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Aim: The hypothesis of this study is to determine the effects of intracerebroventricular (icv) prokineticin 2 infusion on food consumption and body weight and to elucidate whether it has effects on energy expenditure via the hypothalamus-pituitary-thyroid (HPT) axis in adipose tissue., Material and Methods: A total of 40 rats were used in the study and 4 groups were established: Control, Sham, Prokineticin 1.5 and Prokineticin 4.5 (n=10). Except for the Control group, rats were treated intracerebroventricularly via osmotic minipumps, the Sham group was infused with aCSF (vehicle), and the Prokineticin 1.5 and Prokineticin 4.5 groups were infused with 1.5 nMol and 4.5 nMol prokineticin 2, respectively. Food and water consumption and body weight were monitored during 7-day infusion in all groups. At the end of the infusion, the rats were decapitated and serum TSH, fT4 and fT3 levels were determined by ELISA. In addition, PGC-1α and UCP1 gene expression levels in white adipose tissue (WAT) and brown adipose tissue (BAT), TRH from rat hypothalamic tissue were determined by real-time PCR., Results: Icv prokineticin 2 (4.5 nMol) infusion had no effect on water consumption but reduced daily food consumption and body weight (p<0.05). Icv prokineticin 2 (4.5 nMol) infusion significantly increased serum TSH, fT4 and fT3 levels when compared to Control and Sham groups (p<0.05). Also, icv prokineticin 2 (4.5 nMol) infusion increased the expression of TRH in the hypothalamus tissue and expression of PGC-1α UCP1 in the WAT and BAT (p<0.05)., Conclusion: Icv prokineticin 2 (4.5 nMol) infusion may suppress food consumption via its receptors in the hypothalamus and reduce body weight by stimulating energy expenditure and thermogenesis in adipose tissue through the HPT axis., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Context: The gut-derived peptide hormones glucagon-like peptide-1 (GLP-1), oxyntomodulin (OXM), and peptide YY (PYY) are regulators of energy intake and glucose homeostasis and are thought to contribute to the glucose-lowering effects of bariatric surgery., Objective: To establish the metabolomic effects of a combined infusion of GLP-1, OXM, and PYY (tripeptide GOP) in comparison to a placebo infusion, Roux-en-Y gastric bypass (RYGB) surgery, and a very low-calorie diet (VLCD)., Design and Setting: Subanalysis of a single-blind, randomized, placebo-controlled study of GOP infusion (ClinicalTrials.gov NCT01945840), including VLCD and RYGB comparator groups., Patients and Interventions: Twenty-five obese patients with type 2 diabetes or prediabetes were randomly allocated to receive a 4-week subcutaneous infusion of GOP (n = 14) or 0.9% saline control (n = 11). An additional 22 patients followed a VLCD, and 21 underwent RYGB surgery., Main Outcome Measures: Plasma and urine samples collected at baseline and 4 weeks into each intervention were subjected to cross-platform metabolomic analysis, followed by unsupervised and supervised modeling approaches to identify similarities and differences between the effects of each intervention., Results: Aside from glucose, very few metabolites were affected by GOP, contrasting with major metabolomic changes seen with VLCD and RYGB., Conclusions: Treatment with GOP provides a powerful glucose-lowering effect but does not replicate the broader metabolomic changes seen with VLCD and RYGB. The contribution of these metabolomic changes to the clinical benefits of RYGB remains to be elucidated., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Ulcerative colitis (UC) is a major type of inflammatory bowel disease (IBD) and significantly impacts patient quality of life. Previous research revealed that the guanylate cyclase-C (GC-C) signaling pathway is associated with the severity of UC. We aimed to investigate the effect of the GC-C agonist, guanylin (Gn), on inflammatory injury in mice with colitis. An experimental UC model was established in Balb/c mice. Mesalamine served as a positive control. The Gn overexpression vector was administered once per day for 1 week. Intestinal permeability of the mice was measured using fluorescein isothiocyanate-dextran after the treatment. Histopathologic grading was estimated to assess the inflammatory injury of the colon. The expression level of crucial mediators of the GC-C signaling pathway (Gn, Ugn and GC-C) and tight junction proteins (occludin, claudin-1 and ZO-1) was measured in the colon. Additionally, the level of pro-inflammatory cytokines (IL-8 and TNF-α) in serum was measured. After injecting the UC mice with the Gn overexpression vector, the body weight increased, and the frequency of loose stools and bloody stools was decreased. Intestinal permeability and histopathologic score were significantly reduced (P<0.05). The expression level of GC-C, Gn, Ugn, claudin-1 and ZO-1 was significantly increased (P<0.05). The level of IL-8 and TNF-α in the serum was significantly decreased (P<0.01). Therefore, the application of Gn overexpression vector can ameliorate the intestinal inflammatory injury and repair the mucosal barrier in colitis mice, which further suggests the clinical therapeutic potential of GC-C agonists in IBD.

The current study has determined the ability of exendin-4 to augment the antidiabetic benefits of the recently characterised GIP/xenin hybrid, (DAla 2 )GIP/xenin-8-Gln. As such, combined activation of metabolic pathways linked to various gut derived hormones has been shown to exert complementary beneficial metabolic effects in diabetes. (DAla 2 )GIP/xenin-8-Gln and exendin-4 were administered twice daily to high fat fed (HFF) or db/db mice for 28 days and antidiabetic benefits assessed. Persistence of beneficial metabolic effects in HFF mice was also examined. Twice-daily injection of (DAla 2 )GIP/xenin-8-Gln for 28 days in HFF mice significantly reduced energy intake, body weight, circulating glucose, HbA 1c and improved glucose tolerance and insulin sensitivity. Overall pancreatic islet, alpha- and beta-cell areas were reduced, with concurrent reduction in alpha- and beta-cell proliferation that was more apparent in the combined treatment group. Addition of exendin-4 to (DAla 2 )GIP/xenin-8-Gln therapy did not significantly improve metabolic control. Remarkably, beneficial effects were still evident 14 days following complete cessation of peptide administration. Thus, circulating glucose and insulin, HbA 1c concentrations and glucose tolerance were still significantly improved when compared to control HFF mice on day 42, with minimal changes to pancreatic islet architecture. In contrast to HFF mice, combined treatment of db/db mice with (DAla 2 )GIP/xenin-8-Gln plus exendin-4 was required to induce beneficial effects on key metabolic parameters, which were not observed with either treatment alone. This included improvements in glucose tolerance and insulin sensitivity, but no effect on pancreatic architecture. These studies highlight the clear, and persistent, metabolic advantages of sustained activation of GLP-1 receptors, alongside concurrent activation of related GIP and xenin cell signalling pathways, in diabetes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction : Obesity is a global pandemic and new pharmacotherapies which combine weight loss efficacy, long-term safety, and reversal of metabolic co-morbidities are sorely needed. Gut hormones play key roles in regulating satiety and metabolism, and are natural candidates for therapeutic development. Areas covered : The authors discuss recent drug developments for the treatment of obesity using gut hormones. The review was based on a search of PubMed using keywords 'obesity' AND ('therapy' OR 'pharmacotherapy' OR 'gut hormones' OR 'analogues'), limited to the last 10 years. Expert opinion : Analogues of glucagon-like peptide (GLP-1) have been developed for obesity but so far do not provide enough weight loss. Bariatric surgery increases the post-prandial secretion of multiple gut hormones, leading to beneficial effects on weight loss and metabolism. This recognition has led to poly-agonist strategies: GLP-1/glucagon or GLP-1/glucose-dependent insulinotropic peptide (GIP) dual agonism, or even GLP-1/glucagon/GIP triple agonism. New delivery approaches include peptide-conjugate therapies that target key metabolic tissues. Practicable methods for oral delivery of peptide gut hormones are also close to market, expanding the potential market for these treatments. Anti-obesity therapy is therefore poised for an exciting phase, and it will be interesting to see which of these will eventually prevail.

