Plasma Pancreatic Polypeptide Concentrations Research Articles

High Fat Diets Increase Plasma Cholecystokinin and Pancreatic Polypeptide, and Decrease Plasma Insulin and Feed Intake in Lactating Cows

High fat diets often decrease feed intake in dairy cows; however, mechanisms underlying fat-induced depression of feed intake are yet to be established. The postulate that high fat diets decrease feed intake by increasing concentrations of lipid metabolites or satiety hormones in blood was tested by using eight multiparous Holstein cows in a simultaneously replicated 4 × 4 Latin-square design. Treatments were control diet with 1) no fat added, 2) 30 g/kg calcium salts of long-chain fatty acids, 3) 60 g/kg calcium salts of long-chain fatty acids, and 4) 90 g/kg calcium salts of long-chain fatty acids. Cows were fed once daily a diet of concentrate, corn silage, alfalfa haylage and alfalfa hay (50:25:14:11 on a dry matter basis). Dry matter and energy intakes were decreased by inclusion of calcium salts of long-chain fatty acids >30 g/kg of total diet dry matter (P = 0.0001). Plasma nonesterified fatty acids and triglyceride concentrations were increased linearly by feeding increasing amounts of fat (P < 0.003 and P = 0.0001, respectively), whereas plasma β-hydroxybutyrate and glucose concentrations were not influenced by supplemental fat. Fat supplementation increased postfeeding plasma cholecystokinin concentrations and linearly increased plasma pancreatic polypeptide concentrations. Highest concentrations of plasma cholecystokinin (P < 0.001) and pancreatic polypeptide (P < 0.05) were observed in cows fed the 90 g/kg fat supplement. Plasma insulin was lowered linearly by feeding fat (P = 0.0001). Increased concentrations of cholecystokinin and pancreatic polypeptide were associated with decreased intakes of feed and energy, whereas insulin may not be involved in the control of feed intake in cows fed fat.

Enolase inhibition alters metabolic hormones and inflammatory factors to promote neuroprotection in spinal cord injury

Enolase inhibition is a potential therapeutic strategy currently being investigated for treatment of spinal cord injury (SCI) as it reduces pro-inflammatory cytokines and chemokines, alters metabolic factors, and reduces gliosis in acute SCI. Herein, the role of enolase in SCI has been examined to better understand the effects of this enzyme on inflammation, metabolic hormones, glial cell activation, and neuroprotection under these shorter injury conditions. Immunohistochemical analyses of inflammatory markers vimentin, Cox-2, and caspase-1 indicated that enolase inhibition attenuated the elevated levels of inflammation seen following SCI. Iba1, GFAP, NFP, and CSPG staining indicated that enolase inhibition with prolonged administration of ENOblock reduced microglia/astrocyte activation and lead to enhanced neuroprotection in SCI. An analysis of metabolic hormones revealed that ENOblock treatment significantly upregulated plasma concentrations of peptide YY, glucagon-like peptide 1, glucose-dependent insulinotropic peptide, glucagon, and insulin hormones as compared to vehicle-treated controls (Mann-Whitney, p ≤ 0.05). ENOblock did not have a significant effect on plasma concentrations of pancreatic polypeptide. Interestingly, ENOblock treatment inhibited chondroitin sulfate proteoglycan (CSPG), which is produced by activated glia and serves to block regrowth of axons across the lesion site following injury. An increased level of NeuN and MBP with reduced caspase-1 was detected in SCI tissues after ENOblock treatment, suggesting preservation of myelin and induction of neuroprotection. ENOblock also induced improved motor function in SCI rats, indicating a role for enolase in modulating inflammatory and metabolic factors in SCI with important implications for clinical consideration.

Dairy products influence gut hormone secretion and appetite differently: A randomized controlled crossover trial

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 (iAUC0-6h) 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-iAUC0-6h compared with butter or whipped cream, and a higher level of plasma CCK-iAUC0-6h 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.

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.

Acipimox Administration With Exercise Induces a Co-feedback Action of the GH, PP, and PYY on Ghrelin Associated With a Reduction of Peripheral Lipolysis in Bulimic and Healthy-Weight Czech Women: A Randomized Study.

