T2DM group (404.35 pg·h/mL, 95% CI [5.37–803.33], p = 0.047) than in the NGT group. AUCpp was negatively correlated with body mass index (BMI) (r = −0.235, p = 0.038) and positively correlated with postprandial 60 min blood glucose (r = 0.370, p = 0.001) and AUCbg (AUC of blood glucose) (r = 0.323, p = 0.007). Multiple linear regression analysis indicated that there was a linear correlation between BMI, AUCbg, and AUCpp (p = 0.004, p = 0.001), and the regression equation was calculated as: AUCpp = 6592.272 + 86.275 × AUCbg‐95.291 × BMI (R2 = 12.7%, p < 0.05).ConclusionsCompared with NGT subjects, IGR and T2DM patients have an enhanced postprandial PP secretion. In T2DMs, the secretion of PP is mainly affected by BMI and blood glucose.

GPR120 Regulates Pancreatic Polypeptide Secretion From Male Mouse Islets via PLC-Mediated Calcium Mobilization.

The free fatty acid receptor G protein-coupled receptor 120 (GPR120) is expressed in pancreatic islets, but its specific cell distribution and function have not been fully established. In this study, a GPR120-IRES-EGFP knockin (KI) mouse was generated to identify GPR120-expressing cells with enhanced green fluorescence proteins (EGFP). EGFP-positive cells collected from KI mouse islets by flow cytometry had a significantly higher expression of pancreatic polypeptide (PP) evidenced by reverse transcriptase (RT)-quantitative polymerase chain reaction (qPCR). Single-cell RT-PCR and immunocytochemical double staining also demonstrated the coexpression of GPR120 with PP in mouse islets. The GPR120-specific agonist TUG-891 significantly increased plasma PP levels in mice. TUG-891 significantly increased PP levels in islet medium in vitro, which was markedly attenuated by GPR120 small interfering RNA treatment. TUG-891-stimulated PP secretion in islets was fully blocked by pretreatment with YM-254890 (a Gq protein inhibitor), U73122 (a phospholipase C inhibitor), or thapsigargin (an inducer of endoplasmic reticulum Ca2+ depletion), respectively. TUG-891 triggered the increase in intracellular free Ca2+ concentrations ([Ca2+]i) in PP cells, which was also eliminated by YM-254890, U73122, or thapsigargin. GPR120 gene expression was significantly reduced in islets of high-fat diet (HFD)-induced obese mice. TUG-891-stimulated PP secretion was also significantly diminished in vivo and in vitro in HFD-induced obese mice compared with that in normal-chow diet control mice. In summary, this study demonstrated that GPR120 is expressed in mouse islet PP cells and GPR120 activation stimulated PP secretion via the Gq/PLC-Ca2+ signaling pathway in normal-chow diet mice but with diminished effects in HFD-induced obese mice.

Glucose-Dependent Insulinotropic Polypeptide Is a Pancreatic Polypeptide Secretagogue in Humans.

