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  • 1. Ahlkvist, L
    et al.
    Vikman, Jenny
    Pacini, G
    Ahrén, B
    Synergism by individual macronutrients explains the marked early GLP-1 and islet hormone responses to mixed meal challenge in mice2012In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 178, no 1-3, p. 29-35Article in journal (Refereed)
    Abstract [en]

    Apart from glucose, proteins and lipids also stimulate incretin and islet hormone secretion. However, the glucoregulatory effect of macronutrients in combination is poorly understood. We therefore developed an oral mixed meal model in mice to 1) explore the glucagon-like peptide-1 (GLP-1) and islet hormone responses to mixed meal versus isocaloric glucose, and 2) characterize the relative contribution of individual macronutrients to these responses. Anesthetized C57BL/6J female mice were orally gavaged with 1) a mixed meal (0.285 kcal; glucose, whey protein and peanut oil; 60/20/20% kcal) versus an isocaloric glucose load (0.285 kcal), and 2) a mixed meal (0.285 kcal) versus glucose, whey protein or peanut oil administered individually in their mixed meal caloric quantity, i.e., 0.171, 0.055 and 0.055 kcal, respectively. Plasma was analyzed for glucose, insulin and intact GLP-1 before and during oral challenges. Plasma glucose was lower after mixed meal versus after isocaloric glucose ingestion. In spite of this, the peak insulin response (P=0.02), the peak intact GLP-1 levels (P=0.006) and the estimated β-cell function (P=0.005) were higher. Furthermore, the peak insulin (P=0.004) and intact GLP-1 (P=0.006) levels were higher after mixed meal ingestion than the sum of responses to individual macronutrients. Compared to glucose alone, we conclude that there is a marked early insulin response to mixed meal ingestion, which emanates from a synergistic, rather than an additive, effect of the individual macronutrients in the mixed meal and is in part likely caused by increased levels of GLP-1.

  • 2.
    Andersson, Gustav
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Presence of substance P and the neurokinin-1 receptor in tenocytes of the human Achilles tendon2008In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 150, no 1-3, p. 81-87Article in journal (Refereed)
    Abstract [en]

    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.

  • 3.
    Bernhold Brechter, Anna
    et al.
    Umeå University, Faculty of Medicine, Odontology.
    Lerner, Ulf H.
    Umeå University, Faculty of Medicine, Odontology.
    Characterization of bradykinin receptors in a human osteoblastic cell line2002In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 103, no 1, p. 39-51Article in journal (Refereed)
  • 4. Carlini, Valeria P.
    et al.
    Gaydou, Romina C.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    de Barioglio, Susana R.
    Selective serotonin reuptake inhibitor (fluoxetine) decreases the effects of ghrelin on memory retention and food intake2007In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 140, no 1-2, p. 65-73Article in journal (Refereed)
    Abstract [en]

    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.

  • 5.
    Cui, Tao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Tsolakis, Apostolos V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Cunningham, Janet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Li, Su-Chen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Giandomenico, Valeria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Olfactory receptor 51E1 is a potential novel tissue biomarker for the diagnosis and prognosis of small intestine neuroendocrine tumors2012In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 177, no Suppl, p. S18-S18Article in journal (Other academic)
  • 6.
    Ehrström, M
    et al.
    Division of Surgery Karolinska Institutet.
    Näslund, E
    Division of Surgery Karolinska Institutet.
    Levin, F
    Division of Surgery Karolinska Institutet.
    Kaur, R
    Department of Neurology GlaxoSmithKline.
    Kirchgessner, A L
    Department of Neurology GlaxoSmithKline.
    Theodorsson, Elvar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of clinical chemistry. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Hellström, P M
    Department of Gastroenterology and Hepatology Karolinska Institutet.
    Pharmacokinetic profile of orexin A and effects on plasma insulin and glucagon in the rat2004In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 119, no 3, p. 209-212Article in journal (Refereed)
    Abstract [en]