Objective: Anti-lipolytic drugs and exercise are enhancers of growth hormone (GH) secretion. Decreased circulating free fatty acids (FFA) have been proposed to exert ghrelin-GH feedback loop after administration of an anti-lipolytic longer-acting analog of nicotinic acid, Acipimox (OLB, 5-Methylpyrazine-2-carboxylic acid 4-oxide, molecular weight of 154.1 Da). OLB administration strongly suppresses plasma FFA during exercise. Neuroendocrine perturbations of the adipose tissue (AT), gut, and brain peptides may be involved in the etiopathogenesis of eating disorders including bulimia nervosa (BN) and anorexia nervosa. BN is characterized by binge eating, self-induced vomiting or excessive exercise.Approach: To test the hypothesis that treatment with OLB together with exercise vs. exercise alone would induce feedback action of GH, pancreatic polypeptide (PP), peptide tyrosine tyrosine (PYY), and leptin on ghrelin in Czech women with BN and in healthy-weight Czech women (HW). The lipolysis rate (as glycerol release) in subcutaneous abdominal AT was assessed with microdialysis. At an academic medical center, 12 BN and 12 HW (the control group) were randomized to OLB 500 mg 1 h before a single exercise bout (45 min, 2 W/kg of lean body mass [LBM]) once a week vs. identical placebo over a total of 2 weeks. Blood plasma concentrations of GH, PP, PYY, leptin, ghrelin, FFA, glycerol, and concentrations of AT interstitial glycerol were estimated during the test by RIA utilizing 125I-labeled tracer, the electrochemiluminescence technique (ECLIA) or colorimetric kits.Results: OLB administration together with short-term exercise significantly increased plasma GH (P < 0.0001), PP (P < 0.0001), PYY, and leptin concentrations and significantly decreased plasma ghrelin (P < 0.01) concentrations in both groups, whereas short-term exercise with placebo resulted in plasma ghrelin (P < 0.05) decrease exclusively in BN. OLB administration together with short-term exercise significantly lowered local subcutaneous abdominal AT interstitial glycerol (P < 0.0001) to a greater extent in BN.Conclusion: OLB-induced suppression of plasma ghrelin concentrations together with short-term exercise and after the post-exercise recovering phase suggests a potential negative co-feedback of GH, PP, PYY, and leptin on ghrelin secretion to a greater extent in BN. Simultaneously, the exercise-induced elevation in AT interstitial glycerol leading to a higher inhibition of peripheral lipolysis by OLB in BN.Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03338387

Development of small intestinal enzyme activities and their relationship with some gut regulatory peptides in grazing sheep

Growth depends on an animal's capacity to digest and assimilate ingested nutrients, and insufficient supply and impairment will constrain lamb growth. Eight groups of Alpine Finewool lambs were harvested on 0, 3, 7, 14, 21, 28, 42, and 56 d to measure pH and enzymatic activities in the duodenum, proximal jejunum, middle jejunum, distal jejunum, and ileum mucosa or digesta. From the duodenum to the ileum the pH of intestinal mucosa and digesta increased, whereas pH changed very little with age. The trypsin, chymotrypsin, lipase, lactase, and α-amylase activities observed at birth decreased by d 3, followed by a nonuniform enzymatic response in the small intestine. The trypsin activity increased from d 3 to peak, at d 21, followed by a decline. Chymotrypsin activity followed the same general trend but with smaller responses in activities. Trypsin demonstrated greater enzymatic activity than chymotrypsin at the same age. The lipase activity of small intestinal mucosa and digesta changed little with age. The lactase activity was high at birth, decreased by d 3, and then increased, followed by a decrease as lambs approached weaning. α-Amylase activity was similar in the small intestinal mucosa and digesta at birth but increased with age for the duodenum and proximal jejunum. Plasma concentrations of cholecystokinin (CCK), secretin, and gastrin were positively correlated ( < 0.05) with ileal mucosa lipase activity. Plasma concentration of CCK, secretin, gastrin, and gastric inhibitory polypeptide (GIP) were positively correlated ( < 0.05) with ileal mucosa lactase activity. Plasma concentration of pancreatic polypeptide (PP) was negatively correlated ( < 0.05) with lactase activity in the middle jejunum and ileal mucosa. Plasma concentrations of CCK, secretin, gastrin, and GIP were positively correlated ( < 0.05) with α-amylase activity in the ileal mucosa but negatively correlated ( < 0.05) with duodenum, prejejunum, and middle jejunum. Plasma PP concentrations were positively correlated ( < 0.01) with α-amylase activity of duodenum, middle jejunum, and postjejunum mucosa but not with the enzyme activity of postjejunum and ileal mucosa ( > 0.05). Small intestinal enzymatic activities exist and may be sufficient to enhance lamb growth via appropriate nutrient supplementation.