Astrocyte reactivity is disease- and stimulus-dependent, adopting either a proinflammatory A1 phenotype or a protective, anti-inflammatory A2 phenotype. Recently, we demonstrated, using cell culture, animal models and human brain samples, that dopaminergic neurons produce and secrete higher levels of the chemokine-like signaling protein Prokineticin-2 (PK2) as a compensatory protective response against neurotoxic stress. As astrocytes express a high level of PK2 receptors, herein, we systematically characterize the role of PK2 in astrocyte structural and functional properties. PK2 treatment greatly induced astrocyte migration, which was accompanied by a shift in mitochondrial energy metabolism, a reduction in proinflammatory factors, and an increase in the antioxidant genes Arginase-1 and Nrf2. Overexpression of PK2 in primary astrocytes or in the in vivo mouse brain induced the A2 astrocytic phenotype with upregulation of key protective genes and A2 reactivity markers including Arginase-1 and Nrf2, PTX3, SPHK1, and TM4SF1. A small-molecule PK2 agonist, IS20, not only mimicked the protective effect of PK2 in primary cultures, but also increased glutamate uptake by upregulating GLAST. Notably, IS20 blocked not only MPTP-induced reductions in the A2 phenotypic markers SPHK1 and SCL10a6 but also elevation of the of A1 marker GBP2. Collectively, our results reveal that PK2 regulates a novel neuron-astrocyte signaling mechanism by promoting an alternative A2 protective phenotype in astrocytes, which could be exploited for development of novel therapeutic strategies for PD and other related chronic neurodegenerative diseases. PK2 signals through its receptors on astrocytes and promotes directed chemotaxis. PK2-induced astrocyte reactivity leads to an increase in antioxidant and anti-inflammatory proteins while increasing glutamate uptake, along with decreased inflammatory factors. © 2018 Wiley Periodicals, Inc., (© 2018 Wiley Periodicals, Inc.)

Antiobesity medical management has shown unsatisfactory results to date in terms of efficacy, safety, and long-term maintenance of weight loss. This poor performance could be attributed to the complexity of appetite regulation mechanisms; the serious drug side effects; and, crucially, the lack of profile-matching treatment strategies and individualized, multidisciplinary follow-up. Nevertheless, antiobesity pharmacotherapy remains a challenging, exciting field of intensive scientific interest. According to the latest studies, the future of bariatric medicine lies in developing drugs acting at multiple levels of the brain-gut axis. Currently, research is focused on the generation of combination treatments based on gut hormones in a way that mimics changes underlying surgically induced weight loss, in addition to centrally acting agents; these aim to restore energy balance disruptions and enhance energy expenditure. Collectively, the pharmacological resolution of obesity could potentially be achieved with combination regimens targeting different molecules and levels of the energy homeostasis system, in parallel with matching patients' needs, resulting in a favorable metabolic profile.

Peripheral anorectic hormones, such as glucagon-like peptide (GLP)-1, cholecystokinin (CCK)-8 and leptin, suppress food intake. The newly-identified anorectic neuropeptide, nesfatin-1, is synthesised in both peripheral tissues and the central nervous system, particularly by various nuclei in the hypothalamus and brainstem. In the present study, we examined the effects of i.p. administration of GLP-1 and CCK-8 and co-administrations of GLP-1 and leptin at subthreshold doses as confirmed by measurement of food intake, on nesfatin-1-immunoreactive (-IR) neurones in the hypothalamus and brainstem of rats by Fos immunohistochemistry. Intraperitoneal administration of GLP-1 (100 μg/kg) caused significant increases in the number of nesfatin-1-IR neurones expressing Fos-immunoreactivity in the supraoptic nucleus (SON), the area postrema (AP) and the nucleus tractus solitarii (NTS) but not in the paraventricular nucleus (PVN), the arcuate nucleus (ARC) or the lateral hypothalamic area (LHA). On the other hand, i.p. administration of CCK-8 (50 μg/kg) resulted in marked increases in the number of nesfatin-1-IR neurones expressing Fos-immunoreactivity in the SON, PVN, AP and NTS but not in the ARC or LHA. No differences in the percentage of nesfatin-1-IR neurones expressing Fos-immunoreactivity in the nuclei of the hypothalamus and brainstem were observed between rats treated with saline, GLP-1 (33 μg/kg) or leptin. However, co-administration of GLP-1 (33 μg/kg) and leptin resulted in significant increases in the number of nesfatin-1-IR neurones expressing Fos-immunoreactivity in the AP and the NTS. Furthermore, decreased food intake induced by GLP-1, CCK-8 and leptin was attenuated significantly by pretreatment with i.c.v. administration of antisense nesfatin-1. These results indicate that nesfatin-1-expressing neurones in the brainstem may play an important role in sensing peripheral levels of GLP-1 and leptin in addition to CCK-8, and also suppress food intake in rats., (© 2016 British Society for Neuroendocrinology.)