    Orexin A (OXA) is found in the central nervous system (CNS) and in the gut. Peripheral administration of OXA to rats results in an inhibition of fasting motility. Plasma OXA increases during fasting and central administration of OXA increases food intake. The aim of the present study was to assess the pharmacokinetic profile of OXA and the effect of intravenously (IV) administered OXA on plasma concentrations of insulin and glucagon concentrations. Rats were given OXA IV (100 pmol kg-1 min-1) for time periods of 0, 10, 20, 30 min and for 10, 20, 30 min after ceasing a 30-min infusion. After each time period, rats were then sacrificed and blood obtained. OXA was also administered at increasing doses (0, 100, 300 and 500 pmol kg-1 min-1) for 30 min and blood was obtained. Plasma OXA, insulin and glucagon levels were measured using commercially available radioimmunoassay (RIA) kits. The plasma half-life of OXA was 27.1±9.5 min. Stepwise increasing infusion rates of OXA confirmed a linear concentration-time curve and thus first-order kinetics. Its volume of distribution indicated no binding to peripheral tissues. Plasma glucagon decreased during infusion of OXA, while insulin was unaffected. Plasma OXA was raised fourfold after food intake. Thus, OXA has a longer plasma half-life than many other peptides found in the gut. This needs to be taken into account when assessing effects of OXA on biological parameters after peripheral administration.reserved.

  • 7.
    El-Salhy, M
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Danielsson, Åke
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Axelsson, H
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Qian, Bi-Feng
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Neuroendocrine peptide levels in the gastrointestinal tract of mice after unilateral cervical vagotomy2000In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 88, no 1-3, p. 15-20Article in journal (Refereed)
    Abstract [en]

    The effects of left and right unilateral cervical vagotomy on the content of several neuroendocrine peptides were studied in different parts of the murine gastrointestinal tract, known to receive vagal innervation. The neuroendocrine peptides investigated were secretin, gastric inhibitory peptide (GIP), gastrin, motilin, peptide YY (PYY), somatostatin, substance P, VIP, neurotensin, neuropeptide Y (NPY), and galanin. The neuroendocrine peptide concentration was affected after both left and right vagotomy, and that the changes in the concentrations of the neuroendocrine peptide levels occurred in all the gastrointestinal segments investigated, namely antrum, small and large intestine. However, these changes varied, depending on which side was vagotomized and the interval after vagotomy. It is concluded that the vagus nerve had an important impact on the neuroendocrine system in the murine gut. It is suggested, furthermore that the contradictory results obtained earlier on the effect of vagotomy on the gastrointestinal peptides may depend on differences in the vagotomy methods used and on differences in observation time after vagotomy.

  • 8.
    El-Salhy, Magdy
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Östergötlands Läns Landsting, MC - Medicincentrum, EMT-magtarm.
    Sitohy, Basel
    Norrgård, Örjan
    Triple therapy with octreotide, galanin, and serotonin reduces the size and blood vessel density and increases apoptosis of a rat colon carcinoma.2003In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 111, p. 145-152Article in journal (Refereed)
  • 9.
    Ericson, Ann-Charlott
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Kechagias, Stergios
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Internal Medicine. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine.
    Öqvist, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Sjöstrand, Sven-Erik
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Morphological examination of the termination pattern of substance P-immunoreactive nerve fibers in human antral mucosa2002In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 107, no 1-3, p. 79-86Article in journal (Refereed)
    Abstract [en]

    The termination pattern of substance P (SP)-containing axons in human antral mucosa was examined using immunohistochemical techniques at the light and electron microscopic level. SP-immunoreactive (IR) axons were found to extend towards the pit region of the glands, where intraepithelial axons were observed. Electron microscopy showed immunostained axon profiles in close contact with the basement membrane of surface mucous cells. Membrane-to-membrane contacts between labeled axons and myofibroblast-like cells were identified, and SP-IR axons that were apposed to the epithelium were also in contact with subjacent myofibroblast-like cells. The anatomical relationship between SP-IR axons and the cells of the muscularis mucosae was investigated by light microscopy. Immunoreactivity for a-smooth muscle actin (a-sma) was used to visualize the smooth muscle cells, and the a-sma-IR cells were found to create a network that surrounded the gastric glands. Immunostained varicose axons ran alongside and in close apposition to the labeled muscle strands. Ultrastructural examination showed close contacts between SP-IR axon profiles and smooth muscle-like cells. In conclusion, SP-containing neurons may be important for sensory and secretomotor functions in the human antral mucosa.

  • 10. Feng, Wang
    et al.
    Westermark, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Gasslander, Thomas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, MKC-2, GE: Gastrokir.
    Permert, Johan
    Effect of islet amyloid polypeptide on somatostatin inhibition of insulin secretion from isolated rat pancreatic islets.1999In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 72, p. 61-67Article in journal (Refereed)
  • 11.
    Forsgren, Sture
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Anatomi.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Vascular NK-1 receptor occurrence in normal and chronic painful Achilles and patellar tendons: studies on chemically unfixed as well as fixed specimens.2005In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 126, no 3, p. 173-181Article in journal (Refereed)
    Abstract [en]

    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.

