| 1. |
- Ahrén, Bo, et al.
(author)
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DPP-4 inhibition improves glucose tolerance and increases insulin and GLP-1 responses to gastric glucose in association with normalized islet topography in mice with beta-cell-specific overexpression of human islet amyloid polypeptide.
- 2007
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In: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 143:1-3, s. 97-103
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Journal article (peer-reviewed)abstract
- Inhibition of dipeptidyl peptidase-4 (DPP-4) is currently explored as a novel therapy of type 2 diabetes. The strategy has been shown to improve glycemia in most, but not all, rodent forms of glucose intolerance. In this study, we explored the effects of DPP-4 inhibition in mice with [beta-cell overexpression of human islet amyloid polypeptide (IAPP). We therefore administered the orally active and highly selective DPP-4 inhibitor, vildagliptin (3 pmol/mouse daily) to female mice with [beta-cell overexpression of human IAPP. Controls were given plain water, and a series of untreated wildtype mice was also included. After five weeks, an intravenous glucose tolerance test showed improved glucose disposal and a markedly enhanced insulin response in mice treated with vildagliptin. After eight weeks, a gastric tolerance test showed that vildagliptin improved glucose tolerance and markedly (approximately ten-fold) augmented the insulin response in association with augmented (approximately five-fold) levels of intact glucagon-like peptide-1 (GLP-1). Furthermore, after nine weeks, islets were isolated. Islets from vildagliptin-treated mice showed augmented glucose-stimulated insulin response and a normalization of the islet insulin content, which was reduced by approximately 50% in transgenic controls versus wildtype animals. Double immunostaining of pancreatic islets for insulin and glucagon revealed that transgenic islets displayed severely disturbed intra-islet topography with frequently observed centrally located a-cells. Treatment with vildagliptin restored the islet topography. We therefore conclude that DPP-4 inhibition improves islet function and islet topography in mice with [beta-cell specific transgenic overexpression of human IAPP. (c) 2007 Elsevier B.V. All rights reserved.
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| 2. |
- Andersson, Gustav, 1983-, et al.
(author)
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Presence of substance P and the neurokinin-1 receptor in tenocytes of the human Achilles tendon
- 2008
-
In: Regulatory Peptides. - : Elsevier BV. - 0167-0115 .- 1873-1686. ; 150:1-3, s. 81-87
-
Journal article (peer-reviewed)abstract
- Nerve signal substances, such as the tachykinin substance P (SP), may be involved in the changes that occur in response to tendinopathy (tendinosis). It is previously known that the level of SP innervation within tendon tissue is limited, but results of experimental studies have suggested that SP may have stimulatory, angiogenetic and healing effects in injured tendons. Therefore, it would be of interest to know if there is a local SP-supply in tendon tissue. In the present study, the patterns of expression of SP and its preferred receptor, the neurokinin-1 receptor (NK-1 R), in normal and tendinosis human Achilles tendons were analyzed by use of both immunohistochemistry and in situ hybridization. We found that there was expression of SP mRNA in tenocytes, and that tenocytes showed expression of NK-1 R at protein as well as mRNA levels. The observations concerning both SP and NK-1 R were most evident for tenocytes in tendinosis tendons. Our findings suggest that SP is produced in tendinosis tendons, and furthermore that SP has marked effects on the tenocytes via the NK-1 R. It cannot be excluded that the SP effects are of importance concerning the processes of reorganization and healing that occur for tendon tissue in tendinosis. In conclusion, it appears as if SPergic autocrine/paracrine effects occur in tendon tissue during the processes of tendinosis, hitherto unknown effects for human tendons.
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| 3. |
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| 4. |
- Arciszewski, M B, et al.
(author)
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Effects of vasoactive intestinal peptide and galanin on survival of cultured porcine myenteric neurons
- 2005
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In: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 125:1-3, s. 185-192
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Journal article (peer-reviewed)abstract
- Enteric neuronal plasticity is probably fundamental in order to withstand injury or changes in intestinal activity. The role of the neuropeptides in neuroprotection is still enigmatic. The expression of galanin and vasoactive intestinal peptide (VIP) and the effects of the two peptides on survival of small intestinal porcine myenteric neurons cultured for 6 days were studied. Immunocytochemistry and cell counting were used to evaluate the numbers of surviving neurons and their expression of galanin and VIP. To reflect the in vivo situation, cryostat sections of porcine mid-jejunum were used. A concentration-dependent and marked increase in neuronal survival was noted when neurons were grown in the presence of VIP (10(-8) - 10(-6) M), whereas addition of galanin (10(-8) - 10(-6) M) slightly decreased neuronal survival. A dramatic increase in the proportions of myenteric neurons containing VIP or galanin immunoreactivity occurred during culturing. The presence of VIP further increased the number of galanin-expressing neurons. A majority of the galanin-immunoreactive neurons lacked VIP, while all VIP-immunoreactive neurons contained galanin. In conclusion, culturing porcine myenteric neurons in the presence of VIP increases, while the presence of galanin reduces, survival. Culturing significantly increased the proportion of neurons expressing VIP and/or galanin; the presence of VIP further increased the number of galanin-expressing neurons.
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| 5. |
- Arciszewski, MB, et al.
(author)
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Vasoactive intestinal peptide rescues cultured rat myenteric neurons from lipopolysaccharide induced cell death
- 2008
-
In: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 146:1-3, s. 218-223
-
Journal article (peer-reviewed)abstract
- The role of the enteric nervous system in intestinal inflammation is not fully understood and the plethora of cellular activities concurrently ongoing in vivo renders intelligible studies difficult. In order to explore possible effects of bacterial lipopolysaccharide (LPS) on enteric neurons we utilised cultured myenteric neurons from rat small intestine. Exposure to LPS caused markedly reduced neuronal survival and increased neuronal expression of vasoactive intestinal peptide (VIP), while the expression of Toll-like receptor 4 (TLR4) was unchanged. TLR4 was expressed in approximately 35% of all myenteric neurons irrespective of if they were cultured in the presence or absence of LPS. In neurons cultured in medium, without LPS, 50% of all TLR4-immunoreactive neurons contained also VIP. Addition of LPS to the neuronal cultures markedly increased the proportion of TLR4-immunoreactive neurons also expressing VIP, while the proportion of TLR4 neurons devoid of VIP decreased. Simultaneous addition of LPS and VIP to the neuronal cultures resulted in a neuronal survival comparable to controls. CONCLUSIONS: LPS recognition by myenteric neurons is mediated via TLR4 and causes neuronal cell death. Presence of VIP rescues the neurons from LPS-induced neurodegeneration.
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| 6. |
- Bakos, J., et al.
(author)
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Oxytocin levels in the posterior pituitary and in the heart are modified by voluntary wheel running
- 2007
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In: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 139:1-3, s. 96-101
-
Journal article (peer-reviewed)abstract
- We hypothesized that voluntary wheel running results in increased secretion of oxytocin, a peptide involved in the stress response. An additional hypothesis was that prolonged exercise affects oxytocin levels in the heart, which is in line with the potential role of oxytocin in cardiovascular functions. Voluntary wheel running lasted 3 weeks and daily running distances increased progressively reaching maximum levels about 8 km (Sprague-Dawley rats) and 4 km (Lewis strain). The exercise resulted in significant reduction of epididymal fat, slight increase in glucose transporter GLUT4 mRNA levels and significant enhancement of plasma density. Voluntary exercise failed to influence plasma oxytocin levels either in Lewis or Sprague-Dawley rats, but it resulted in a significant decrease of oxytocin concentrations in the posterior pituitary. Plasma oxytocin concentrations were not modified even if the measurements were made in the dark phase of the day. In voluntary wheel running Sprague-Dawley rats, the content of oxytocin in the right heart atrium was lower than in controls. Thus, the present findings demonstrate that prolonged voluntary wheel running results in a decrease in pituitary oxytocin content without evident changes in hormone concentrations in peripheral blood. However, prolonged exercise used has a significant impact on oxytocin levels in the heart. (c) 2006 Elsevier B.V. All rights reserved.