Lower plasma levels of glucose-dependent insulinotropic peptide (GIP) and pancreatic polypeptide (PP) in patients with ductal adenocarcinoma of the pancreas and their relation to the presence of impaired glucoregulation and weight loss

BackgroundThe 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. MethodsIn 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. ResultsSignificantly 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). ConclusionsWe 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.

Effect of heat exposure and exercise on food intake regulation: A randomized crossover study in young healthy men

ObjectiveThe 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. MethodsA 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. ResultsRelative 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). ConclusionsExercise 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.

Gastrointestinal hormones and their role in obesity.

Pandemic obesity is the most pressing health issue of this century. The most successful treatment so far is bariatric surgery, but for various reasons, surgery cannot be applied to all patients who require treatment. Gastrointestinal hormones are likely to play a key role in the success of bariatric surgery. This article examines in detail three of these gut hormones: peptide YY, oxyntomodulin and pancreatic polypeptide, and reviews how recent developments may offer new targets for therapy. Both the free fatty acid 2 and the melanocortin 4 receptors have been discovered to regulate peptide YY and glucagon-like peptide-1 secretion, and drugs targeting these may represent new antiobesity therapies. Dual agonism of glucagon-like peptide-1 and glucagon receptors, for example with oxyntomodulin, has synergistic effects in reducing appetite and increasing energy expenditure. Plasma pancreatic polypeptide concentration correlates with visceral adiposity, and may serve as a biomarker for metabolic syndrome. Gut hormones continue to show promise on an individual basis as anti-obesity treatments, but combination therapies are needed to achieve beneficial effects comparable to bariatric surgery. Innovative pathways for stimulating native gut hormone secretion may well provide an alternative method for weight loss without necessitating the administration of gut hormone analogues via injection.

Circulating pancreatic polypeptide concentrations predict visceral and liver fat content.

Context and objective:No current biomarker can reliably predict visceral and liver fat content, both of which are risk factors for cardiovascular disease. Vagal tone has been suggested to influence regional fat deposition. Pancreatic polypeptide (PP) is secreted from the endocrine pancreas under vagal control. We investigated the utility of PP in predicting visceral and liver fat.Patients and Methods:Fasting plasma PP concentrations were measured in 104 overweight and obese subjects (46 men and 58 women). In the same subjects, total and regional adipose tissue, including total visceral adipose tissue (VAT) and total subcutaneous adipose tissue (TSAT), were measured using whole-body magnetic resonance imaging. Intrahepatocellular lipid content (IHCL) was quantified by proton magnetic resonance spectroscopy.Results:Fasting plasma PP concentrations positively and significantly correlated with both VAT (r = 0.57, P < .001) and IHCL (r = 0.51, P < .001), but not with TSAT (r = 0.02, P = .88). Fasting PP concentrations independently predicted VAT after controlling for age and sex. Fasting PP concentrations independently predicted IHCL after controlling for age, sex, body mass index (BMI), waist-to-hip ratio, homeostatic model assessment 2-insulin resistance, (HOMA2-IR) and serum concentrations of triglyceride (TG), total cholesterol (TC), and alanine aminotransferase (ALT). Fasting PP concentrations were associated with serum ALT, TG, TC, low- and high-density lipoprotein cholesterol, and blood pressure (P < .05). These associations were mediated by IHCL and/or VAT. Fasting PP and HOMA2-IR were independently significantly associated with hepatic steatosis (P < .01).Conclusions:Pancreatic polypeptide is a novel predictor of visceral and liver fat content, and thus a potential biomarker for cardiovascular risk stratification and targeted treatment of patients with ectopic fat deposition.