Glucose-dependent insulinotropic polypeptide (GIP) has been suggested to stimulate the secretion of pancreatic polypeptide (PP), an islet hormone thought to regulate gut motility, appetite, and glycemia. To determine whether human GIP1-42 (hGIP) stimulates PP secretion. As glycemia modulates the secretion of PP, we measured plasma PP concentrations from 2 studies in healthy men (n = 10) and in patients with type 2 diabetes (T2D) (n = 12), where hGIP1-42 had been administered intravenously during fasting glycemia, hyperglycemia (12 mmol/L), and insulin-induced hypoglycemia (targets: 2.5 mmol/L [healthy]; 3.5 mmol/L [T2D]). Porcine GIP1-42 (pGIP) was also infused intra-arterially in isolated porcine pancreata (n = 4). Mean fasting plasma glucose concentrations were approximately 5 mmol/L (healthy) and approximately 8 mmol/L (T2D). At fasting glycemia, PP concentrations were higher during intravenous hGIP1-42 infusion compared with saline in healthy men (mean [standard error of the mean, SEM], net incremental areas under the curves (iAUCs)[0-30min], 403 [116] vs -6 [57] pmol/L × min; P = 0.004) and in patients with T2D (905 [177] vs -96 [86] pmol/L × min; P = 0.009). During hyperglycemic clamping, mean [SEM] PP concentrations were significantly higher during hGIP1-42 infusion compared with saline in patients with T2D (771 [160] vs -183 [117] pmol/L × min; P = 0.001), but not in healthy individuals (-8 [86] vs -57 [53] pmol/L × min; P = 0.69). When plasma glucose levels were declining in response to exogenous insulin, mean [SEM] PP concentrations were higher during hGIP1-42 infusion compared with saline in healthy individuals (294 [88] vs -82 [53] pmol/L × min; P = 0.0025), but not significantly higher in patients with T2D (586 [314] vs -120 [53]; P = 0.070). At target hypoglycemia, PP levels surged in both groups during both hGIP1-42 and saline infusions. In isolated pancreata, pGIP1-42 increased mean [SEM] PP output in the pancreatic venous effluent (baseline vs infusion, 24[5] vs 79 [16] pmol/min x min; P = 0.044). GIP1-42 increases plasma PP secretion in healthy individuals, patients with T2D, and isolated porcine pancreata. Hyperglycemia blunts the stimulatory effect of hGIP1-42 in healthy individuals, but not in patients with T2D.

Utility of the plasma pancreatic polypeptide response to modified sham feeding in diabetic gastroenteropathy and non-ulcer dyspepsia.

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). 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. 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 (≥20pg/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. 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.

Structure and function of the exocrine pancreas in patients with type 1 diabetes.

In the last 10years, several studies have shown that the pancreas of patients with type 1 diabetes (T1D), and even of subjects at risk for T1D, was smaller than the pancreas from healthy subjects. This arose the question of the relationships between the endocrine and exocrine parts of the pancreas in T1D pathogenesis. Our review underlines that histological anomalies of the exocrine pancreas are common in patients with T1D: intralobular and interacinar fibrosis, acinar atrophy, fatty infiltration, leucocytic infiltration, and pancreatic arteriosclerosis are all frequent observations. Moreover, 25% to 75% of adult patients with T1D present with pancreatic exocrine dysfunction. Our review summarizes the putative causal factors for these structural and functional anomalies, including: 1/ alterations of insulin, glucagon, somatostatin and pancreatic polypeptide secretion, 2/ global pancreatic inflammation 3/ autoimmunity targeting the exocrine pancreas, 4/ vascular and neural abnormalities, and 5/ the putative involvement of pancreatic stellate cells. These observations have also given rise to new theories on T1D: the primary event of T1D pathogenesis could be non-specific, e.g bacterial or viral or chemical, resulting in global pancreatic inflammation, which in turn could cause beta-cell predominant destruction by the immune system. Finally, this review emphasizes that it is advisable to evaluate pancreatic exocrine function in patients with T1D presenting with gastro-intestinal complaints, as a clinical trial has shown that pancreatic enzymes replacement therapy can reduce the frequency of hypoglycemia and thus might improve quality of life in subjects with T1D and exocrine failure.

MON-332 Metastatic Pancreatic Neuroendocrine Tumor: A Very Rare Cause of Ectopic ACTH Production (ACTHoma)