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| 7. |
- Benrick, Anna, 1979, et al.
(author)
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A non-conservative polymorphism in the IL-6 signal transducer (IL6ST)/gp130 is associated with myocardial infarction in a hypertensive population.
- 2008
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In: Regulatory peptides. - : Elsevier BV. - 0167-0115. ; 146:1-3, s. 189-96
-
Journal article (peer-reviewed)abstract
- Inflammation is a key component in the development of atherosclerosis, and myocardial infarction (MI); therefore we investigated the association between an interleukin-6 signal transducer (IL6ST)/gp130 polymorphism, gp130 function and risk of MI. Structural modeling suggested that a non-conservative single nucleotide polymorphism in the gp130, Gly148Arg, can change the stability and functional properties of the molecule. In vitro studies were done with BAF/3 cells lacking endogenous gp130. Cells stably transfected with the gp130 148Arg variant proliferated less and showed slightly lower STAT-3 phosphorylation in response to gp130 stimulation as compared to cells transfected with gp130 148Gly. In a prospectively followed hypertensive cohort we identified 167 patients who suffered a MI during the study and compared them to matched controls (mean age 57 years, 73% males, n=482). Carriers of the 148Arg variant (f(Arg)=0.12) of the gp130 receptor had decreased odds ratio for MI in univariate analysis (0.56, 95% CI 0.34-0.91, p=0.02). In conclusion, a genetically determined structural variant of the IL-6 receptor subunit gp130 is, independently of other known risk factors, associated with decreased risk of MI. The variant is also associated with decreased IL-6 responsiveness and could lead to a configuration change in the gp130 receptor.
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| 8. |
- Björkqvist, Maria, et al.
(author)
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Somatostatin, misoprostol and galanin inhibit gastrin- and PACAP-stimulated secretion of histamine and pancreastatin from ECL cells by blocking specific Ca(2+) channels.
- 2005
-
In: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 130:1-2, s. 81-90
-
Journal article (peer-reviewed)abstract
- The oxyntic mucosa is rich in ECL cells. They secrete histamine and chromogranin A-derived peptides, such as pancreastatin, in response to gastrin and pituitary adenylate cyclase-activating peptide (PACAP). Secretion is initiated by Ca2+ entry. While gastrin stimulates secretion by opening L-type and N-type Ca2+ channels, PACAP stimulates secretion by activating L-type and receptor-operated Ca2+ channels. Somatostatin, galanin and prostaglandin E2 (PGE2) inhibit gastrin- and PACAP-stimulated secretion from the ECL cells. In the present study, somatostatin and the PGE2 congener misoprostol inhibited gastrin- and PACAP-stimulated secretion 100%, while galanin inhibited at most 60–65%. Bay K 8644, a specific activator of L-type Ca2+ channels, stimulated ECL-cell secretion, an effect that was inhibited equally effectively by somatostatin, misoprostol and galanin (75–80% inhibition). Pretreatment with pertussis toxin, that inactivates inhibitory G-proteins, prevented all three agents from inhibiting stimulated secretion (regardless of the stimulus). Pretreatment with nifedipine (10 μM), an L-type Ca2+ channel blocker, reduced PACAP-evoked pancreastatin secretion by 50–60%, gastrin-evoked secretion by not, vert, similar 80% and abolished the response to Bay K 8644. The nifedipine-resistant response to PACAP was abolished by somatostatin and misoprostol but not by galanin. Gastrin and PACAP raised the intracellular Ca2+ concentration in a biphasic manner, believed to reflect mobilization of internal Ca2+ followed by Ca2+ entry. Somatostatin and misoprostol blocked Ca2+ entry (and histamine and pancreastatin secretion) but not mobilization of internal Ca2+. The present observations on isolated ECL cells suggest that Ca2+ entry rather than mobilization of internal Ca2+ triggers exocytosis, that gastrin and PACAP activate different (but over-lapping) Ca2+ channels, that somatostatin, misoprostol and galanin interact with inhibitory G-proteins to block Ca2+ entry via L-type Ca2+ channels, and that somatostatin and misoprostol (but not galanin) in addition block N-type and/or receptor-operated Ca2+ channels.
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| 9. |
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| 10. |
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| 11. |
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| 12. |
- Carlini, Valeria P., et al.
(author)
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Selective serotonin reuptake inhibitor (fluoxetine) decreases the effects of ghrelin on memory retention and food intake
- 2007
-
In: Regulatory Peptides. - : Elsevier BV. - 0167-0115 .- 1873-1686. ; 140:1-2, s. 65-73
-
Journal article (peer-reviewed)abstract
- Ghrelin (Ghr) is an appetite stimulating hormone that is produced peripherally, by the stomach, and centrally as well. Previous investigations show that Ghr increases food intake and memory retention in rats, and that extra-hypothalamic structures, such as the hippocampus, participate in these effects. In the present work we analyzed the effect on food intake and memory retention induced by Ghr after serotonin (5-HT) availability modification at the serotoninergic synapses. Animals only treated with a selective serotonin reuptake inhibitor (SSRI), fluoxetine (FLU) 5 mg/kg or clomipramine (CLO) 2.5 and 5 mg/kg, showed a significant reduction in both food intake and memory retention. On the contrary, Ghr administration induces a significant increase in food intake and a dose-dependent increase in short and long term memory retention. When the animals were treated with FLU prior to Ghr injection, the food intake induced, as well as the expression of short and long term memory retention, was decreased. In conclusion, evidence presented in this paper suggests that the effects of Ghr on both feeding and memory retention in extra-hypothalamic structures such as the hippocampus, could depend on the availability of 5-HT.
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| 13. |
- Cramp, R.L., et al.
(author)
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The effects of saltwater acclimation on neurotransmitters in the lingual salt glands of the estuarine crocodile, Crocodylus porosus
- 2007
-
In: Regulatory Peptides. - : Elsevier BV. - 0167-0115. ; 140:1-2, s. 55-64
-
Journal article (peer-reviewed)abstract
- Introduction Most avian and reptilian salt glands display marked phenotypic plasticity when animals are exposed to hyperosmotic conditions. In addition, the activity of most salt glands is under considerable control by the nervous system and nerves containing cholinergic, adrenergic and peptidergic neurotransmitters have been identified in avian and reptilian salt gland tissues. The present study sought to determine whether the salt glands of the estuarine crocodile, Crocodylus porosus contain the peptidergic neurotransmitters SP, CGRP, VIP, and PACAP and the gaseous neurotransmitter, NO. In addition, we sought to determine whether there was any evidence for the adaptation of the C. porosus salt gland nervous system to hyperosmotic conditions. Methods Salt glands from freshwater- and saltwater-acclimated C. porosus hatchlings were sectioned and examined immunohistochemically for neurotransmitters within the tissue. Results Neurons containing SP, CGRP, VIP, PACAP and NO synthase were identified within C. porosus salt glands. There was no difference in the overall number (density) of neurons within SW-acclimated tissues when compared with FW-acclimated animals. However, there was a significant reduction in density of neurons containing SP and PACAP in SW-acclimated animals. Conclusion C. porosus salt glands display phenotypic plasticity following exposure to hyperosmotic conditions. In addition to cholinergic and adrenergic neurons, they contain a variety of peptidergic neurotransmitters and the gaseous neurotransmitter NO. Additionally, there appears to be some evidence of acclimation of the nervous system of C. porosus to hypersaline conditions, although the functional significance of these changes remains to be determined.