Glucagon-like peptide-1 (GLP-1), peptide YY (3-36) [PYY(3-36)], amylin, ghrelin, insulin, and leptin are thought to act as hormonal signals from periphery to brain to control food intake. Here, we determined the effects of solid-phase extraction of plasma in measuring these hormones in blood of lean and diet-induced obese rats. Individual enzyme-linked immunoassays and a multiplex assay were used to measure active GLP-1, total PYY, active amylin, active ghrelin, insulin, leptin, and total GIP in response to (1) addition of known amounts of the peptides to lean and obese plasma, (2) a large meal in lean and obese rats, and (3) intravenous infusions of anorexigenic doses of GLP-1, PYY(3-36), amylin, and leptin in lean rats. Extraction of lean and obese plasma prior to assays produced consistent recoveries across assays for GLP-1, PYY, amylin, ghrelin, and insulin, reflecting losses inherent to the extraction procedure. Plasma extraction prior to assays generally revealed larger meal-induced changes in plasma GLP-1, PYY, amylin, ghrelin, and insulin in lean and obese rats. Plasma extraction and the multiplex assay were used to compare plasma levels of GLP-1, PYY, and amylin after a large meal with plasma levels produced by IV infusions of anorexigenic doses of GLP-1, PYY(3-36), and amylin. Infusions produced dose-dependent increases in plasma peptide levels, which were well above their postprandial levels. These results do not support the hypothesis that postprandial plasma levels of GLP-1, PYY(3-36), and amylin are sufficient to decrease food intake by an endocrine mechanism., (© 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)

Background: Central serotonergic pathways influence brain areas involved in vagal cardiovascular regulation and, thereby, influence sympathetic efferent activity. Selective serotonin reuptake inhibitors (SSRIs) affect multiple serotonergic pathways, including central autonomic pathways. However, only a few studies have assessed SSRI-mediated effects on autonomic reactivity in healthy individuals using heart rate variability (HRV)., Methods: The present study assessed the influence of long-term treatment with escitalopram (ESC) on autonomic reactivity to an intravenous application of 50 µg cholecystokinin tetrapeptide (CCK-4) in 30 healthy young men using a double-blind, placebo (PLA)-controlled, randomized, within-subject cross-over design. Main outcome measures were time- and frequency-domain HRV parameters, assessed at both baseline and immediately after CCK-4 application., Results: Results showed substantial effects for the treatment × CCK-4 challenge interaction with respect to heart rate (p < 0.001; pη(2) = 0.499), SDNN (p < 0.001; pη(2) = 576), RMSSD (p = 0.015; pη(2) = 194), NN50% (p = 0.008; pη(2) = 0.224), and LF% (p = 0.014; pη(2) = 0.196), and moderate effects with respect HF% (p = 0.099; pη(2) = 0.094), with PLA subjects showing a higher increase in HR and SDNN and a higher decrease in RMSSD, NN50, LF and HF than subjects in the ESC condition. Thus, ESC treatment significantly blunted the autonomic reactivity to CCK-4. Secondary analysis indicated no effect of the 5-HTTLPR polymorphism on CCK-4-induced autonomic response., Conclusions: Our results support findings suggesting an effect of SSRI treatment on autonomic regulation and provide evidence that ESC treatment is associated with blunted autonomic reactivity in healthy men., (© The Author 2015. Published by Oxford University Press on behalf of CINP.)

Diabetes is a metabolic disease and is a major cause of mortality and morbidity in epidemic proportions. A type I diabetic patient is dependent on daily injections of insulin, for survival and also to maintain a normal life, which is uncomfortable, painful and also has deleterious effects. Extensive efforts are being made worldwide for developing noninvasive drug delivery systems, especially via oral route. Oral route is the most widely accepted means of administration. However it is not feasible for direct delivery of peptide and protein drugs. To overcome the gastro-intestinal barriers various types of formulations such as polymeric micro/nanoparticles, liposomes, etc. are investigated. In the recent years lot of advances have taken place in developing and understanding the oral peptide delivery systems. Simultaneously, the development and usage of other peptides having anti-diabetic potentials are also considered for diabetes therapy. In this review we are focusing on the advances reported during the past decade in the field of oral insulin delivery along with the possibility of other peptidic incretin hormones such as GLP-1, exendin-4, for diabetes therapy., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background and Purpose: Prokineticin 2 (PK2) has recently been shown to acutely reduce food intake in rodents. We aimed to determine the CNS sites and receptors that mediate the anorectic effects of peripherally administered PK2 and its chronic effects on glucose and energy homeostasis., Experimental Approach: We investigated neuronal activation following i.p. administration of PK2 using c-Fos-like immunoreactivity (CFL-IR). The anorectic effect of PK2 was examined in mice with targeted deletion of either prokineticin receptor 1 (PKR1) or prokineticin receptor 2 (PKR2), and in wild-type mice following administration of the PKR1 antagonist, PC1. The effect of IP PK2 administration on glucose homeostasis was investigated. Finally, the effect of long-term administration of PK2 on glucose and energy homeostasis in diet-induced obese (DIO) mice was determined., Key Results: I.p. PK2 administration significantly increased CFL-IR in the dorsal motor vagal nucleus of the brainstem. The anorectic effect of PK2 was maintained in mice lacking the PKR2 but abolished in mice lacking PKR1 and in wild-type mice pre-treated with PC1. DIO mice treated chronically with PK2 had no changes in glucose levels but significantly reduced food intake and body weight compared to controls., Conclusions and Implications: Together, our data suggest that the anorectic effects of peripherally administered PK2 are mediated via the brainstem and this effect requires PKR1 but not PKR2 signalling. Chronic administration of PK2 reduces food intake and body weight in a mouse model of human obesity, suggesting that PKR1-selective agonists have potential to be novel therapeutics for the treatment of obesity., (© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.)

Background: This randomized, open-label trial aimed to compare the metabolic effects of olanzapine orally disintegrating tablets (ODT) and solid oral tablets (SOT) in bipolar depressed and mixed outpatients., Methods: Participants were openly randomized to receive olanzapine ODT (n = 13) or SOT (n = 10), 10 to 20 mg, once daily. Weight, body mass index (BMI), Food Craving Inventory (FCI), and Three-Factor Eating Questionnaire (3-FEQ) scores were assessed at baseline and at weeks 1, 2, 4, 6, and 8. Fasting glucose and lipid levels were assessed at baseline and at week 8. Insulin and leptin concentrations were measured just prior to olanzapine baseline dosing, 1 and 2 hours following administration of baseline dose, and at weeks 4 and 8., Results: Patients showed significant increases in weight, BMI, and leptin area under the concentration-time curve (AUC), but not in FCI or 3-FEQ scores, over 8 weeks of treatment with olanzapine ODT and SOT. However, no significant differences between olanzapine formulations (ODT vs SOT) were observed in any of the measures assessed, except for a significantly lower triglyceride concentration in the ODT group at week 8., Conclusions: There was no consistent difference in metabolic profile between olanzapine ODT and SOT formulations during short-term treatment of bipolar depressed patients. Potential differences related to effects on triglyceride concentration warrant further confirmation.