Improvement in β-cell function after diet-induced weight loss is associated with decrease in pancreatic polypeptide in subjects with type 2 diabetes

ObjectiveThe aim of our study was to evaluate the effect of a lifestyle intervention program on β-cell function and to explore the role of gastrointestinal peptides in subjects with T2D. MethodsSubjects with T2D (n=74) received 24weeks of intervention: 12weeks of slimming diet (−500kcal/day) and the subsequent 12weeks of diet were combined with aerobic exercise. All subjects were examined at weeks 0, 12 and 24. β-cell function was assessed during standard meal tests. Insulin secretory rate (ISR) was calculated by C-peptide deconvolution, and β-cell function was quantified with a mathematical model. Plasma concentrations of gastrointestinal peptides were measured in a fasting state and during hyperinsulinemia induced by hyperinsulinemic isoglycemic clamp. ResultsMean weight loss was 5.03±4.38kg (p<0.001) in weeks 0–12. Weight did not change significantly in weeks 12–24. Both insulin secretion at the reference level and glucose sensitivity increased in weeks 0–12 (by 33%±54% and by 26%±53%, respectively, p<0.001) and remained unchanged in weeks 12–24. Both fasting and hyperinsulinemic plasma concentrations of pancreatic polypeptide (PP) decreased in weeks 0–12 (p<0.05 for both) and did not change significantly in weeks 12–24. Changes in insulin secretion at the reference level correlated negatively with plasma concentrations of PP during hyperinsulinemia (r=−0.36; p<0.001). Changes in glucose sensitivity correlated negatively with changes in plasma concentrations of PP, both in fasting and during hyperinsulinemia (r=−0.2; p=0.01 for both). The correlations remained significant after adjustment for changes in body-mass-index. ConclusionsAfter diet-induced weight loss, β-cell function improved in T2D subjects and remained unchanged after the addition of exercise. We demonstrate for the first time that these changes are associated with a decrease in PP secretion.

Changes in blood pancreatic polypeptide and ghrelin concentrations in response to feeding in sheep1

The roles of pancreatic polypeptide (PP) have not been determined in ruminant animals. The aim of the present study was to examine the role of PP in the regulation of ghrelin secretion in sheep. Two experiments were conducted using four 2-yr-old Suffolk wethers fed a maintenance diet of alfalfa hay cubes. In Exp. 1, the effects of feeding on blood ghrelin and PP concentrations were examined in scheduled-fed sheep. Blood samples were collected every 10 min from 30 min before to 360 min after feeding. Plasma PP concentrations were transiently increased from the preprandial average value to the values from 30 to 60 min after feeding and gradually decreased (P < 0.05) to stable values from 150 to 180 min. The values from 30 to 60 min were greater (P < 0.05) than those from 150 to 360 min. In contrast, plasma ghrelin concentrations were gradually decreased (P < 0.01) by feeding. The values from 60 to 360 min were less (P < 0.01) than the preprandial average value. In Exp. 2, the effects of continuous PP infusion on ghrelin secretion were examined in feed-deprived sheep. The animals were deprived of feed for 48 h before PP infusion. The PP-treated group intravenously received synthetic bovine PP at a rate of 10 pmol.kg(-1 )of BW.min(-1) for 180 min. Blood samples were collected every 10 min from 30 min before to 180 min after the commencement of PP infusion. Plasma PP concentrations reached a plateau within 30 min after the commencement of PP infusion. Plasma ghrelin concentrations were decreased (P = 0.002, 0.016, 0.007) by PP infusion at 160, 170, and 180 min, respectively. In conclusion, plasma ghrelin and PP concentrations were decreased and increased, respectively, in response to feeding in ruminant animals. Furthermore, PP could depress ghrelin secretion.