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| 14. |
- de la Cour, Charlotta, et al.
(author)
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Secretion of ghrelin from rat stomach ghrelin cells in response to local microinfusion of candidate messenger compounds: A microdialysis study
- 2007
-
In: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 143:1-3, s. 118-126
-
Journal article (peer-reviewed)abstract
- Ghrelin is produced by A-like cells (ghrelin cells) in the mucosa of the acid-producing part of the stomach. The mobilization of ghrelin is stimulated by nutritional deficiency and suppressed by nutritional abundance. In an attempt to identify neurotransmitters and regulatory peptides that may contribute to the physiological, nutrient-related regulation of ghrelin secretion, we challenged the ghrelin cells in situ with a wide variety of candidate messengers, including known neurotransmitters (e.g. acetylcholine, catecholamines), candidate neurotransmitters (e.g. neuropeptides), local tissue hormones (e.g. serotonin, histamine, bradykinin, endothelin), circulating gut hormones (e.g. gastrin, CCK, GIP, neurotensin, PYY, secretin) and other circulating hormones/regulatory peptides (e.g. calcitonin, glucagon, insulin, PTH). Microdialysis probes were placed in the submucosa of the acid-producing part of the rat stomach. Three days later, the putative messenger compounds were administered via the microdialysis probe (reverse microdialysis) at a screening dose of 0.1 mmol 1(-1) for regulatory peptides and 0.1 and 1 mmol 1(-1) for amines and amino acids. The rats were awake during the experiments. The resulting microdialysate ghrelin concentration was monitored continuously for 3 h (radioimmunoassay), thereby revealing stimulators or inhibitors of ghrelin secretion. Dose-response curves were constructed for each candidate messenger that significantly (p < 0.05) affected ghrelin mobilization at the screening dose. Peptides that showed a (non-significant) tendency to affect ghrelin release at the screening dose were also given at a dose of 0.3 or 1 mmol 1(-1). Adrenaline, noradrenaline, endothelin and secretin stimulated ghrelin release, while somatostatin and GRP inhibited. Whether these agents act directly or indirectly on the ghrelin cells remains to be investigated. All other candidate messengers were without measurable effects, including acetylcholine, serotonin, histamine, GABA, aspartic acid, glutamic acid, glycine, VIP, PACAP, CGRP, substance P, NPY, PYY, PP, gastrin, CCK, GIP, insulin, glucagon, GLP and glucose. (c) 2007 Elsevier B.V. All rights reserved.
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| 15. |
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| 16. |
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| 17. |
- Egecioglu, Emil, 1977, et al.
(author)
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Hypothalamic gene expression following ghrelin therapy to gastrectomized rodents.
- 2008
-
In: Regulatory peptides. - : Elsevier BV. - 0167-0115 .- 1873-1686. ; 146:1-3, s. 176-82
-
Journal article (peer-reviewed)abstract
- We investigated whether ghrelin depletion (by gastrectomy surgery) and/or treatment/replacement with the gastric hormone ghrelin alters the expression of key hypothalamic genes involved in energy balance, in a manner consistent with ghrelin's pro-obesity effects. At 2 weeks after surgery mice were treated with ghrelin (12 nmol/mouse/day, sc) or vehicle for 8 weeks. Gastrectomy had little effect on the expression of these genes, with the exception of NPY mRNA in the arcuate nucleus that was increased. Ghrelin treatment (to gastrectomized and sham mice) increased the mRNA expression of orexigenic peptides NPY and AgRP while decreasing mRNA expression of the anorexigenic peptide POMC. Two weeks gavage treatment with the ghrelin mimetic, MK-0677, to rats increased NPY and POMC mRNA in the arcuate nucleus and MCH mRNA in the lateral hypothalamus. Thus, while predicted pro-obesity ghrelin signalling pathways were activated by ghrelin and ghrelin mimetics, these were largely unaffected by gastrectomy.
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| 18. |
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| 19. |
- Ekström, Jörgen, 1944, et al.
(author)
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Parasympathetic non-adrenergic, non-cholinergic transmission in rat parotid glands: effects of cholecystokinin-A and -B receptor antagonists on the secretory response.
- 2008
-
In: Regulatory peptides. - : Elsevier BV. - 0167-0115. ; 146:1-3, s. 278-84
-
Journal article (peer-reviewed)abstract
- Recent studies show i.v. administered pentagastrin and cholecystokinin to evoke protein/amylase secretion from the rat parotid gland and to stimulate gland protein synthesis, the two phenomena being abolished by cholecystokinin receptor antagonists. In the rat parotid gland, non-adrenergic, non-cholinergic transmission mechanisms contribute to secretion of fluid and protein/amylase. Since cholecystokinin may act as a neurotransmitter, activation of cholecystokinin receptors of the gland might contribute to the parasympathetic nerve-evoked secretion. In this study, the parasympathetic innervation was stimulated in non-atropinized (in periods of 2 min) or atropinized (in periods of 3 min) pentobarbitone-anaesthetized rats before and after administration of the cholecystokinin-A receptor antagonist lorglumide (48 mg/kg, i.v.) and the cholecystokinin-B receptor antagonist itriglumide (5.5 mg/kg, i.v.). The non-adrenergic, non-cholinergic transmission fatigues rapidly resulting in declining responses. Therefore, atropinized rats, not receiving the cholecystokinin receptor antagonists, had to serve as controls. Neither at a stimulation frequency of 10 Hz nor of 40 Hz were the secretory responses of the atropinized rats affected by the receptor antagonists. After lorglumide, the saliva volume and the amylase output were (expressed as percentage of the response to the stimulation period before the administration of the antagonist) 98.0+/-3.8% (vs. control 91.1+/-4.0%) and 91.9+/-4.9% (vs. 87.7+/-3.7%) at 10 Hz, respectively, and 79.8+/-4.5% (vs. 77.3+/-2.1%) and 73.6+/-5.3% (vs. 71.7+/-2.3%) at 40 Hz, respectively. After itriglumide, the corresponding percentage figures for saliva volume and amylase output were, at 10 Hz, 99.5+/-8.9% (vs. 92.0+/-2.8%) and 95.8+/-11.8% (vs. 89.2+/-6.4%), respectively, and, at 40 Hz, 74.0+/-3.1% (vs. 79.6+/-2.2%) and 66.6+/-3.3% (vs. 63.9+/-6.0%), respectively. Similarly, the antagonists were without effect on the parotid secretory responses of non-atropinized rats subjected to stimulation at 10 Hz. Thus, under physiological conditions, the cholecystokinin receptors of the parotid gland are likely to be stimulated by circulating hormones rather than by nervous activity.
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| 20. |
- Erlanson-Albertsson, Charlotte, et al.
(author)
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Vagotomy and accompanying pyloroplasty down-regulates ghrelin mRNA but does not affect ghrelin secretion.
- 2008
-
In: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 151, s. 14-18
-
Journal article (peer-reviewed)abstract
- In this study, we have examined how the lack of vagus activity affects the long-term secretion of total and active ghrelin. We subjected mice to sham-operation, pyloroplasty or vagotomy and pyloroplasty. The study lasted for 2 weeks, during which body weight development and daily food intake was monitored. At the end of the study, the mice were sacrificed, and serum and fundus were collected. Measurements of total and active serum ghrelin revealed no difference between the surgical groups and sham-operated mice, despite the fact that fundic ghrelin mRNA was down-regulated. The results presented here suggest that the vagus activity is not required for the long-term secretion of neither total nor active ghrelin in mice. They also suggest that fundic ghrelin mRNA expression is affected by pyloroplasty and vagotomy but that this effect does not translate into changes in ghrelin levels in the circulation.