Recently, glucagon-like peptide 1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP) have received much attention regarding possible roles in aetiology and treatment of type 2 diabetes. However, peptides co-secreted from the same enteroendocrine cells are less well studied. The present investigation was designed to characterise the in vitro and in vivo effects of xenin, a peptide co-secreted with GIP from intestinal K-cells. We examined the enzymatic stability, insulin-releasing activity and associated cAMP production capability of xenin in vitro. In addition, the effects of xenin on satiety, glucose homoeostasis and insulin secretion were examined in vivo. Xenin was time dependently degraded (t(1/2)=162±6 min) in plasma in vitro. In clonal BRIN-BD11 cells, xenin stimulated insulin secretion at 5.6 mM (P<0.05) and 16.7 mM (P<0.05 to P<0.001) glucose levels compared to respective controls. Xenin also exerted an additive effect on GIP, GLP1 and neurotensin-mediated insulin secretion. In clonal β-cells, xenin did not stimulate cellular cAMP production, alter membrane potential or elevate intra-cellular Ca(2)(+). In normal mice, xenin exhibited a short-acting (P<0.01) satiety effect at high dosage (500 nmol/kg). In overnight fasted mice, acute injection of xenin enhanced glucose-lowering and elevated insulin secretion when injected concomitantly or 30 min before glucose. These effects were not observed when xenin was administered 60 min before the glucose challenge, reflecting the short half-life of the native peptide in vivo. Overall, these data demonstrate that xenin may have significant metabolic effects on glucose control, which merit further study.

Guanylyl cyclase C (GCC) is the receptor specifically expressed by intestinal cells for the paracrine hormones guanylin and uroguanylin and diarrheagenic bacterial heat-stable enterotoxins. This tissue-specific receptor coordinates lineage-dependent regulation of epithelial homeostasis, and its disruption contributes to intestinal tumorigenesis. It coordinates regenerative and metabolic circuits by restricting the cell cycle and proliferation and programming metabolic transitions central to organizing the dynamic crypt-surface axis. Further, mice deficient in GCC signaling are more susceptible to colon cancer induced by Apc mutations or the carcinogen azoxymethane. Moreover, guanylin and uroguanylin are gene products most commonly lost, early, in colon cancer in animals and humans. The role of GCC as a tumor suppressing receptor regulating proliferation and metabolism, together with the universal loss of guanylin and uroguanylin in tumorigenesis, suggests a model in which colorectal cancer is a paracrine hormone deficiency syndrome. In that context, activation of GCC reverses the tumorigenic phenotype by limiting growth of colorectal cancer cells by restricting progression through the G1/S transition and reprogramming metabolic circuits from glycolysis to oxidative phosphorylation, limiting bioenergetic support for rapid proliferation. These observations suggest a pathophysiological hypothesis in which GCC is a lineage-dependent tumor suppressing receptor coordinating proliferative homeostasis whose dysregulation through hormone loss contributes to neoplasia. The correlative therapeutic hypothesis suggests that colorectal cancer is a disease of hormone insufficiency that can be prevented or treated by oral supplementation with GCC ligands.

Short bowel syndrome (SBS) is the predominant cause of intestinal failure and is associated with a high degree of morbidity and mortality. One of the reasons this occurs is because of the dramatic reduction in nutrient absorptive capacity. There are many causes for the development of SBS, but the most common is extensive surgical resection. The bowel has an impressive ability to adapt both morphologically and functionally. This adaptation becomes critical in decreasing morbidity and mortality. It is also critical for the improvement of quality of life and long-term outcomes. Provision of sufficient nutritional and fluid support is essential to the management of SBS patients. The primary goal is to prevent or eliminate the need for total parenteral nutrition. Specific diets and hormonal therapy may enhance the adaptation process depending on the characteristics of the remaining bowel. For those patients who experience both intestinal failure and life-threatening complications from total parenteral nutrition, bowel transplantation may be indicated.

Objective: The incretin hormone glucagon-like peptide-1 (GLP-1) reduces plasma glucose in type 2 diabetic patients by stimulating insulin secretion and inhibiting glucagon secretion. The biguanide metformin is believed to lower plasma glucose without affecting insulin secretion. We conducted this study to investigate the effect of a combination therapy with GLP-1 and metformin, which could theoretically be additive, in type 2 diabetic patients., Research Design and Methods: In a semiblinded randomized crossover study, seven patients received treatment with metformin (1,500 mg daily orally) alternating with GLP-1 (continuous subcutaneous infusion of 2.4 pmol x kg(-1) x min(-1)) alternating with a combination of metformin and GLP-1 for 48 h. Under fixed energy intake, we examined the effects on plasma glucose, insulin, C-peptide, glucagon, and appetite., Results: Fasting plasma glucose (day 2) decreased from 13.9 +/- 1 (no treatment) to 11.2 +/- 0.4 (metformin) and 11.5 +/- 0.5 (GLP-1) and further decreased to 9.4 +/- 0.7 (combination therapy) (P = 0.0005, no difference between monotherapy with GLP-1 and metformin). The 24-h mean plasma glucose (day 2) decreased from 11.8 +/- 0.5 (metformin) and 11.7 +/- 0.8 (GLP-1) to 9.8 +/- 0.5 (combination) (P = 0.02, no difference between GLP-1 and metformin). Insulin levels were similar between the three regimens, but glucagon levels were significantly reduced with GLP-1 compared with metformin (P = 0.0003). Combination therapy had no additional effect on appetite scores., Conclusions: Monotherapy with GLP-1 and metformin have equal effects on plasma glucose and additive effects upon combination.

We report here that glucagon-like peptide 2(GLP-2) and its receptor constitute a distinct projection system connecting the nucleus of the solitary tract with the dorsomedial hypothalamic nucleus (DMH). The DMH contains a dense plexus of GLP-2 immunoreactive fibres and is the only hypothalamic nucleus expressing GLP-2 receptor mRNA. Consistent with this, central application of GLP-2 activates the expression of neurones solely in the DMH. Furthermore, central administration of GLP-2 causes a dose-related, a pharmacologically and behaviourally specific inhibition of food intake in rats. Surprisingly, the alleged GLP-1 receptor antagonist, Exending (9-39), proved a functional antagonist of centrally applied GLP-2. These data implicate GLP-2 as an important neurotransmitter in the regulation of food intake and likely bodyweight. Our data therefore point to the DMH as a crossroad for endocrine and visceral information affecting feeding behaviour.

Glucagon-like peptide (GLP)-2 is formed from proglucagon in the intestinal L cells and is secreted postprandially in parallel with the insulinotropic hormone GLP-1, the latter of which, in addition, acts to inhibit gastric secretion and motility by inhibiting central parasympathetic outflow. We now studied the effect of GLP-2 on gastric secretion stimulated by sham feeding to test the hypothesis that also GLP-2 acts as an enterogastrone. Eight healthy volunteers were studied twice on separate days. They were sham fed with and without GLP-2 infused iv at a rate of 0.8 pmol/kg x min. Gastric contents were aspirated continuously by a nasogastric tube for determination of acid secretion, volume, and osmolarity. Sham feeding increased gastric acid secretion nearly 5-fold. Infusion of GLP-2 reduced incremental acid secretion by 65+/-6%, compared with saline infusion (delta8.75+/-0.37 vs. delta3.04+/-0.47 mmol x 60 min; P<0.01). Plasma concentrations of GLP-2 rose from a basal mean of 3.3+/-0.9 to a mean of 115+/-8 pmol/L (range, 57-149 pmol/L) during infusion of GLP-2 and remained at basal level during saline infusion. Plasma concentrations of GLP-1, gastrin, cholecystokinin, and secretin remained low and unchanged on both study days. We conclude that GLP-2 is a powerful inhibitor of gastric acid secretion in man. Further investigations will show to what extent GLP-2 contributes to the inhibitory effects on gastric secretion exerted by hormones from the distal small intestine, under physiological circumstances.