Introduction Ectopic ACTH syndrome (EAS)is responsible for 10% of Cushing’s syndrome. Multiple tumors, most commonly small cell carcinoma of lung are associated with EAS. Pancreatic neuroendocrine tumors (pNETs) are usually associated with secretion of pancreatic polypeptide, gastrinomas, insulinomas, glucagonomas and vasoactive intestinal peptide (VIPomas). EAS or “ACTHomas” are rarely associated with pNETs. Case 76y/o man with ah/o hairy cell leukemia, bladder cancer (both in remission), and stage M1 unresectable pNET tumor with liver metastases presented with generalized weakness. Discovery of his pNET was incidentally noted during routine surveillance with CT monitoring following successful bladder cancer treatment six years ago. Treatment of his pNET initially began with Everolimus and then switched to Lanreotide injections. No evidence of Cushing’s Syndrome at the time of diagnosis. The lesions remained stable in size and patient was doing well. Physical exam was notable for lethargy, frailty, and absence of Cushingoid features. Labs showed serum glucose 231mg/dl, sodium 141mEq/L, potassium 2.4mEq/L, AM cortisol 116 ug/dL (range 6.7-22.6ug/dl) and ACTH was 209.6pg/mL (range 7.2-63.3pg/mL). Renin-aldosterone levels were normal. Cortisol level did not suppress with low dose or high dose dexamethasone. His hospital course was significant for persistent hypokalemia despite aggressive supplementation, difficult to control blood glucose, and worsening kidney function. EAS with pNET is very refractory to management and may be rapidly progressive. They occasionally demonstrate classic manifestations of Cushingoid features. However, they often lack the traditional phenotypic features of Cushing syndrome. Treatment options for EAS in the setting of an unresectable tumor include medical management versus bilateral adrenalectomy. Metyrapone, a cortisol synthesis inhibitor, can be an effective therapy. Ketoconazole, an antifungal that inhibits cortisol production can be an alternative, but may need weeks to achieve control. Etomodate can rapidly reduce cortisol levels, but requires intensive care monitoring. Somatostatin analogs may be effective by reducing ectopic ACTH production and stabilize tumor growth. Medical versus surgical management of Cushing’s syndrome was discussed with the patient and family, but they opted for hospice care. Conclusion We present a case of pNET associated with late onset EAS without obvious signs of Cushing’s syndrome. To our knowledge this late presentation of ACTH secretion in the setting of a stable pNET has not been previously reported in the literature. EAS due to pNET is rare and metabolic abnormalities can occur rapidly without other Cushingoid manifestations which can pose significant management challenges. High index of suspicion is required for early diagnosis. Due to the aggressive nature, the 5 years survival rate is 16%.

Dose Effect of Whey Protein on Gut Hormone Responses in Pre-Diabetics and Type 2 Diabetics

BACKGROUND: GLP-1 and GIP have been shown to increase following a 50 g dose of whey protein prior to a high glycemic load in type 2 diabetics. However, this increase is reduced in diabetics compared to healthy individuals. Pancreatic polypeptide (PP) and peptide tyrosine tyrosine (PYY) also increase, while ghrelin decreases after the consumption of whey protein; however, it is not known if a similar hormone response occurs with a lower dose of whey protein consumption prior to a glycemic load or if there is a dose effect. Our hypothesis was that 20 g and 30 g of whey protein would elicit an increase in GLP-1, GIP, PP, and PYY and decrease ghrelin in a dose dependent manner. PURPOSE: The purpose of this study was to examine the effect of two different doses of whey protein ingested 30 min prior to a 50 g OGTT on gut hormone and incretin response. METHODS: Nine diabetic and pre-diabetic participants (n=9, mean ± SD; age: 64.3 + 8.1 yrs; BMI: 29.4 + 6.0 kg/m2; HbA1c: 6.4 + 0.6%) completed three trials. The randomly assigned trials consisted of: ingestion of 250ml of water (CON); 250 ml of water + 20 g whey (20g); 250ml of water + 30 g whey (30g), prior to completing a 50 g OGTT. Blood was collected at -30, 0, 15, 30, 60, 90, 120, and 150 min for the measurement of GIP, GLP-1, ghrelin, PP, and PYY. The whey protein mixture was administered immediately following the -30 min and the 50 g OGTT began immediately after the 0 min blood draw. Metabolites were measured using multiplex fluorescent detection. One- way repeated measure ANOVA was used for statistical analysis for each dependent variable (P < 0.05). RESULTS: 20g and 30g of whey protein significantly increased integrated area under the curve (AUC) of GIP 32% and 38% compared to CON. 30g significantly decreased ghrelin AUC -13.9% and -20% compared to 20g and CON. 30g significantly increased PP AUC 28% compared to CON only. There were no differences in ghrelin and PP AUC between 20g and CON. There were no significant differences for GLP-1 and PYY between all trials. CONCLUSION: 30 g of whey protein prior to a glucose challenge increased the secretion of GIP and PP and decreased ghrelin in type 2 and pre-diabetics. There seems to be a dose affect relationship between whey, ghrelin, and PP. 30 g of whey preload may induce insulinotropic and satiety effects stemming from GIP, PP, and ghrelin responses in type 2 and pre-diabetics.