Human pancreatic polypeptide has a marked diurnal rhythm that is affected by ageing and is associated with the gastric TFF2 circadian rhythm

Normal circadian variations in vasoactive intestinal polypeptide, somatostatin, cholecystokinin and pancreatic polypeptide were measured to determine if these alter with aging and to identify gastrointestinal regulatory hormones that might control the dramatic diurnal variation in the gastric cytoprotective trefoil protein TFF2. Plasma pancreatic polypeptide concentrations showed a marked diurnal rhythm ( p < 0.0001). Basal and postprandial pancreatic polypeptide concentrations increased with age ( p < 0.01). The timing of the diurnal rhythm was consistent with pancreatic polypeptide inhibiting TFF2 secretion and there was a negative association between pancreatic polypeptide and TFF2 concentrations ( p < 0.002). The much higher pancreatic polypeptide concentrations in older people will induce increased satiety that may contribute to ‘anorexia of ageing’. These results identify potential therapies for treatment of gastric mucosal morbidity and age-associated loss of appetite.

A Role for Pancreatic Polypeptide in the Regulation of Gastric Emptying and Short-Term Metabolic Control

Previous studies using pancreatic polypeptide (PP) infusions in humans have failed to show an effect on gastric emptying, glucose metabolism, and insulin secretion. This might be due to the use of nonhuman sequences of the peptide. The objective of this study was to use synthetic human PP to study gastric emptying rates of a solid meal and postprandial hormone secretion and glucose disposal as well as the gastric emptying rate of water. This was a single-blind study. The study was performed at a university hospital. Fourteen healthy adult subjects were studied. Infusion of saline or PP at 0.75 or 2.25 pmol/kg.min was given to eight subjects (gastric emptying of solid food), and infusion of saline or PP at 2.25 pmol/kg.min was given to six subjects (gastric emptying of water). The main outcome measures were gastric emptying of solids (scintigraphy), hunger ratings (visual analog scale), and plasma concentrations of PP, insulin, glucagon, somatostatin, glucagon-like peptide 1, glucose, and gastric emptying of plain water (scintigraphy). PP prolonged the lag phase and the half-time of emptying of the solid meal. The change in hunger rating, satiety, desire to eat after the meal, or prospective consumption was not affected. The postprandial rise in plasma glucose was prolonged by PP. The postprandial rise in insulin was also delayed by PP. PP had no significant effect on the emptying of water. PP inhibits gastric emptying of solid food and delays the postprandial rise in plasma glucose and insulin. PP is suggested to have a physiological role in the pancreatic postprandial counterregulation of gastric emptying and insulin secretion.

Erythromycin Antagonizes the Deceleration of Gastric Emptying by Glucagon-Like Peptide 1 and Unmasks Its Insulinotropic Effect in Healthy Subjects

Glucagon-like peptide 1 (GLP-1) has been proposed to act as an incretin hormone due to its ability to enhance glucose-stimulated insulin secretion. Because GLP-1 also decelerates gastric emptying, it physiologically reduces rather than augments postprandial insulin secretory responses. Therefore, we aimed to antagonize the deceleration of gastric emptying by GLP-1 to study its effects on insulin secretion after a meal. Nine healthy male volunteers (age 25 +/- 4 years, BMI 25.0 +/- 4.9 kg/m2) were studied with an infusion of GLP-1 (0.8 pmol.kg(-1).min(-1) from -30 to 240 min) or placebo. On separate occasions, the prokinetic drugs metoclopramide (10 mg), domperidone (10 mg), cisapride (10 mg, all at -30 min per oral), or erythromycin (200 mg intravenously from -30 to -15 min) were administered in addition to GLP-1. A liquid test meal (50 g sucrose and 8% mixed amino acids in 400 ml) was administered at 0 min. Capillary and venous blood samples were drawn for the determination of glucose (glucose oxidase), insulin, C-peptide, GLP-1, glucagon, gastric inhibitory polypeptide (GIP), and pancreatic polypeptide (specific immunoassays). Gastric emptying was assessed by the phenol red dilution technique. Statistical analyses were performed using repeated-measures ANOVA and Duncan's post hoc test. GLP-1 significantly decelerated the velocity of gastric emptying (P < 0.001). This was completely counterbalanced by erythromycin, whereas the other prokinetic drugs used had no effect. Postprandial glucose concentrations were lowered by GLP-1 (P < 0.001 vs. placebo), but this effect was partially reversed by erythromycin (P < 0.05). Insulin secretory responses to the meal were lower during GLP-1 administration (P < 0.05 vs. placebo). However, when erythromycin was added to GLP-1, insulin concentrations were similar to those in placebo experiments. The suppression of meal-related increments in glucagon secretion by GLP-1 was reversed by erythromycin (P < 0.001). The time course of GIP secretion was delayed during GLP-1 administration (P < 0.05), but when erythromycin was added, the pattern was similar to placebo experiments. GLP-1 administration led to a reduction in pancreatic polypeptide plasma concentrations (P < 0.05). In contrast, pancreatic polypeptide levels were markedly increased by erythromycin (P < 0.001). Intravenous erythromycin counteracts the deceleration of gastric emptying caused by GLP-1, probably by interacting with the parasympathetic nervous system (pancreatic polypeptide responses). Despite augmented rises in insulin secretion, the glucose-lowering effect of GLP-1 is markedly reduced when the deceleration of gastric emptying is antagonized, illustrating the importance of this facet of the multiple antidiabetic actions of GLP-1.