Combination therapy with enterotrophic agents may be useful in patients with the short bowel syndrome. The gut hormones neurotensin (NT) and glucagon-like peptide 2 (GLP-2) are potent enterotrophic factors when administered alone; however, their combined effects are not known. Using a GLP-2-producing tumor (STC-1), we determined whether administration of NT enhances the effect of GLP-2 on intestinal growth. Athymic mice were injected with STC-1 cells (6 x 10(6)) subcutaneously. Twenty-three days after STC-1 implantation, mice received either NT (300 microg/kg or 600 microg/kg) or saline solution (control) subcutaneously three times a day for 6 days. Two groups of tumor-free mice received either saline or NT for 6 days. At sacrifice, jejunum and ileum were collected, weighed, and analyzed for DNA and protein content. In the jejunum, NT combined with GLP-2 (from STC-1) increased weight, protein content (markers of mucosal hypertrophy), and DNA content (a marker of mucosal hyperplasia), compared to either NT or GLP-2 alone. In the ileum, the combination of NT and GLP-2 significantly increased weight and/or protein content compared to NT or GLP-2 alone. Administration of NT enhances the enterotrophic effects of GLP-2, augmenting hypertrophy of the entire small bowel and hyperplasia of the jejunum. The combination of NT and GLP-2 may be useful to enhance intestinal growth in patients with the short bowel syndrome.

The effect of i.v. infusion of gastrin (CCK-4), cholecystokinin (CCK-8) and pancreatic polypeptide (PP), 20 and 200 ng/kg/min for 1 h, on gastrointestinal electrical activity and arterial pressure was studied in conscious miniature pigs. During infusion of CCK-8 a transient hypertension was observed. In the antrum, the 3 peptides provoked an increase in slow wave activity and a decrease in spike activity. In the intestine, CCK-8 induced an increase in ileal spiking activity, whereas infusion of PP resulted in an increased frequency of long spike bursts in the caecum.

Background: Glucagon-like peptide-2 is formed from proglucagon in the intestinal L-cells and is secreted postprandially in parallel with the insulinotropic hormone GLP-1 (glucagon-like peptide-1), which in addition acts to inhibit gastric motility (enterogastrone effect) by inhibiting central parasympathetic outflow. GLP-2 has no effect on the endocrine pancreas. We here tested the hypothesis that GLP-2 acts as an enterogastrone., Methods: Fourteen anesthetized pigs with their splanchnic nerves cut were subjected to insulin hypoglycemia, and force transducers were sutured to the antrum to record motility. GLP-2 was infused intravenously in doses from 1 to 6 pmol/kg/min after the onset of antral motility in response to hypoglycemia., Results: Insulin hypoglycemia invariably and greatly increased the frequency and amplitude of antral phasic contractions. Infusions of GLP-2 dose dependently (1-6 pmol/kg/min) inhibited antral motility. At 2 pmol/kg/min, resulting in plasma GLP-2 concentrations of 102.5+/-19 pmol/l (normal postprandial range, 30-82 pmol/l), the motility index was inhibited by 91%+/-14%., Conclusions: Both of the intestinal glucagon-like peptides may operate as hormonal transmitters of the ileal brake effect.

The effect of octreotide on morning hyperglycemia and GH levels was evaluated in eight insulin-dependent diabetic patients. Octreotide (50 mcg) was administered through subcutaneous injections at different hours (20:00, 22:00 and 24:00 h) or through continuous subcutaneous night infusion from midnight to 08:00 at increasing rate between 03:00 and 08:00 h. After octreotide injection at midnight we noticed a sharp decrease of both glycemia (p < 0.005) and GH (p < 0.05) at 04:00 h, but not at 08:00 h. Only the night continuous infusion at increasing rate was able to reduce glycemia and GH at 04:00 and at 08:00 h (p < 0.001 and p < 0.01 respectively). The injections of octreotide at 20:00 and 22:00 h lowered GH values at 24:00 h (p < 0.01 and p < 0.05 vs insulin alone) but did not show any significant effect on blood glucose levels and GH at 04:00 and 08:00 h. In conclusion, only the continuous subcutaneous night infusion of octreotide at increasing rate during the last hours of the night was able to reduce simultaneously morning hyperglycemia and GH levels in insulin-dependent diabetic patients, whereas evening subcutaneous injections at different times did not show any appreciable effect.

Recently, we have reported that central administration of glucagon-like peptide-1 (GLP-1) strongly decreased food intake of chicks. The aim of the present study was to elucidate whether suppressed food intake by central injection of GLP-1 would be modified by an appetite stimulant such as fasting and neuropeptide Y (NPY). Birds (2 days old) were starved for 3 or 6 h and then GLP-1 (0.03 microg/10 microl) or saline was injected by the intracerebroventricular (i.c.v.) route. Birds starved for 6 h ate significantly more food than those starved for 3 h, while irrespective of the time for fasting GLP-1 strongly inhibited food intake as rapidly as 10 min after i.c.v injection. The suppressive effect on food intake continued until 4 h after injection. Central administration of NPY (2.5 microg/10 microl) greatly enhanced food intake, but co-injection of GLP-1 (0.01, 0.02 or 0.03 microg/10 microl) decreased food intake in a dose-dependent fashion. Under GLP-1 (0.03 microg/10 microl) treatment, whether NPY modifies food intake of chicks in a dose-dependent manner was investigated by co-injection of graded levels of NPY (0.4, 1.0 and 2.5 microg/10 microl). GLP-1 completely inhibited the effect of NPY on food intake without a dose response. These results suggest that central GLP-1 may interact with NPY and may be the most potent inhibitor of food intake in the chicken.

Background: Glucagon-like peptide-1 7-36 amide (GLP-1) and peptide YY (PYY) are colocalized in the L-cell of the ileal mucosa, and both peptides may function as enterogastrone hormones. However, it is not known whether they interact with regard to the effect on acid secretion., Methods: The effect of intravenous infusion of GLP-1 and PYY, either alone or in combination, on pentagastrin-induced acid secretion in eight healthy volunteers was examined. The peptides were infused at two different rates: 0.25 pmol/kg/min (low rate) and 0.5 pmol/kg/min (high rate)., Results: Given alone, GLP-1 and PYY inhibited acid secretion by 26 +/- 5% and 18 +/- 5% (low rate) and 45 +/- 8% and 38 +/- 7% (high rate), respectively. Combined infusion resulted in an inhibition of 32 +/- 5% (low rate) and 62 +/- 7% (high rate). Both infusion rates resulted in GLP-1 and PYY plasma concentrations below or similar to postprandial levels., Conclusion: The present study suggests that the interaction between GLP-1 and PYY in man is of the additive type. The results indicate that GLP-1 and PYY have an important role in the physiologic control of gastric acid secretion.