  • 12.
    Grönberg, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Janson, Eva Tiensuu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Saras, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Neuroendocrine markers are expressed in human mammary glands2010In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 160, no 1-3, p. 68-74Article in journal (Refereed)
    Abstract [en]

    Background

    Regulatory peptides have previously been detected in epithelial cells of human mammary glands. As these peptides are produced by scattered neuroendocrine cells in the epithelium of other tissues the aim of this study was to investigate whether the mammary glands express molecular markers for neuroendocrine cells.

    Material and methods

    Specimens from 28 human mammary glands were retrieved. The distribution of immunoreactive cells was determined using immunohistochemistry with antibodies versus a set of endocrine markers including peptide hormones, chromogranins/secretogranins, vesicular monoamine transporters, synaptophysin, serotonin and synaptic vesicle protein 2.

    Results

    Cells of the luminal epithelium of ducts and lobules of human mammary glands expressed vesicular monoamine transporter 2 and chromogranin B, as well as the previously reported regulatory peptides obestatin, ghrelin, adrenomedullin and apelin. Using consecutive sections, it was revealed that the immunoreactivity patterns of the regulatory peptides and vesicular monoamine transporter 2 were similar. Interestingly, immunoreactivity for secretogranin II, secretogranin III and chromogranin B was identified in myoepithelial cells. No immunoreactivity was detected for chromogranin A or synaptophysin.

    Conclusion

    Specific cells in the epithelium and myoepithelium of mammary glands express neuroendocrine markers suggesting that mammary glands may have neuroendocrine functions.

  • 13.
    Gunnarsson, Tove
    et al.
    Department of Clinical Neuroscience and Family Medicine, Division of Psychiatry, Karolinska Institute, Huddinge Hospital, Sweden.
    Eklundh, Thomas
    Department of Clinical Neuroscience and Family Medicine, Division of Psychiatry, Karolinska Institute, Huddinge Hospital, Sweden.
    Eriksson, Mats
    Department of Internal Medicine, Karolinska Institute, Huddinge Hospital, Sweden.
    Qureshi, G. Ali
    Clinical Research Center, Novum, Karolinska Institute, Huddinge Hospital, Sweden.
    Sjöberg, Stefan
    Department of Internal Medicine, Karolinska Institute, Huddinge Hospital, Sweden.
    Nordin, Conny
    Linköping University, Department of Clinical and Experimental Medicine, Psychiatry. Linköping University, Faculty of Health Sciences.
    Cholecystokinin peptides in cerebrospinal fluid: a study in healthy male subjects1997In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 68, no 1, p. 57-61Article in journal (Refereed)
    Abstract [en]

    The clinical reliability of measuring cholecystokinin (CCK) peptides in the cerebrospinal fluid (CSF) has not been fully elucidated. Therefore, we have assayed CCK-8S and CCK-4 in CSF obtained from 14 healthy male subjects, lumbar-punctured at the L4–5 level following a strictly standardised procedure. CSF concentrations of free CCK-8S and free CCK-4 were used as dependent variables while age, height, body weight, atmospheric pressure and some other factors served as independent variables. It was shown that the CCK-8S ratio between the second (7–12 ml) and first (0–6 ml) CSF fractions, correlated significantly with the atmospheric pressure at the time of puncture. Neither CCK-8S nor CCK-4 displayed concentration gradients in CSF. The CCK-4 levels, expressed as pmol l−1 in the total amount of CSF were found to be positively correlated with the neuraxis distance in the lying position and negatively with the neuraxis distance in the sitting position. Furthermore, CCK-4, expressed as pmol l−1 per min of tapping-time (pmol l−1 min−1), showed a negative correlation with storage time, presumably mirroring a proteolytic process. CCK-8S and CCK-4 intercorrelated positively independently of whether expressed as pmol l−1 or pmol l−1 min−1. In conclusion, the results of this exploratory study indicate that the neuraxis distance (in the sitting and lying positions) and storage-time have to be accounted for when interpreting data on CSF levels of CCK-4. Attention has to be paid to the potential influence of atmospheric pressure on the concentration ratio of CCK-8S.

  • 14. Hellström, Per M.
    GLP-1: broadening the incretin concept to involve gut motility2009In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 156, no 1-3, p. 9-12Article in journal (Refereed)
    Abstract [en]

    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.