Gallbladder motility and gut hormone plasma levels in subjects with and without gallstones

Hormonal control of gallbladder motility is still unclear in patients with cholelithiasis. In a case-control study, we determined the characteristics of gallbladder emptying evaluated sonographically and the hormone levels of somatostatin, gastrin, and pancreatic polypeptide, before and after a fatty meal in 10 gallstone patients compared with 20 healthy subjects. Patients with lithiasis had a larger residual volume (median 12,0 ml vs 6,5 ml; P = 0.01) and a lower gallbladder ejection fraction (43% vs 70%, P = 0.02) than healthy subjects. During fasting, plasma pancreatic polypeptide concentrations were significantly higher in lithiasis patients (P < 0.03). In contrast, no differences between the two groups of patients were observed during the post prandial period. Somatostatin and gastrin plasma levels were similar in the two groups. Lastly, the serum bile salt levels were in the normal range and were not different between groups both during fasting and postprandial states. We conclude that large basal plasma concentrations of pancreatic polypeptide, a gut peptide inducing gallbladder relaxation, may constitute a factor facilitating lithogenesis.

Pancreatic Polypeptide Is Involved in the Regulation of Body Weight in Pima Indian Male Subjects

Pancreatic polypeptide (PP) is released from the pancreas in response to a meal. In humans, low-circulating PP levels have been observed in obesity, and administration of pharmacological doses of PP has been shown to decrease food intake. The aim of the present study was to investigate whether low circulating PP is associated with weight gain in Pima Indians. Plasma PP concentrations were measured after an overnight fast and 30 min after a standardized mixed meal in 33 nondiabetic male subjects who had a follow-up visit 4.9 +/- 2.5 years later. Cross-sectionally, fasting and postprandial PP levels were negatively associated with body size and adiposity. Prospectively, the change in PP response to the meal was negatively associated with the change in body weight (r = -0.53, P = 0.002). In contrast, a high fasting PP level was positively associated with change in body weight (r = 0.45, P = 0.009). In conclusion, our results provide evidence that, even within the physiological range, PP contributes to the regulation of energy balance in humans. However this contribution appears to be more complex than anticipated because of the opposite effect of fasting and postprandial PP on the risk of future weight gain.

Effects of modified sham feeding on ghrelin levels in healthy human subjects.