Cholinergic signaling mediates the effects of xenin-25 on secretion of pancreatic polypeptide but not insulin or glucagon in humans with impaired glucose tolerance.

We previously demonstrated that infusion of an intestinal peptide called xenin-25 (Xen) amplifies the effects of glucose-dependent insulinotropic polypeptide (GIP) on insulin secretion rates (ISRs) and plasma glucagon levels in humans. However, these effects of Xen, but not GIP, were blunted in humans with type 2 diabetes. Thus, Xen rather than GIP signaling to islets fails early during development of type 2 diabetes. The current crossover study determines if cholinergic signaling relays the effects of Xen on insulin and glucagon release in humans as in mice. Fasted subjects with impaired glucose tolerance were studied. On eight separate occasions, each person underwent a single graded glucose infusion- two each with infusion of albumin, Xen, GIP, and GIP plus Xen. Each infusate was administered ± atropine. Heart rate and plasma glucose, insulin, C-peptide, glucagon, and pancreatic polypeptide (PP) levels were measured. ISRs were calculated from C-peptide levels. All peptides profoundly increased PP responses. From 0 to 40 min, peptide(s) infusions had little effect on plasma glucose concentrations. However, GIP, but not Xen, rapidly and transiently increased ISRs and glucagon levels. Both responses were further amplified when Xen was co-administered with GIP. From 40 to 240 min, glucose levels and ISRs continually increased while glucagon concentrations declined, regardless of infusate. Atropine increased resting heart rate and blocked all PP responses but did not affect ISRs or plasma glucagon levels during any of the peptide infusions. Thus, cholinergic signaling mediates the effects of Xen on insulin and glucagon release in mice but not humans.

The role of pancreatic polypeptide in pancreatic diseases.

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.

Pancreatic Polypeptide in Parkinson's Disease: A Potential Marker of Parasympathetic Denervation.

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). 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. 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. Early-to-moderate stage PD patients demonstrated significantly decreased PP response after sham feeding suggestive of vagal denervation.

Pancreatic Polypeptide: Biologically Active Neuropeptide and their Clinical Significance

Imbalances in normal regulation of food intake can cause obesity and related disorders. Pancreatic polypeptide (PP) share considerable amino acid sequence homology act as a robust anorexigenic hormone effectively modulates food intake and energy homeostasis, thus potentially aiding anti-obesity therapeutics. They are found in widely disparate locations, including the pancreas (PP), the distal gut (PYY), and the central nervous system (NPY). Intra-gastric and intra-intestinal infusion of nutrients stimulate PP secretion from the gastrointestinal tract, in turn that causes vagal stimulation and exerts complex actions via the neuropeptide Y4 receptor (Family of G-protein coupled Receptors) in arcuate nucleus of the hypothalamus, there by subsequently activating key hypothalamic nuclei and dorsal vagal complex of the brainstem to influence energy homeostasis and body composition. In this review our efforts have been devoted to summarize the detail about the pancreatic polypeptide their functions and mechanisms.

Identification and characterization of a phospholipase A1 activity type three secreted protein, PP_ExoU from Pseudomonas plecoglossicida NB2011, the causative agent of visceral granulomas disease in large yellow croaker (Larimichthys crocea).