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| 21. |
- Forsgren, Sture, et al.
(author)
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Vascular NK-1 receptor occurrence in normal and chronic painful Achilles and patellar tendons : studies on chemically unfixed as well as fixed specimens.
- 2005
-
In: Regulatory Peptides. - : Elsevier BV. - 0167-0115 .- 1873-1686. ; 126:3, s. 173-181
-
Journal article (peer-reviewed)abstract
- It is not known as to whether the Achilles and patellar tendons contain neurokinin-1 (NK-1) receptors. This is a drawback when considering the fact that pain symptoms are frequent in these and as recent studies show that the pain symptoms might be cured via interference with blood vessel function. In the present study, the human Achilles and patellar tendons were examined concerning immunohistochemical expression of the NK-1 receptor. Chemically unfixed and fixed specimens, TRITC and PAP stainings and a battery of NK-1 receptor antibodies, including antibodies against the C-terminus and the N-terminal region, were utilized. NK-1 receptor immunoreaction could be detected in inner parts of the walls of large blood vessels and in the walls of small blood vessels. To some extent, NK-1 immunoreaction was also detectable in small nerve fascicles and in tenocytes. It was found to be of utmost importance to apply both chemically unfixed and fixed specimens. The use of chemically unfixed tissue was found advantageous in order to depict the immunoreactions in the blood vessel walls. The observations represent new findings and are of relevance as substance P (SP) is known to be of importance where neurogenic angiogenesis contributes to diseases and as SP on the whole has profound effects concerning blood vessel regulation.
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| 22. |
- Friis-Hansen, Lennart, et al.
(author)
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Characteristics of gastrin controlled ECL cell specific gene expression
- 2007
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In: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 140:3, s. 153-161
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Journal article (peer-reviewed)abstract
- Background: The ECL cells are histamine-producing endocrine cells in the oxymic mucosa that synthesize and secrete proteins and peptides. They are the primary target for gastrin and mediate the control of gastrin on acid secretion and oxyntic mucosal growth. Knowledge of the molecular biology of the ECL cell is therefore important for understanding gastric physiology. Accordingly, we wanted to identify genes that are characteristically expressed in the ECL cells and controlled by gastrin. Methods: Using Affymetrix GeneChips((R)), RNA expression profiles were generated from ECL cells isolated by counterflow elutriation from hyper- or hypogastrinemic rats. Contamination from non-endocrine cells was eliminated by subtraction of the expression profiles of the fundic and antral mucosa. Results: The expression of 365 genes was ECL cell characteristic. Gastrin was found to control the expression of 120 which could be divided into two major groups depending on the known or anticipated biological function of the encoded protein: genes encoding proteins involved in the secretory process and genes encoding proteins needed to generate energy for secretion. Interestingly, gastrin stimulation also increased ECL cells expression of anti-apoptotic genes. Conclusion: The ECL cell specific expression profile is reminiscent of that of neurons and other endocrine cells exhibiting high expression of genes encoding proteins involved in the synthesis, storage and secretion of neuropeptides or peptide hormones. Gastrin regulated the expression of one third of these genes and is thus involved in the control of secretion from the ECL cells.
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| 23. |
- Hellström, Per M., 1954-
(author)
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GLP-1 : broadening the incretin concept to involve gut motility
- 2009
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In: Regulatory Peptides. - : Elsevier BV. - 0167-0115 .- 1873-1686. ; 156:1-3, s. 9-12
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Journal article (peer-reviewed)abstract
- The incretin effect of the gut peptide hormone glucagon-like peptide-1 (GLP-1) is a combined result of inhibition of gastric emptying and stimulation of insulin secretion via an incretin mechanism. The temporal pattern of these events implicate that gastric emptying is primarily delayed, while later in the digestive process insulin is released for nutrient disposal. Since the inhibitory effect of GLP-1 on gastric motility is very outspoken, we considered it of value to study its effects on gut motility. Animal experimentation in the rat clearly showed that not only gastric emptying, but also small bowel motility with the migrating myoelectric complex was profoundly inhibited by GLP-1 at low doses. Similar effects were seen with analogues of the peptide. Extending the studies to man supported our earliest data indicating that the migrating motor complex of the small intestine was affected, and even more noticeable, the summarized motility index inhibited. Further extension of our studies to patients with irritable bowel syndrome (IBS) displayed similar results. This encouraged us to embark on a clinical pain-relief multi-centre study in IBS patients using a GLP-1 analogue, ROSE-010, with longer half-life than the native peptide. The outcome of the IBS study proved ROSE-010 to be superior to placebo with a pain-relief response rate of 24% for ROSE-010 compared to 12% for placebo. Taken together, the GLP-1 analogue ROSE-010 is believed to cause relaxation of the gut and can thereby relieve an acute pain attack of IBS, even though its precise mechanism is yet to be defined.
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| 24. |
- Johansson, Ewa, 1964, et al.
(author)
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Identification of flotillin-1 as an interacting protein for antisecretory factor
- 2008
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In: Regulatory Peptides. - : Elsevier BV. - 0167-0115. ; 146:1-3, s. 303-309
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Journal article (peer-reviewed)abstract
- Antisecretory factor (AF) also named S5a/Rpn10 was originally identified through its capacity to inhibit intestinal hypersecretion and was later shown to be a component in the proteasome complex. AF is also a potent anti-inflammatory agent and can act as a neuromodulator. In this study we used yeast two-hybrid screens, with yeast strain PJ692A transformed with the bait vector pGBKT7 (AF aa 1–105) against yeast strain Y187 pretransformed with human brain or placenta cDNA libraries, to identify AF-binding proteins. Flotillin-1 was identified as a specific interacting factor with AF. Immunohistochemistry showed co-localization of AF and flotillin-1 in nervous tissue. Flotillin-1 is an integral membrane protein and a component of lipid rafts, a membrane specialization involved in transport processes. Intracellular AF may affect secretory processes by regulating the localization of signal proteins to lipid rafts. © 2007 Elsevier B.V. All rights reserved. Keywords: S5a/Rpn10; Two-yeast hybrid; Lipid raft; Dot blot; Immunofluorescence
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| 25. |
- Kim, Malin, et al.
(author)
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Antisecretory factor modulates GABAergic transmission in the rat hippocampus.
- 2005
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In: Regulatory peptides. - : Elsevier BV. - 0167-0115. ; 129:1-3, s. 109-18
-
Journal article (peer-reviewed)abstract
- Antisecretory Factor (AF) is a protein that has been implicated in the suppression of intestinal hypersecretion and inflammation. Intestinal secretion and inflammation are partly under local and central neural control raising the possibility that AF might exert its action by modulating neural signaling. In the present study we have investigated whether AF can modulate central synaptic transmission. Evoked glutamatergic and GABAergic synaptic transmissions were investigated using extracellular recordings in the CA1 region of hippocampal slices from adult rats. AF (0.5 microg/ml) suppressed GABA(A)-mediated synaptic transmission by about 40% while having no effect on glutamatergic transmission. Per oral administration of cholera toxin as well as feeding of rats with a diet containing hydrothermally processed cereals, known to upregulate endogenous AF plasma activity, mimicked the effect of exogenously administered AF on hippocampal GABAergic transmission. Our results identify AF as a neuromodulator and further raise the possibility that the hippocampus and AF are involved in a gut-brain loop controlling intestinal secretion and inflammation.