For the model of paralytic ileus caused by the severe surgery it has been studied the influence of different doses of hemocorrector of "Lactosorbal" on distal colon motility. It has been established that stimulating effect of "Lactosorbal" on the motility of distal colon is of the dose-dependent nature. The results of the current survey are making the ground for multiple use of "Lactosorbal" to reach the most beneficial outcome of severe paralytic ileus resulting from major traumatic surgery in clinic.

Intravenous glucagon-like peptide (GLP)-1 [7-36 amide] can normalize plasma glucose in non-insulin-dependent diabetic (NIDDM) patients. Since this is no form for routine therapeutic administration, effects of subcutaneous GLP-1 at a high dose (1.5 nmol/kg body weight) were examined. Three groups of 8, 9 and 7 patients (61 +/- 7, 61 +/- 9, 50 +/- 11 years; BMI 29.5 +/- 2.5, 26.1 +/- 2.3, 28.0 +/- 4.2 kg/m2; HbA1c 11.3 +/- 1.5, 9.9 +/- 1.0, 10.6 +/- 0.7%) were examined: after a single subcutaneous injection of 1.5 nmol/kg GLP [7-36 amide]; after repeated subcutaneous injections (0 and 120 min) in fasting patients; after a single, subcutaneous injection 30 min before a liquid test meal (amino acids 8%, and sucrose 50 g in 400 ml), all compared with a placebo. Glucose (glucose oxidase), insulin, C-peptide, GLP-1 and glucagon (specific immunoassays) were measured. Gastric emptying was assessed with the indicator-dilution method and phenol red. Repeated measures ANOVA was used for statistical analysis. GLP-1 injection led to a short-lived increment in GLP-1 concentrations (peak at 30-60 min, then return to basal levels after 90-120 min). Each GLP-1 injection stimulated insulin (insulin, C-peptide, p < 0.0001, respectively) and inhibited glucagon secretion (p < 0.0001). In fasting patients the repeated administration of GLP-1 normalized plasma glucose (5.8 +/- 0.4 mmol/l after 240 min vs 8.2 +/- 0.7 mmol/l after a single dose, p = 0.0065). With the meal, subcutaneous GLP-1 led to a complete cessation of gastric emptying for 30-45 min (p < 0.0001 statistically different from placebo) followed by emptying at a normal rate. As a consequence, integrated incremental glucose responses were reduced by 40% (p = 0.051). In conclusion, subcutaneous GLP-1 [7-36 amide] has similar effects in NIDDM patients as an intravenous infusion. Preparations with retarded release of GLP-1 would appear more suitable for therapeutic purposes because elevation of GLP-1 concentrations for 4 rather than 2 h (repeated doses) normalized fasting plasma glucose better. In the short term, there appears to be no tachyphylaxis, since insulin stimulation and glucagon suppression were similar upon repeated administrations of GLP-1 [7-36 amide]. It may be easier to influence fasting hyperglycaemia by GLP-1 than to reduce meal-related increments in glycaemia.

Peptide YY is an ileocolonic peptide known to inhibit postprandial and cholecystokinin-induced pancreatic exocrine secretion. It has also been shown to increase intestinal water and electrolyte absorption. These findings implicate PYY as being potentially useful for controlling watery diarrhea. Although its inhibitory effect on stimulated pancreatic secretion has been well established, PYY effects on interdigestive, unstimulated pancreatic secretion is not known. This study was designed to evaluate the effect of PYY on basal pancreatic exocrine secretion in a conscious rat. Male Sprague-Dawley rats were prepared with catheters for internal biliary bypass, pancreatic juice collection, and intraduodenal reinfusion of pancreatic juice. Jugular and carotid catheters were inserted for drug infusions and blood sampling. After overnight recovery, fasting rats were infused over 6 hours with saline or PYY (400 or 800 pmol/kg/hr). Pancreatic juice was measured and sampled at 60-minute intervals for volume and its protein and bicarbonate content. The remainder was reinfused into the duodenum. Before and after the experiment, pancreatic juice was automatically reinfused by a photocell-controlled peristaltic pump system. Intraductal pancreatic secretion was not affected by PYY at a dose of 400 pmol/kg/hr. PYY at a dose of 800 pmol/kg/hr significantly reduced the volume of pancreatic secretion and its protein and bicarbonate content. Pancreatic secretory response normalized within 24 hours. In conclusion, unstimulated pancreatic exocrine secretion can be inhibited by exogenous PYY in the rat.

In order to determine the influence of neuropeptide Y (NPY) on the biosynthesis of prolactin (PRL), we have studied the effects of NPY and some NPY analogs on PRL gene expression in the male rat anterior pituitary gland. The following peptides (4 micrograms/100 g body wt): NPY, peptide YY (PYY), NPY13-36 (a Y2 receptor agonist) and [Leu31,Pro34]NPY (a Y1 receptor agonist) were injected into the left lateral ventricle of adult male rats. Control animals received only the vehicle (0.9% NaCl). All the animals were perfused with 4% paraformaldehyde 4 h after injection and processed for in situ hybridization. The intracerebroventricular injection of NPY, PYY, and NPY13-36 induced a significant increase in the hybridization signal (22-40% over control). On the other hand, the Y1 receptor agonist [Leu31,Pro34]NPY did not influence PRL mRNA levels. These data then suggest that activation of the Y2 NPY receptor subtype at the central level can positively regulate PRL gene expression.

The aim of our study was to determine whether a meal modifies the antisecretory response induced by PYY and the structural requirements to elicit antisecretory effects of analogue PYY(22-36) for potential antidiarrhea therapy. The variations in short-circuit current (Isc) due to the modification of ionic transport across the rat intestine were assessed in vitro, using Ussing chambers. In fasted rats, PYY induced a dose- and time-dependent reduction in Isc, with a sensitivity threshold at 5 x 10(-11) M (delta Isc -2 +/- 0.5 microA/cm2). The reduction was maximal at 10(-7) M (Isc -23 +/- 2 microA/cm2), and the concentration producing half-maximal inhibition was 10(-9) M. At 10(-7) M, reduction of 1sc by PYY reached 90% of response to 5 x 10(-5) M bumetanide. The PYY effect was partly reversed by 10(-5) M forskolin (Isc + 13.43 +/- 2.91 microA/h.cm2, p < 0.05) or 10(-5) M dibutyryl adenosine 3',5' cyclic monophosphate (Isc + 12 +/- 1.69 microA/cm2, p < 0.05). Naloxone and tetrodotoxin did not alter the effect of PYY. In addition, PYY and its analogue P915 reduced net chloride ion secretion to 2.85 and 2.29 microEq/cm2 (p < 0.05), respectively. The antisecretory effect of PYY was accompanied by dose- and time-dependent desensitization when jejunum was prestimulated by a lower dose of peptide. The antisecretory potencies exhibited by PYY analogues required both a C-terminal fragment (22-36) and an aromatic amino acid residue (Trp or Phe) at position 27. At 10(-7) M the biological activity of PYY was lower in fed than fasted rats (p < 0.001). Our results confirm the antisecretory effect of PYY, but show that the fed period is accompanied by desensitization, similar to the transient desensitization observed in the fasted period with cumulative doses. This suggests that PYY may act as a physiological mediator that reduces intestinal secretion.