Pseudomonas plecoglossicida NB2011, the causative agent of visceral granulomas disease in farmed Larimichthys crocea in China, encodes a predicted type three effector PP_ExoU, a homolog of the cytotoxin ExoU of Pseudomonas aeruginosa. In this study, secretion of PP_ExoU was tested in various broth, the protein was expressed with the pET30a prokaryotic system, the phospholipase A (PLA) activity of the recombinant protein was determined with fluorogenic phospholipid substrates, fusion expression with green fluorescent protein in transfected HeLa cells was investigated, and the lactate dehydrogenase (LDH) level was measured. The results showed the protein was type three secreted in several media; the recombinant protein displayed significant PLA1 activity with ubiquitin. Fluorescence was observed on the cell membrane and scattered in the cytoplasm of HeLa cells expressing catalytic wild-type PP_ExoU, blebbing and stretching developed in the cell membranes indicating of membrane damage. Fluorescence scattered in the cytoplasm of cells expressing the catalytic inactive protein. A significant LDH level was detected in HeLa cells expressing wild-type PP_exoU, but not in the Ser/Asp-mutated protein, suggestion mutation of predicted catalytic residues abolished the PLA activity. This is the first report on the function of a secreted type three protein from P.plecoglossicida.

Central GIP signaling stimulates peripheral GIP release and promotes insulin and pancreatic polypeptide secretion in nonhuman primates.

Glucose-dependent insulinotropic polypeptide (GIP) has important actions on whole body metabolic function. GIP and its receptor are also present in the central nervous system and have been linked to neurotrophic actions. Metabolic effects of central nervous system GIP signaling have not been reported. We investigated whether centrally administered GIP could increase peripheral plasma GIP concentrations and influence the metabolic response to a mixed macronutrient meal in nonhuman primates. An infusion and sampling system was developed to enable continuous intracerebroventricular (ICV) infusions with serial venous sampling in conscious nonhuman primates. Male baboons (Papio sp.) that were healthy and had normal body weights (28.9 ± 2.1 kg) were studied (n = 3). Animals were randomized to receive continuous ICV infusions of GIP (20 pmol·kg-1·h-1) or vehicle before and over the course of a 300-min mixed meal test (15 kcal/kg, 1.5g glucose/kg) on two occasions. A significant increase in plasma GIP concentration was observed under ICV GIP infusion (66.5 ± 8.0 vs. 680.6 ± 412.8 pg/ml, P = 0.04) before administration of the mixed meal. Increases in postprandial, but not fasted, insulin (P = 0.01) and pancreatic polypeptide (P = 0.04) were also observed under ICV GIP. Effects of ICV GIP on fasted or postprandial glucagon, glucose, triglyceride, and free fatty acids were not observed. Our data demonstrate that central GIP signaling can promote increased plasma GIP concentrations independent of nutrient stimulation and increase insulin and pancreatic polypeptide responses to a mixed meal.

Pancreatic polypeptide responses to isoglycemic oral and intravenous glucose in humans with and without intact vagal innervation

Abstract Secretion of pancreatic polypeptide (PP) from the pancreatic PP cells is controlled partly by vagal mechanisms. Release is stimulated by cephalic stimulation and enteral but not parenteral nutrients. Ambient glucose levels modulate circulating PP levels as hypoglycemia stimulates while hyperglycemia inhibits secretion. The glucose sensing mechanism has yet to be determined but may involve a vagal pathway. To investigate the role of enteral stimuli with or without intact vagal innervation, while controlling for the glucose excursion caused by the OGTT, we measured PP plasma levels by an in-house radioimmunoassay in truncally vagotomized (n=15) and control individuals ( n = 10). All participants were studied by a 50-g oral glucose tolerance test (OGTT) with or without dipeptidyl peptidase 4 (DPP-4) inhibition (DPP-4i) and a subsequent isoglycemic intravenous glucose infusion (IGII). We included measurements from the DPP-4i day to determine the potential effect of DPP-4-cleaved peptides on PP secretion. In both vagotomized and controls, oral glucose elicited PP secretion. In controls, but not in the vagotomized participants, intravenous glucose significantly inhibited PP secretion suggesting a vagal glucose sensing mechanism dependent on intact vagal innervation. DPP-4i did not alter PP secretion in either group.