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| 26. |
- Kristensson, E, et al.
(author)
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Acute psychological stress raises plasma ghrelin in the rat.
- 2006
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In: Regulatory Peptides. - : Elsevier BV. - 0167-0115 .- 1873-1686. ; 134:2-3, s. 114-117
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Journal article (peer-reviewed)abstract
- Ghrelin is produced by the A-like cells of the stomach and mobilized by food deprivation. It was reported recently that acute psychological stress increases ghrelin gene expression in rat oxyntic mucosa. The aim of this study was to examine the effect of such stress on circulating ghrelin levels. To this end, we measured plasma ghrelin in Wistar Kyoto (WKY) rats (a high-anxiety strain) and Sprague–Dawley (SPD) rats (a low-anxiety strain), exposed to water avoidance stress for 60 min. Blood was collected before and after the stress. Acute stress increased the plasma ACTH concentration not, vert, similar5-fold (p < 0.01) in both strains of rats, while plasma ghrelin increased by 85% (p < 0.01) in the SPD rats and by 40% (p < 0.001) in the WKY rats. Ghrelin levels after acute stress were higher (p < 0.05) in the SPD rats than in the WKY rats. Sham stress did not affect plasma ghrelin. We conclude that acute psychological stress mobilizes ghrelin and that the SPD rats respond with a higher plasma ghrelin concentration than the WKY rats.
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| 27. |
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| 28. |
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| 29. |
- Lindqvist, Andreas, et al.
(author)
-
Effects of sucrose, glucose and fructose on peripheral and central appetite signals.
- 2008
-
In: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 150, s. 26-32
-
Journal article (peer-reviewed)abstract
- In the Western world, consumption of soft drinks has increased the last three decades and is partly responsible for the epidemic-like increase in obesity. Soft drinks, originally sweetened by sucrose, are now sweetened by other caloric sweeteners, such as fructose. In this study, we investigated the short-term effect of sucrose, glucose or fructose solutions on food intake and body weight in rats, and on peripheral and central appetite signals. Rats received water containing either of the sugars and standard rat chow for two weeks. Rats receiving water alone and standard chow were controls. All rats offered the sugar solutions increased their total caloric intake. The increased caloric intake occurred despite the fact that the rats offered either of the sugar solutions consumed less chow. As a consequence of the increased caloric intake, the sugar-drinking rats had elevated serum levels of free fatty acids, triglycerides and cholesterol. In addition, consuming sugar solutions resulted in increased serum leptin, decreased serum PYY and down-regulated hypothalamic NPY mRNA. Serum ghrelin was increased in rats receiving fructose solution. Moreover, consumption of sucrose or fructose solution resulted in up-regulated hypothalamic CB1 mRNA. Hypothalamic POMC mRNA was down-regulated in rats receiving glucose or fructose. In conclusion, consumption of glucose, sucrose or fructose solution results in caloric overconsumption and body weight gain through activation of hunger signals and depression of satiety signals as well as activation of reward components. The weight-promoting effect of these sugar solutions may possibly be ameliorated by the down-regulation of NPY mRNA and increased serum leptin.
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| 30. |
- Lindqvist, Andreas, et al.
(author)
-
Ghrelin affects gastrectomy-induced decrease in UCP1 and beta(3)-AR mRNA expression in mice.
- 2007
-
In: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 142:1-2, s. 24-28
-
Journal article (peer-reviewed)abstract
- this study we investigated the effects of gastrectomy (Gx) and of the gastric hormone, ghrelin, on the expression of proteins in brown adipose tissue (BAT) that are thought to be involved in thermogenesis. Heat production in BAT is known to depend upon activation and increased expression of β3-adrenergic receptors (β3-AR) and the consequent up-regulation of uncoupling protein 1 (UCP1). Mice were subjected to Gx or sham operation. One week later they started to receive daily subcutaneous injections of either saline or ghrelin (12 nmol) for two or eight weeks. Neither Gx nor ghrelin affected daily food intake. Gx did not lower body weight gain (except during the first post-operative week) but Gx mice responded to eight weeks of ghrelin treatment with a greater body weight increase (37%, p < 0.05) than saline-injected Gx mice; sham-operated mice did not respond to ghrelin. Gx resulted in a greatly reduced expression of both UCP1 and β3-AR mRNA in BAT (50% reduction or more, p < 0.01) compared to sham-operated mice. Eight weeks of ghrelin treatment raised the UCP1 as well as the β3-AR mRNA expression in the Gx mice, whereas two weeks of ghrelin treatment decreased UCP1 and β3-AR mRNA expression compared to Gx mice receiving saline. In fact, mRNA expression in Gx mice after treatment with ghrelin for eight weeks was similar to that in saline-treated sham-operated mice. Ghrelin did not affect UCP1 and β3-AR mRNA in sham-operated mice neither two nor eight weeks after the operation. The results suggest 1) that signals from the stomach stimulate BAT UCP1 (and possibly thermogenesis) and 2) that ghrelin may contribute to the control of UCP1 expression.
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| 31. |
- Lindqvist, Andreas, et al.
(author)
-
Overeating of palatable food is associated with blunted leptin and ghrelin responses.
- 2005
-
In: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 130:Jun 16, s. 123-132
-
Journal article (peer-reviewed)abstract
- Palatable food is rich in fat and/or sucrose. In this study we examined the long-term effects of such diets on food intake, body weight, adiposity and circulating levels of the satiety peptide leptin and the hunger peptide ghrelin. The experiments involved rats and mice and lasted 5 weeks. In rats, we examined the effect of diets rich in fat and/or sucrose and in mice the effect of a high fat diet with or without sucrose in the drinking water. Animals fed with the palatable diets had a larger intake of calories, gained more weight and became more adipose than animals fed standard rat chow. Fasted animals are known to have low serum leptin and high serum ghrelin and to display elevated serum leptin and lowered serum ghrelin postprandially. With time, a sucrose-rich diet was found to raise the fasting level of leptin and to lower the fasting level of ghrelin in rats. A fat-rich diet suppressed serum ghrelin without affecting serum leptin; high sucrose and high fat in combination greatly reduced serum ghrelin and raised serum leptin in the fasted state. The mRNA expression of leptin in the rat stomach was up-regulated by sucrose-rich (but not by fat-rich) diets, whereas the expression of ghrelin seemed not to be affected by the palatable diets. Mice responded to sucrose in the drinking water with elevated serum leptin (fasted state) and to all palatable diets with low serum ghrelin. The expression of both leptin and ghrelin mRNA in the stomach was suppressed in fasted mice that had received a high fat diet for 5 weeks. We conclude that the expression of leptin mRNA in stomach and the concentration of leptin in serum were elevated in response to sucrose-rich rather than fat-rich diets, linking leptin with sucrose metabolism. In contrast, the expression of ghrelin and the serum ghrelin concentration were suppressed by all palatable diets, sucrose and fat alike. In view of the increased body weight and adiposity neither elevated leptin nor suppressed ghrelin were able to control/restrain the overeating that is associated with palatable diets.
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| 32. |
- Ludvigsen, Eva, et al.