The influence of peripheral injection of peptide YY (PYY) on neuronal activity in the rat brain was examined by immunohistochemical detection of c-fos protein. Numerous c-fos-immunoreactive nuclei were found in the area postrema, nucleus tractus solitarius (commissural and medial subnuclei), central amygdala and thalamus (periventricular and medial) of rats injected i.p. with PYY at a dose of 300 micrograms/kg. c-fos-like immunoreactivity was found to be less when lower doses of PYY (50-200 micrograms/kg, i.p.) were injected. Either no or few cells were detected after i.p. injection of the vehicle alone. These data provide anatomical support for the centrally mediated actions of peripheral PYY on gut function.

Central administrations of neuropeptide Y and peptide YY (PYY) produce robust increases in food intake, and this response may be contingent upon the availability of insulin. In contrast, beta 2-adrenergic agonists decrease food intake, and this effect also appears to be dependent on circulating insulin. To investigate a possible interaction between PYY and beta 2-adrenergic function, rats were given systemic injections of terbutaline, a beta 2 agonist, at doses of 0, 5, 10, and 50 mg/kg prior to injections of 0.57 nmol PYY in the paraventricular nucleus of the hypothalamus. Terbutaline pretreatment significantly decreased feeding elicited by PYY in a dose-dependent fashion. This suggests that beta 2-adrenoreceptor activity is involved in PYY-induced feeding.

Central injection of peptide YY (PYY) elicits a powerful feeding response with a short latency in satiated rats. Because of this effect, PYY has been implicated as a neurochemical signal in bulimia nervosa. Serotonin agonists and opioid antagonists induce anorectic effects upon feeding behavior in humans and animals. Therefore, to investigate a possible interaction between PYY-induced eating and these anorexigenic agents rats were given injections of either naloxone (100 micrograms/3 microliters, ICV, and 10 mg/kg, SC), fluoxetine (3-30 micrograms/3 microliters and 5-10 mg/kg, IP), or clomipramine (3-30 micrograms/3 microliters and 5-10 mg/kg, IP) prior to fourth ventricular injections of PYY (15 micrograms/18 microliters). Central and peripheral naloxone and IP but not central injections of fluoxetine blocked PYY-induced intake. Clomipramine had no effect. This suggests that PYY-stimulated feeding may require the action of endogenous opioids and may be inhibited by serotonergic function.

The possible cooperation of neuropeptide Y (NPY) and alpha-1-adrenergic mechanisms in the release of oxytocin (OT) in conscious, nonsuckled lactating rats was examined following microinjections of NPY and its analogs and/or alpha-adrenergic drugs into the supraoptic nucleus (SON) or anterior paraventricular nucleus/anterior commissural nucleus (PVN/ACN). The alpha-1-adrenergic agonist phenylephrine dose dependently increased plasma OT after injection into the SON or the PVN/ACN, and this was prevented by treatment with the specific alpha-alpha-1-adrenergic receptor antagonist prazosin, but not by the alpha-2 antagonist rauwolscine. The alpha-2-adrenergic agonist clonidine did not increase plasma OT. Injection of NPY or of the related peptide YY (PYY) alone into the SON or the PVN/ACN also dose dependently increased plasma OT; this was also significantly attenuated by prazosin. Plasma OT responses to NPY and PYY differed significantly in dynamics and duration, which may be related to large differences found in the patterns of displaceable binding of [125I]NPY and [125I]PYY to hypothalamic membranes. The stimulatory action of NPY was mimicked by a preferential Y-1 receptor agonist, but not by an agonist of the Y-2 NPY receptor. Coinjection of NPY or PYY and phenylephrine into either the SON or the PVN/ACN area produced a greater than additive discharge of OT, especially in the SON. This increase was mostly due to a markedly enhanced initial release of OT, and was also completely eliminated by prazosin. The NPY-alpha-1 interaction in stimulating plasma OT was not mediated by direct binding of the peptides to alpha-1-adrenergic receptor sites. These results indicate that 1) the stimulatory noradrenergic influence on OT secretion in the lactating rat is mediated by the alpha-1 adrenergic receptor via an action in the PVN/ACN and SON; 2) NPY also stimulates OT secretion in the lactating rat through the Y-1 receptor subtype in the PVN/ACN and SON; 3) NPY markedly enhances the OT secretory responses to alpha-1 receptor stimulation, particularly in the SON. The cooperative stimulation by NE and NPY may be of physiological importance in mediating the episodic release of OT in response to suckling.

The role of luminal bile salts (taurocholate) in regulation of rat pancreatic secretion was examined by studies on the effects of luminal stimulants on the pancreas during infusion of various concentrations of taurocholate into the duodenum of conscious rats. Rats with external bile and pancreatic fistulae were used. For 24 h before the experiment, pancreatic juice was excluded from the intestine but bile was continuously returned to the duodenum. From the beginning of the experiment, 8-200 mM of taurocholate was infused at a rate of 1 ml/h instead of returning the bile. Pancreatic juice was collected for a 2-h period and then 2 micrograms of pancreatic secretory trypsin inhibitor-61 (PSTI-61) (= monitor peptide) or partially purified putative CCK-releasing peptide from rat intestine (intestinal CCK-RP) was injected into the duodenum (1 ml/min). Continuous infusion of taurocholate maintained a constant rate of pancreatic secretion, except at a concentration of 8 mM, which resulted in a slight increase in pancreatic secretion. Both PSTI-61 and intestinal CCK-RP significantly increased pancreatic secretions during infusion of 20 or 40 mM taurocholate, but had no significant effect during infusion of 80 or 200 mM taurocholate. Therefore, higher concentrations of taurocholate in the intestine prevented the stimulatory effects of luminal stimulants, probably by preventing the latter from reaching CCK cells.