Central GIP signaling stimulates peripheral GIP release and promotes insulin and pancreatic polypeptide secretion in nonhuman primates

Central GIP signaling stimulates peripheral GIP release and promotes insulin and pancreatic polypeptide secretion in nonhuman primates

Pancreatic polypeptide responses to isoglycemic oral and intravenous glucose in humans with and without intact vagal innervation

Secretion of pancreatic polypeptide (PP) from the pancreatic PP cells is controlled partly by vagal mechanisms. Release is stimulated by cephalic stimulation and enteral but not parenteral nutrients. Ambient glucose levels modulate circulating PP levels as hypoglycemia stimulates while hyperglycemia inhibits secretion. The glucose sensing mechanism has yet to be determined but may involve a vagal pathway. To investigate the role of enteral stimuli with or without intact vagal innervation, while controlling for the glucose excursion caused by the OGTT, we measured PP plasma levels by an in-house radioimmunoassay in truncally vagotomized (n=15) and control individuals (n=10). All participants were studied by a 50-g oral glucose tolerance test (OGTT) with or without dipeptidyl peptidase 4 (DPP-4) inhibition (DPP-4i) and a subsequent isoglycemic intravenous glucose infusion (IGII). We included measurements from the DPP-4i day to determine the potential effect of DPP-4-cleaved peptides on PP secretion. In both vagotomized and controls, oral glucose elicited PP secretion. In controls, but not in the vagotomized participants, intravenous glucose significantly inhibited PP secretion suggesting a vagal glucose sensing mechanism dependent on intact vagal innervation. DPP-4i did not alter PP secretion in either group.

The role of pancreatic polypeptide in the regulation of energy homeostasis

Imbalances in normal regulation of food intake can cause obesity and related disorders. Inadequate therapies for such disorders necessitate better understanding of mechanisms that regulate energy homeostasis. Pancreatic polypeptide (PP), a robust anorexigenic hormone, effectively modulates food intake and energy homeostasis, thus potentially aiding anti-obesity therapeutics. Intra-gastric and intra-intestinal infusion of nutrients stimulate PP secretion from the gastrointestinal tract, leading to vagal stimulation that mediates complex actions via the neuropeptide Y4 receptor in arcuate nucleus of the hypothalamus, subsequently activating key hypothalamic nuclei and dorsal vagal complex of the brainstem to influence energy homeostasis and body composition. Novel studies indicate affinity of PP for the relatively underexplored neuropeptide y6 receptor, mediating actions via the suprachiasmatic nucleus and pathways involving vasoactive intestinal polypeptide and insulin like growth factor 1. This review highlights detailed mechanisms by which PP mediates its actions on energy balance through various areas in the brain.

Pancreatic polypeptide regulates glucagon release through PPYR1 receptors expressed in mouse and human alpha-cells

BackgroundPlasma levels of pancreatic polypeptide (PP) rise upon food intake. Although other pancreatic islet hormones, such as insulin and glucagon, have been extensively investigated, PP secretion and actions are still poorly understood. MethodsThe release of PP upon glucose stimulation and the effects of PP on glucagon and insulin secretion were analyzed in isolated pancreatic islets. Expression of PP receptor (PPYR1) was investigated by immunoblotting, quantitative RT-PCR on sorted pancreatic islet cells, and immunohistochemistry. ResultsIn isolated mouse pancreatic islets, glucose stimulation increased PP release, while insulin secretion was up and glucagon release was down. Direct exposure of islets to PP inhibited glucagon release. In mouse islets, PPYR1 protein was observed by immunoblotting and quantitative RT-PCR revealed PPYR1 expression in the FACS-enriched glucagon alpha-cell fraction. Immunohistochemistry on pancreatic sections showed the presence of PPYR1 in alpha-cells of both mouse and human islets, while the receptor was absent in other islet cell types and exocrine pancreas. ConclusionsGlucose stimulates PP secretion and PP inhibits glucagon release in mouse pancreatic islets. PP receptors are present in alpha-cells of mouse and human pancreatic islets. General significanceThese data demonstrate glucose-regulated secretion of PP and its effects on glucagon release through PPYR1 receptors expressed by alpha-cells.