(author)
-
Regulation of insulin and glucagon secretion from rat pancreatic islets in vitro by somatostatin analogues
- 2007
-
In: Regulatory Peptides. - : Elsevier BV. - 0167-0115 .- 1873-1686. ; 138:1, s. 1-9
-
Journal article (peer-reviewed)abstract
- Somatostatin is an inhibitor of hormone secretion through specific receptors (sst1-5). The aim of this study was to investigate the putative regulatory role of somatostatin analogues on the secretion of insulin and glucagon by rat pancreatic islets. After 48 h exposure only the non-selective agonists (somatostatin, octreotide and SOM-230) inhibited insulin accumulation. The inhibition of insulin secretion was accompanied by increased islet insulin contents. None of the analogues showed a consistent effect on the glucagon accumulation in the medium after 48 h. Since we observed a difference in the regulatory effect between the non-selective and selective analogues, combinations of selective analogues were studied. Combination of sst2 + sst5 agonists inhibited the medium insulin accumulation, while combination of sst1 + sst2 analogues caused a decrease in glucagon accumulation. After removal of somatostatin a rebound effect with increased insulin secretion were observed. This effect was reversed after 6 h. For SOM-230 insulin secretion continued to be suppressed even after the analogue was removed and returned to control values after 3 h. As for glucagon secretion there was an initial decline after culture with octreotide, while the other substances failed to induce any changes. In summary, non-selective somatostatin analogues or combinations of receptor selective analogues may cause inhibition of hormone secretion from rat pancreatic islets. For insulin and glucagon, combinations of sst2 + sst5 and sst1 + sst2, respectively may exert this effects. Thus, our data suggest that more than one sst must be involved to down-regulate islet glucagon and insulin secretion.
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| 33. |
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| 34. |
- Mosén, Henrik, et al.
(author)
-
Impaired glucose-stimulated insulin secretion in the GK rat is associated with abnormalities in islet nitric oxide production.
- 2008
-
In: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 151, s. 139-146
-
Journal article (peer-reviewed)abstract
- We investigated implications of nitric oxide (NO) derived from islet neuronal constitutive NO synthase (ncNOS) and inducible NOS (iNOS) on insulin secretory mechanisms in the mildly diabetic GK rat. Islets from GK rats and Wistar controls were analysed for ncNOS and iNOS by HPLC, immunoblotting and immunocytochemistry in relation to insulin secretion stimulated by glucose or l-arginine in vitro and in vivo. No obvious difference in ncNOS fluorescence in GK vs control islets was seen but freshly isolated GK islets displayed a marked iNOS expression and activity. After incubation at low glucose GK islets showed an abnormal increase in both iNOS and ncNOS activities. At high glucose the impaired glucose-stimulated insulin release was associated with an increased iNOS expression and activity and NOS inhibition dose-dependently amplified insulin secretion in both GK and control islets. This effect by NOS inhibition was also evident in depolarized islets at low glucose, where forskolin had a further amplifying effect in GK but not in control islets. NOS inhibition increased basal insulin release in perfused GK pancreata and amplified insulin release after glucose stimulation in both GK and control pancreata, almost abrogating the nadir separating first and second phase in controls. A defective insulin response to l-arginine was seen in GK rats in vitro and in vivo, being partially restored by NOS inhibition. The results suggest that increased islet NOS activities might contribute to the defective insulin response to glucose and l-arginine in the GK rat. Excessive iNOS expression and activity might be deleterious for the beta-cells over time.
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| 35. |
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| 36. |
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| 37. |
- Ohlsson, Bodil, et al.
(author)
-
Oxytocin is expressed throughout the human gastrointestinal tract.
- 2006
-
In: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 135:2006 May 4, s. 7-11
-
Journal article (peer-reviewed)abstract
- Background/Aim: Several studies have described that oxytocin exerts stimulatory or inhibitory effects on gut functions. Recently, mRNA for oxytocin and its receptor was found throughout the entire human gastrointestinal (GI) tract. The aim of this study was to examine the cellular localization and distribution of the corresponding proteins. Material and methods: Full-thickness biopsies from 24 patients, covering the entire GI tract, were collected during operations at the Department of Surgery in Malmo and Lund. The biopsies were taken from non-affected margins. The biopsies were fixed by immersion, rinsed in buffered sucrose, and kept frozen at -70 degrees C. Indirect immunofluorescence with primary antibodies to oxytocin and its receptor was used. Results: Oxytocin was expressed in nerve cell bodies and nerve fibres in the myenteric and submucous ganglia all along the GI tract. Immunoreactive nerve cell bodies in myenteric ganglia predominated in the proximal (antrum and duodenum) and distal gut, while those in the submucous ganglia were more numerous in the ileum and colon. The oxytocin receptor was not detectable by two different antibodies in any tissue in the GI tract. Conclusion: Oxytocin is expressed in the myenteric and submucous ganglia and nerve fibres along the entire human GI tract. The role for oxytocin in the physiology and pathophysiology of the bowel remains to be settled. (c) 2006 Elsevier B.V. All rights reserved.
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| 38. |
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| 39. |
- Portela-Gomes, Guida Maria, et al.
(author)
-
Prohormone convertases 1/3, 2, furin and protein 7B2 (Secretogranin V) in endocrine cells of the human pancreas
- 2008
-
In: Regulatory Peptides. - : Elsevier BV. - 0167-0115 .- 1873-1686. ; 146:1-3, s. 117-124
-
Journal article (peer-reviewed)abstract
- Prohormone convertases (PCs) are proteinases that cleave inactive prohormones to biologically active peptides. Seven PCs have been identified; two of them, PC1/3 and PC2, have only been localized in neuroendocrine (NE) tissues; a third, furin, in both endocrine and exocrine tissues. We have studied the immunoreactivity of PC1/3, PC2 and furin in the four major NE cell types of the human pancreas by using double immunofluorescence techniques. The study also included the expression of NE secretory protein 7B2 (secretogranin V), a member of the granin family, which influences the function of PC2. The results showed that the three PCs and 7B2 were expressed only in endocrine pancreas, furin also in exocrine cells. Insulin (B) cells harboured PC1/3 and PC2, but not furin. Glucagon (A) cells were immunoreactive to all three PCs; all glucagon cells expressed PC2, but one subpopulation showed PC1/3 immunoreactivity and another furin. Only a few somatostatin (D) cells contained PC2, but no other proconvertase. Pancreatic polypeptide (PP) cells were non-reactive to all three PCs. 7B2 occurred only in insulin and glucagon cells. A varying co-localization pattern was observed between PCs and between PCs and 7B2, with the exception of PC1/3 and furin which were not co-localized. In conclusion, our study shows that PCs are localized in insulin and glucagon cells and do seem to be important in these cell types for processing of hormone and other protein precursors, especially chromogranins, but for the two other major cell types probably other enzymes are of importance.
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| 40. |
- Portela-Gomes, G. M., et al.
(author)
-
The importance of chromogranin A in the development and function of endocrine pancreas
- 2008
-
In: Regulatory Peptides. - : Elsevier BV. - 0167-0115 .- 1873-1686. ; 151:1-3, s. 19-25
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Chromogranin (Cg) A is expressed in neuroendocrine and neuronal tissues. It is involved in the generation of secretory granules and is cleaved to form biologically active peptides. Targeted ablation of the Chga gene resulted in increased plasma catecholamines, high blood pressure, and decreased size and number of adrenal medullary chromaffin granules. The aim of this study was to determine whether Chga null mice display changes in the morphology and function of the endocrine pancreas. MATERIALS AND METHODS: Sections of pancreata from Chga-/-, Chga+/- and Chga+/+ mice, were immunostained with antibodies against synaptophysin, CgA, CgB, secretogranin II and the four major pancreatic islet hormones. Plasma was analysed for glucose, insulin, glucagon, somatostatin and pancreatic polypeptide (PP). RESULTS: CgA epitopes were undetectable in the islets of Chga-/- animals. CgB and secretogranin II epitopes were expressed in the islets of all animal groups albeit with decreased expression in Chga-/- islets. The islet number and size were decreased in the Chga-/- animals compared with Chga+/+. The proportion of insulin cells was decreased but somatostatin and PP cells were increased in Chga-/- mice compared to Chga+/+ mice. The nuclear size was decreased in insulin cells and increased in somatostatin cells in Chga-/- mice. Plasma insulin level was markedly decreased in the Chga-/- mice although fasting plasma glucose and glucagon were normal. CONCLUSION: Ablation of the Chga gene affected the islet volume, the composition, distribution and nuclear size of islet cell types and plasma insulin concentration. Our data indicate decreased insulin cell function and increased glucagon cell function. Our study shows that CgA exerts a significant influence on the endocrine pancreas with importance in maintaining islet volume, cellular composition and function.