The mechanisms involved in the preprandial rise and postprandial fall of circulating ghrelin levels are as yet unknown. Many hormonal and metabolic responses to nutrient intake begin during the cephalic or preabsorptive phase and are mostly mediated by the autonomous nervous system. The aim of the present study was to investigate the effects of the cephalic phase on ghrelin response to feeding in human subjects. The modified sham feeding (MSF), a well established technique in which nutrients are smelled, chewed, and tasted, but not swallowed, was used. Sixteen healthy volunteers (seven men and nine women; mean age +/- sd: 31 +/- 8 yr; body mass index, 22 +/- 3 kg/m(2)) were studied after overnight fasting. Seven of them received a standardized mixed meal, and nine underwent MSF. Blood samples for ghrelin, insulin, and glucose were taken at time -30, 0, 15, 30, 45, 60, 120 min during both tests. Pancreatic polypeptide determinations were evaluated at all times as markers of vagal activity only during MSF. Ghrelin levels significantly increased from time -30 to 0 min before the two tests, then significantly decreased: after the real feeding from 933 +/- 479 pg/ml (277 +/- 142 pmol/liter) to 455 +/- 185 pg/ml (135 +/- 55 pmol/liter; P < 0.05), and after the sham feeding from 917 +/- 313 pg/ml (272 +/- 93 pmol/liter) to 519 +/- 261 pg/ml (154 +/- 77 pmol/liter; P < 0.05). There were no significant differences between the patterns of the responses as evaluated by ANOVA (P = 0.863). As expected after MSF, plasma pancreatic polypeptide concentrations promptly increased from 58 +/- 29 pg/ml (14 +/- 7 pmol/liter) to 113 +/- 38 pg/ml (27 +/- 9 pmol/liter) at 15 min (P < 0.01). Both insulin and glucose levels increased during the actual mixed meal, whereas they were not significantly modified by MSF. In conclusion, circulating ghrelin concentrations are decreased by sham feeding as they are by real feeding in humans. These findings underline the importance of the cephalic response to nutrient intake, i.e. the role of vagal activity, in the control of ghrelin secretion.

Timing of vagal stimulation affects postprandial lipid metabolism in humans , ,

Vagal stimulation combined with an oral fat load enhances postprandial lipemia in animals and humans. We assessed whether the observed postprandial increase in plasma lipids could be explained by changes in exogenous (chylomicron) or endogenous (VLDL) lipid metabolism and whether the timing of vagal stimulation in relation to fat intake was important. Vagal stimulation was achieved by using the modified sham feeding (MSF) technique, in which food is tasted and chewed but not swallowed. Seven healthy men consumed an oral fat load (50 g) on one occasion (control protocol). On 2 other occasions, they consumed an oral fat load combined with MSF of an appetizing meal. MSF was performed for either 1 h before or 1 h after the oral fat load. Blood was collected for 7 h and was analyzed for hormones and metabolites. The postprandial triacylglycerol response differed significantly (P < 0.001) between the 3 protocols. Both MSF studies resulted in significantly higher plasma pancreatic polypeptide concentrations compared with the control. Compared with MSF for 1 hour after fat intake, MSF for 1 h before fat intake resulted in significantly higher plasma insulin concentrations (P = 0.013), a more rapid rise in chylomicron triacylglycerol concentrations (P = 0.04), and higher VLDL triacylglycerol and apoliprotein B-100 concentrations. Vagal stimulation enhanced postprandial lipemia via effects on both chylomicron and VLDL metabolism. MSF before fat intake had more dramatic effects on postprandial lipemia than did MSF after fat intake, possibly because of increased parasympathetic activity at the time of ingestion.

Important role of hypothalamic Y2 receptors in body weight regulation revealed in conditional knockout mice.

Neuropeptide Y is implicated in energy homeostasis, and contributes to obesity when hypothalamic levels remain chronically elevated. To investigate the specific role of hypothalamic Y2 receptors in this process, we used a conditional Y2 knockout model, using the Cre-lox system and adenoviral delivery of Cre-recombinase. Hypothalamus-specific Y2-deleted mice showed a significant decrease in body weight and a significant increase in food intake that was associated with increased mRNA levels for the orexigenic NPY and AgRP, as well as the anorexic proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) in the arcuate nucleus. These hypothalamic changes persisted until at least 34 days after Y2 deletion, yet the effect on body weight and food intake subsided within this time. Plasma concentrations of pancreatic polypeptide and corticosterone were 3- to 5-fold increased in hypothalamus-specific Y2 knockout mice. Germ-line Y2 receptor knockout also produced a significant increase in plasma levels of pancreatic polypeptide. However, these mice differed from conditional knockout mice in that they showed a sustained reduction in body weight and adiposity associated with increased NPY and AgRP but decreased POMC and CART mRNA levels in the arcuate nucleus. The transience of the observed effects on food intake and body weight in the hypothalamus-specific Y2 knockout mice, and the difference of this model from germ-line Y2 knockout mice, underline the importance of conditional models of gene deletion, because developmental, secondary, or extrahypothalamic mechanisms may mask such effects in germ-line knockouts.