  • 15.
    Hellström, Per M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Smithson, A.
    Stowell, G.
    Greene, S.
    Kenny, E.
    Damico, C.
    Leone-Bay, A.
    Baughman, R.
    Grant, M.
    Richardson, P.
    Receptor-mediated inhibition of small bowel migrating complex by GLP-1 analog ROSE-010 delivered via pulmonary and systemic routes in the conscious rat2012In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 179, no 1-3, p. 71-76Article in journal (Refereed)
    Abstract [en]

    Background: ROSE-010, a Glucagon-Like Peptide-1 (GLP-1) analog, reduces gastrointestinal motility and relieves acute pain in patients with irritable bowel syndrome (IBS). The rat small bowel migrating myoelectric complex (MMC) is a reliable model of pharmacological effects on gastrointestinal motility. Accordingly, we investigated whether ROSE-010 works through GLP-1 receptors in gut musculature and its effectiveness when administered by pulmonary inhalation. Materials and methods: Rats were implanted with bipolar electrodes at 5, 15 and 25 cm distal to pylorus and myoelectric activity was recorded. First, intravenous or subcutaneous injections of ROSE-010 or GLP-1 (1, 10, 100 mu g/kg) with or without the GLP-1 receptor blocker exendin(9-39)amide (300 mu g/kg.h), were studied. Second, ROSE-010 (100, 200 mu g/kg) Technosphere (R) powder was studied by inhalation. Results: The baseline MMC cycle length was 17.5 +/- 0.8 min. GLP-1 and ROSE-010. administered intravenously or subcutaneously, significantly inhibited myoelectric activity and prolonged MMC cycling; 100 mu g/kg completely inhibited spiking activity for 49.1 +/- 4.2 and 73.3 +/- 7.7 min, while the MMC cycle length increased to 131.1 +/- 11.4 and 149.3 +/- 15.5 min, respectively. Effects of both drugs were inhibited by exendin(9-39) amide. Insufflation of ROSE-010 (100, 200 mu g/kg) powder formulation totally inhibited myoelectric spiking for 52.6 +/- 5.8 and 70.1 +/- 5.4 min, and increased MMC cycle length to 102.6 +/- 18.3 and 105.9 +/- 9.5 min, respectively. Conclusions: Pulmonary delivery of ROSE-010 inhibits gut motility through the GLP-1R similar to natural GLP-1. ROSE-010 causes receptor-mediated inhibition of MMC comparable to that of intravenous or subcutaneous administration. This suggests that ROSE-010 administered as a Technosphere (R) inhalation powder has potential in IBS pain management and treatment.

  • 16.
    Holmberg, Sara K S
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Johnson, A E
    Bergqvist, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Källström, Lillemor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, Ulleråker, University Hospital.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Localization of neuropeptide Y receptor Y5 mRNA in the guinea pig brain2004In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 117, p. 61-67Article in journal (Refereed)
    Abstract [en]

    Neuropeptide Y (NPY) has prominent stimulatory effects on food intake in virtually all animals that have been studied. In mammals, the effect is primarily mediated by receptors Y1 and Y5, which seem to contribute to different aspects of feeding behavior in guinea pigs and rats/mice. Interestingly, differences in receptor distribution among mammalian species have been reported. To get a broader perspective on the role of Y5, we describe here studies of guinea pig (Cavia porcellus), a species which due to its phylogenetic position in the mammalian radiation is an interesting complement to previous studies in rat and mouse. Guinea pig brain sections were hybridized with two 35S-labeled oligonucleotides complementary to Y5 mRNA. The highest expression levels of Y5 mRNA were observed in the hippocampus and several hypothalamic and brain stem nuclei implicated in the regulation of feeding, such as the paraventricular, arcuate and ventromedial hypothalamic nuclei. This contrasts with autoradiography studies that detected low Y5-like binding in these areas, a discrepancy observed also in rat and human. Y5 mRNA expression was also seen in the striatum, in great contrast to mouse and rat. Taken together, these data show that Y5 mRNA distribution displays some interesting species differences, but that its expression in feeding centers seems to be essentially conserved among mammals, adding further support for an important role in food intake.