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| 41. |
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| 42. |
- Qader, Saleem, et al.
(author)
-
Long-term infusion of nutrients (total parenteral nutrition) suppresses circulating ghrelin in food-deprived rats.
- 2005
-
In: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 131:Aug 12, s. 82-88
-
Journal article (peer-reviewed)abstract
- Background: Ghrelin derives from endocrine cells (A-like cells) in the stomach (mainly the oxyntic mucosa). Its concentration in the circulation increases during fasting and decreases upon re-feeding. This has fostered the notion that the absence of food in the upper gastrointestinal (GI) tract stimulates the secretion of ghrelin. The purpose of the present study was to determine the concentration of ghrelin in serum and oxyntic mucosa after replacing food with intravenous (iv) infusion of nutrients for 8 days using the technique known as total parenteral nutrition (TPN). Materials and methods: Male Sprague-Dawley rats (200-250 g) were given nutrients (lipids, glucose, amino acids, minerals and vitamins) by iv infusion for 8 days during which time they were deprived of food and water; another group was deprived of food for 24-48 h (fasted controls), while fed controls had free access to food and water. Serum ghrelin, gastrin and pancreastatin concentrations were measured together with the ghrelin content of the oxyntic mucosa. Plasma insulin and glucose as well as serum lipid concentrations were also determined. Results: Fasted rats had higher serum ghrelin than TPN rats and fed controls. The oxyntic mucosal ghrelin concentration (and content) was lower in TPN rats than in fasted rats or fed controls. The serum gastrin and pancreastatin concentrations were lower in TPN rats and fasted rats than in fed controls. The plasma insulin concentration was 87 pmol/l +/- 8 (SEM) in TPN rats compared to 101 16 pmol/l in fed controls; it was 26 14 pmol/l in fasted rats. The basal plasma glucose level was 11 +/- 0.6 mmol/l in TPN rats and 12 +/- 0.8 mmol/l in fed controls; it was 7 +/- 0.3 mmol/l in fasted rats. In TPN rats, the serum concentrations of free fatty acids, triglycerides and cholesterol were increased by 100%, 50% and 25%, respectively, compared to fed controls. Fasted rats had higher circulating concentrations of free fatty acids (20%) and lower concentrations of triglycerides (- 40%) than fed controls; fasted rats did not differ from fed controls with respect to serum cholesterol. Conclusion: The circulating ghrelin concentration is high in situations of nutritional deficiency (starvation) and low in situations of nutritional plenty (free access to food or TPN). The actual presence or absence of food in the GI tract seems irrelevant. Circulating insulin and glucose concentrations did not differ much between TPN rats and fed controls, serum lipids, however, were elevated in the TPN rats. We suggest that elevated blood lipid levels contribute to the suppression of circulating ghrelin in rats subjected to TPN for 8 days.
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| 43. |
- Qader, Saleem, et al.
(author)
-
Proghrelin-derived peptides influence the secretion of insulin, glucagon, pancreatic polypeptide and somatostatin: A study on isolated islets from mouse and rat pancreas.
- 2008
-
In: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 146:1-3, s. 230-237
-
Journal article (peer-reviewed)abstract
- Proghrelin, the precursor of the orexigenic and adipogenic peptide hormone ghrelin, is synthetized in endocrine (A-like) cells in the gastric mucosa. During its cellular processing, proghrelin gives rise to the 28-amino acid peptide desacyl ghrelin, which after octanoylation becomes active acyl ghrelin, and to the 23-amino acid peptide obestatin, claimed to be a physiological opponent of acyl ghrelin. This study examines the effects of the proghrelin products, alone and in combinations, on the secretion of insulin, glucagon, pancreatic polypeptide (PP) and somatostatin from isolated islets of mice and rats. Surprisingly, acyl ghrelin and obestatin had almost identical effects in that they stimulated the secretion of glucagon and inhibited that of PP and somatostatin from both mouse and rat islets. Obestatin inhibited insulin secretion more effectively than acyl ghrelin. In mouse islets, acyl ghrelin inhibited insulin secretion at low doses and stimulated at high. In rat islets, acyl ghrelin inhibited insulin secretion in a dose-dependent manner but the IC50 for the acyl ghrelin-induced inhibition of insulin release was 7.5 × 10− 8 M, while the EC50 and IC50 values, with respect to stimulation of glucagon release and to inhibition of PP and somatostatin release, were in the 3 × 10− 12–15 × 10− 12 M range. The corresponding EC50 and IC50 values for obestatin ranged from 5 × 10− 12 to 20 × 10− 12 M. Desacyl ghrelin per se did not affect islet hormone secretion. However, at a ten times higher concentration than acyl ghrelin (corresponding to the ratio of the two peptides in circulation), desacyl ghrelin abolished the effects of acyl ghrelin but not those of obestatin. Acyl ghrelin and obestatin affected the secretion of glucagon, PP and somatostatin at physiologically relevant concentrations; with obestatin this was the case also for insulin secretion. The combination of obestatin, acyl ghrelin and desacyl ghrelin in concentrations and proportions similar to those found in plasma resulted in effects that were indistinguishable from those induced by obestatin alone. From the data it seems that the effects of endogenous, circulating acyl ghrelin may be overshadowed by obestatin or blunted by desacyl ghrelin.
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| 44. |
- Quinn, JG, et al.
(author)
-
Effect of reserpine on the generation of the chromogranin A-derived neuropeptide WE-14 in rat oxyntic mucosa
- 2005
-
In: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 124:1-3, s. 1-6
-
Journal article (peer-reviewed)abstract
- WE-14, a post-translational product of the neuroendocrine protein chromogranin A (CgA), is generated in distinct subpopulations of endocrine cells. The objective of this study was to investigate the generation of WE-14 in the endocrine cell types of the oxyntic mucosa of the stomach, after treatment with reserpine, an irreversible inhibitor of vesicular monoamine uptake 2 (VMAT2). Reserpine (10 mg/kg) was administered subcutaneously and tissue analysed 1, 3, 5 and 18 h following treatment. The oxymic mucosa was analysed immunohistochemically employing a site-specific WE-14 antiserum, a region-specific CgA antiserum and an antiserum against histidine decarboxylase (HDC), a marker of the histamine-producing ECL cells in the oxyntic mucosa. The number of oxyntic endocrine cells exhibiting WE-14 immunostaining increased more than 100-fold 18 h after reserpine administration relative to vehicle treated controls. Double immunostaining with HDC revealed that most, but not all, of the WE-14 positive cells were ECL cells. These results suggest that reserpine has the ability to influence the post-translational processing of CgA to generate WE-14 in rat stomach ECL cells, presumably as a consequence of reduced VMAT2-driven accumulation of histamine.
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| 45. |
- Rudholm, Tobias, et al.