The gastrointestinal peptides secretin and cholecystokinin were found to inhibit the incorporation of 3H-thymidine in the lymphocyte transformation reaction in response to phytohemagglutinin. Both peptides inhibited lymphocyte activation in a dose responsive fashion. This inhibition was not due to the toxicity of these substances, as the lymphocytes remained intact and capable of excluding trypan blue. Neither glucagon nor gastrin had any effects of lymphocyte transformation.

We have studied the basal release of cholecystokinin (CCK) and the CCK response to gastrin-releasing peptide (GRP) in man. GRP infusion was followed by a substantial and immediate release of CCK. Pancreatico-duodenectomy or antrectomy with or without duodenal exclusion or antrectomy with truncal vagotomy did not significantly change the basal release of CCK or the GRP-induced CCK release. These results indicate that both basal and GRP-induced release of CCK predominantly originate from the small intestine below the duodenum and the upper part of the jejunum and is unchanged by duodenal exclusion and vagal denervation of the small intestine.

The effect of an infusion of two doses of peptide YY (PYY), a novel putative gastrointestinal hormone, has been assessed on mouth to caecum intestinal transit time and on the rate of gastric emptying after ingestion of an inert 200 ml liquid meal thought unlikely to interrupt fasting gastrointestinal motility patterns. A low dose of PYY was chosen to give plasma concentrations within the range seen postprandially in healthy subjects, while the high dose mimicked the raised levels seen in several malabsorptive conditions. During infusion of PYY at 0.18 pmol/kg/min plasma concentrations rose from a basal of 8 +/- 2 pmol/l to 38 +/- 5 pmol/l and at 0.51 pmol/kg/min to 87 +/- 10 pmol/l. Mouth to caecum transit time was delayed from 67 +/- 4 mins on the saline infusion day to 94 +/- 7 mins (p less than 0.01) on the low dose and 192 +/- 9 mins (p less than 0.001) on the high dose infusion day. Time to 50% gastric emptying was prolonged from 37 +/- 8 mins during saline infusion to 63 +/- 10 mins (p less than 0.05) during low and 130 +/- 12 mins (p less than 0.001) during high dose infusion. Thus the infusion of PYY shows a dose related inhibition of mouth to caecum intestinal transit time and of the rate of gastric emptying and suggests this novel hormonal peptide to be of importance in gastrointestinal physiology.

The action of watery rat gut extracts on glucose-induced insulin release in anaesthetized rats was examined before and after removal of GIP by immunoadsorption. Infusions of GIP-containing rat gut extracts nearly doubled the insulin release induced by intravenous glucose (1 g X kg -1 X h -1). Peak insulin secretion was 98 +/- 11 mU/l (mean +/- SEM) after intravenous glucose and increased to 178 +/- 16 mU/l following infusion of glucose plus gut extract (p less than 0.005). After injection of GIP antiserum in sufficient amounts to neutralize the GIP activity in the gut extract preparation, the additional insulin release due to the gut extract was reduced by only 30%. After complete removal of GIP from gut extracts by immuno-absorption, more than 50% of the incretin effect remained. These data suggest that the insulinotropic activity of rat gut extracts can only be partially related to GIP. The existence of additional insulinotropic gut factors which may also be released following oral glucose is postulated.

Vasoactive inhibitory peptide (VIP) and secretin were compared in regard to the stimulation of pancreatic bicarbonate secretion and the augmentation of pancreatic response to caerulein or a peptone meal in chronic gastric and pancreatic fistula dogs. Dose-response analysis showed that maximal bicarbonate response to VIP was about 17% of that to secretin. Both caerulein and endogenous cholecystokinin, released by a peptone meal, clearly potentiated pancreatic bicarbonate response to VIP in a manner similar to secretin. The interactions of these two peptides showed that VIP is a potent inhibitor of secretin-induced pancreatic secretion. From the dose-response curves to secretin alone and secretin plus VIP, Michaelis-Menten analysis showed typical competitive inhibition, which indicates that VIP and secretin share a common receptor site.

Eight fasting patients with non-insulin-dependent diabetes (NIDD) and six healthy controls were given an intravenous infusion of porcine gastric inhibitory polypeptide (GIP). During the GIP infusion mean plasma pancreatic polypeptide level increased significantly in both groups, whereas the mean serum insulin level increased in the NIDD group only, indicating a more important role for GIP in these patients than in healthy subjects.

The purpose of this study was to determine whether the inhibitory action of peptide YY (PYY) on gastric acid secretion is attributable to the release of gastric somatostatin in rats. Two groups of rats (six rats/group) were anesthetized with urethane and prepared with gastric fistulas and jugular catheters. Pentagastrin (18 micrograms/kg-h) was given intravenously for 150 min to stimulate gastric acid secretion. Intravenous PYY (130 micrograms/kg-h) inhibited pentagastrin-stimulated gastric acid secretion significantly (P less than 0.05). Administration of iv PYY resulted in a 41% reduction (P less than 0.05) in pentagastrin-stimulated gastric acid secretion. In another group of anesthetized rats, administration of PYY (10(-7), 10(-8) M) failed to stimulate a release of somatostatin from the isolated-perfused rat stomach. Our findings indicate that PYY can inhibit gastric acid secretion independently of release of gastric somatostatin in the rat.

The effects of intracerebroventricular (icv) vasoactive intestinal polypeptide (VIP), secretin, glucagon, and cholecystokinin-octapeptide (CCK-8) on the thermoregulatory and cardiovascular systems were studied in conscious rats. The icv injection of VIP at a dose of 10 micrograms produced hyperthermia with an increase in the positive difference between the interscapular brown adipose tissue (BAT) and colonic temperatures (TBAT-Tco), but had little effect on nonevaporative heat loss. Mean arterial blood pressure and heart rate increased following the icv VIP. The results were consistent at ambient temperatures (Ta) of 18, 23, and 28 degrees C. The icv injection of secretin at doses of 1 and 10 micrograms at Ta of 23 degrees C produced hypothermia with a decrease in (TBAT-Tco) and elevated blood pressure without any change in heart rate. The 10 micrograms of icv glucagon had no effect on the thermoregulatory and cardiovascular systems. The large dose of icv CCK-8 (10 micrograms) induced persistent hyperthermia. Nonsulfated-form CCK-8 and CCK-tetrapeptide, however, were ineffective on all variables measured. These results indicate that the central VIP activates BAT thermogenesis and induces hyperthermia, but has a minimum effect on nonevaporative heat loss. Although VIP, secretin, and glucagon have similarities in terms of chemical structure, their effects on body temperature, BAT thermogenesis, and the cardiovascular system are quite different.

Eight fasting students were given an infusion of porcine gastric inhibitory polypeptide (GIP) and glucose with or without atropine on two separate days. Mean serum insulin levels increased significantly and similarly on both occasions, indicating that both the glucose- and GIP-induced insulin release is unaffected by atropine. Plasma pancreatic polypeptide (PP) rose significantly during the GIP infusion on the day without atropine, suggesting a role for GIP in the intestinal phase of the PP release.