(author)
-
Release of regulatory gut peptides somatostatin, neurotensin and vasoactive intestinal peptide by acid and hyperosmolal solutions in the intestine in conscious rats
- 2009
-
In: Regulatory Peptides. - : Elsevier BV. - 0167-0115 .- 1873-1686. ; 152:1-3, s. 8-12
-
Journal article (peer-reviewed)abstract
- The impact of exposure of the intestinal mucosa to acid and hyperosmolal solutions on the release of the inhibitory gut peptides somatostatin (SOM), neurotensin (NT) and vasoactive intestinal peptide (VIP) was studied in conscious rats during pentagastrin-stimulated gastric acid secretion. The animals were equipped with a chronic gastric fistula to measure acid secretion and a jejunal Thiry-Vella loop for intestinal challenge with saline, hydrochloric acid (HCl, 200 mmol L-1) or hyperosmolal polyethylene glycol (PEG, 1200 mOsm kg(-1)). Gut peptide concentrations were measured in intestinal perfusates, and in plasma samples collected during stimulated acid secretion, and at the end of experiments with luminal challenge of the loops. After pentagastrin-stimulation acid secretion was dose-dependently inhibited by intravenous administration of the gastrin receptor antagonist gastrazole, as well as ranitidine and esomeprazole by maximally 73 +/- 10%; 95 +/- 3%; 90 10%, respectively. Acid perfusion of the Thiry-Vella loop caused a prominent release of SOM both to the lumen (from 7.2 +/- 5.0 to 1279 +/- 580 pmol L-1) and to the circulation (from 18 +/- 5.2 to 51 +/- 9.0 pmol L-1) simultaneously with an inhibition of gastric acid secretion. The release of NTand VIP was not affected to the same extent. PEG perfusion of the loop caused a release of SOM as well as NT and VIP, but less. Simultaneously acid secretion was slightly decreased. In conclusion, intestinal perfusion with acid or hyperosmolal solutions mainly releases SOM, which seems to exert a major inhibitory action in the gut, as shown by inhibition of acid secretion. The other peptides NT and VIP also participate in this action but to a much lesser degree. The operative pathways of these gut peptides hence involve both endocrine (SOM) and paracrine actions (SOM, NT, VIP) in order to exert inhibitory functions on the stomach. The inhibitory action of gastrazole, was in a similar range as that of SOM implying that physiological acid-induced inhibition of gastric acid may primarily be exerted through inhibition of gastrin endocrine secretion.
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| 46. |
- Salehi, S Albert, et al.
(author)
-
Pulses of somatostatin release are slightly delayed compared with insulin and antisynchronous to glucagon
- 2007
-
In: Regulatory Peptides. - : Elsevier BV. - 0167-0115 .- 1873-1686. ; 144:1-3, s. 43-49
-
Journal article (peer-reviewed)abstract
- It was early proposed that somatostatin-producing delta-cells in pancreatic islets have local inhibitory effects on the release of insulin and glucagon. Recent observations that pulses of insulin and glucagon are antisynchronous make it important to examine the temporal characteristics of glucose-induced somatostatin release. Analysis of 30 s fractions from the perfused rat pancreas indicated that increase of glucose from 3 to 20 mmol/l results in initial suppression of somatostatin release followed by regular 4-5 min pulses. During continued exposure to 20 mmol/l glucose, the pulses of somatostatin overlapped those of insulin with a delay of 30 s. Somatostatin and glucagon pulses were coupled in antisynchronous fashion (phase shift 2.4 +/- 0.2 min), supporting the idea that the delta-cells have a local inhibitory effect on glucagon release. It was possible to remove the pulses of somatostatin and glucagon with maintenance of the insulin rhythmicity by addition of I mu mol/l of the P2Y(1) receptor antagonist MRS 2179.
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| 47. |
- Salehi, S Albert, et al.
(author)
-
Secretory and electrophysiological characteristics of insulin cells from gastrectomized mice: Evidence for the existence of insulinotropic agents in the stomach.
- 2007
-
In: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 139:1-3, s. 31-38
-
Journal article (peer-reviewed)abstract
- Mice were subjected to gastrectomy (GX) or sham operation (controls). Four to six weeks later the pancreatic islets were isolated and analysed for cAMP or alternatively incubated in a Krebs-Ringer based medium in an effort to study insulin secretion and cAMP accumulation in response to glucose or the adenylate cyclase activator forskolin. Freshly isolated islets from GX mice had higher cAMP content than islets from control mice, a difference that persisted after incubation for I h at a glucose concentration of 4 mmol/l. Addition of forskolin to this medium induced much greater cAMP and insulin responses in islets from GX mice than in islets from control mice. In contrast, the insulin response to high glucose (16.7 mmol/l) was much weaker in GX islets than in control islets. Glucose-induced insulin release was associated with a 2-fold rise in the cAMP content in control islets. Surprisingly no rise in cAMP was noted in GX islets incubated at high glucose. Capacitance measurements conducted on isolated insulin cells from GX mice revealed a much lower exocytotic response to a single 500 ms depolarisation (from -70 mV to zero) than in control insulin cells. Addition of cAMP to the cytosol enhanced the exocytotic response in insulin cells from control mice but not from GX mice. The depolarisation-triggered inward Ca2+ current in insulin cells from GX mice did not differ from that in control mice, and hence the reduced exocytotic response following GX cannot be ascribed to a decreased Ca2+ influx. Experiments involving a train of ten 500 ms depolarisations revealed that the exocytotic response was prominent in control insulin cells but modest in GX insulin cells. It seems that cAMP is capable of eliciting insulin release from insulin cells of GX mice only when cAMP is generated in a specific microdomain conceivably through the intervention of membrane-associated adenylate cyclases that can be activated by forskolin. The GX-evoked impairment of depolarisation-induced exocytosis and glucose-stimulated insulin release may reflect the lack of a gastric agent that serves to maintain an appropriate insulin response to glucose and an appropriate exocytotic response to depolarisation by raising cAMP in a special glucose-sensitive compartment possibly regulated by a soluble adenylate cyclase. (c) 2006 Elsevier B.V. All rights reserved.
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| 48. |
- Sand, Elin, et al.
(author)
-
Survival and neurotransmitter plasticity in cultured rat colonic myenteric neurons.
- 2007
-
In: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 140:3, s. 109-116
-
Journal article (peer-reviewed)abstract
- The enteric nervous system is of great importance for maintenance and proper function of the gastrointestinal tract. The aim of this study was to quantify myenteric neuronal subpopulations expressing calcitonin gene-related peptide (CGRP), galanin, neuropeptide Y (NPY), somatostatin, vasoactive intestinal peptide (VIP) and nitric oxide synthase (NOS) in rat colon in vivo and after culturing. Further we investigated if culturing in the presence of CGRP, galanin, VIP, S-nitroso-N-acetyl-d,l-penicillamine (SNAP, a NO donor) or N-nitro-l-arginine methyl ester (l-NAME, a NOS inhibitor) affect neuronal survival. After 4 days of culturing the proportions of neurons expressing CGRP, NPY, somatostatin or VIP increased as compared to in vivo, while the proportions of neurons expressing galanin or NOS did not change. Neuronal survival was unaffected after culturing in media enriched with CGRP, galanin, VIP, SNAP or l-NAME. Neither did addition of CGRP, galanin nor VIP to the cultures affect the relative numbers of neurons expressing CGRP, galanin or VIP respectively. Addition of SNAP or l-NAME did not change the percentage of neurons expressing NOS. In conclusion, cultured rat colonic myenteric neurons increase their expression of CGRP, NPY, somatostatin and VIP, suggesting that these neuropeptides are of importance for neuronal survival.
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| 49. |
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| 50. |
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