  • 17.
    Höckerfelt, U
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Franzén, L
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Forsgren, S
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Substance P (NK1) receptor in relation to substance P innervation in rat duodenum after irradiation.2001In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 98, no 3, p. 115-26Article in journal (Refereed)
    Abstract [en]

    It has previously been shown that high dose of irradiation to the rat abdomen leads to an increased level of substance P (SP) in the duodenum. In the present study the pattern of distribution of NK1 receptors (NK1-R) in rat duodenum after irradiation (5-30 Gy), was examined at the same time-point (7 days) after irradiation, comparisons being made with the distribution of SP-innervation. Immunohistochemical methods were used. In controls, NK1-R-like immunoreactivity (-LI) was detected in epithelial cells, in cells in the region of the intestinal cells of Cajal within the deep muscular plexus (ICC-DMP), in neuronal cells in the myenteric plexus, and variably in granulocytes in the mucosa. Irradiation with 5-10 Gy did not lead to obvious changes in the pattern of NK1-R-LI. After irradiation with the highest doses (25-30 Gy), the mucosa was often gravely damaged, displaying granulation tissue. No epithelial NK1-R-LI was detected in this tissue, but was present in less affected mucosa after these doses. In the region of the ICC-DMP, in the myenteric plexus, and in granulocytes, NK1-R-LI was detected also after high dose irradiation. However, the degree of NK1-R-LI in the region of the ICC-DMP was somewhat lower than seen in controls and after low doses. SP-immunoreactive nerve fibers were present in the regions where NK1-R-LI was detected. These findings support a suggestion that an increased level of SP after irradiation may contribute to the dose-dependent gastrointestinal adverse effects that occur after radiotherapy.

  • 18. Høyerup, P.
    et al.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Schmidt, P. T.
    Brandt, C. F.
    Askov-Hansen, C.
    Mortensen, P. B.
    Jeppesen, P. B.
    Glucagon-like peptide-2 stimulates mucosal microcirculation measured by laser Doppler flowmetry in end-jejunostomy short bowel syndrome patients2013In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 180, no 1, p. 12-16Article in journal (Refereed)
    Abstract [en]

    Background: In animal and human studies glucagon-like peptide-2 (GLP-2) has been shown to increase blood flow in the superior mesenteric artery and the portal vein. This study describes the effect of GLP-2 measured directly on the intestinal mucosal blood flow by laser Doppler flowmetry (LDF) in end-jejunostomy short bowel syndrome (SBS) patients. Methods: In five SBS patients with end-jejunostomy a specially designed laser Doppler probe was inserted into the stoma nipple, and blood flow measured directly on the jejunal mucosa for 105. min in relation to no treatment, systemic saline infusion, topical adrenaline application and a subcutaneous injection of 800μg native GLP-2. Results: The GLP-2 injection increased jejunal mucosal blood flow by 79 ± 37% compared to conditions, where no treatment was given (p < 0.001). The significant effect was present at least 105. min. Systemic saline infusion and topical, mucosal adrenaline application did not affect mucosal microcirculation. Conclusions: GLP-2 raises jejunal microcirculation in SBS patients with end-jejunostomy. This may explain the redness and increase in the end-jejunostomy nipple size imminently after commencing GLP-2 injections. The potential beneficial effects of this GLP-2-mediated increase of blood flow in the mesenteric bed should be investigated in clinical conditions other than the short bowel syndrome.

  • 19. Kölby, L
    et al.
    Wängberg, B
    Ahlman, H
    Modlin, IM
    Theodorsson, Elvar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Nilsson, O
    Altered influence of CCK-B/gastrin receptors on HDC expression in cells after neoplastic transformation.1999In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 85, p. 115-123Article in journal (Refereed)
  • 20.
    Larhammar, Dan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Ocampo, Daniel Daza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Bergqvist, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Sundström, Görel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Evolution of vertebrate neuropeptide receptors2010In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 164, no 1, p. 20-20Article in journal (Other academic)
  • 21.
    Ludvigsen, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Taylor, John
    Culler, Michael
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Janson, Eva Tiensuu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sandler, Stellan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Regulation of insulin and glucagon secretion from rat pancreatic islets in vitro by somatostatin analogues2007In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 138, no 1, p. 1-9Article in journal (Refereed)
    Abstract [en]

    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.

  • 22.
    Lundell, Ingrid
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Rabe Bernhardt, Nadine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Johnsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Internalization studies of chimeric neuropeptide Y receptors Y1 and Y2 suggest complex interactions between cytoplasmic domains2011In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 168, no 1-3, p. 50-58Article in journal (Refereed)
    Abstract [en]

    Agonist stimulation readily internalizes neuropeptide Y receptor Y1 while there are contradictory results for the Y2 receptor. In order to explore putative functional differences between the Y1 and Y2 receptors we generated reciprocal chimeras by swapping the third intracellular loop, the carboxy terminus or both between human Y1 and Y2. Internalization was studied in a quantitative radioligand binding assay with removal of surface-bound ligand in an acidic-wash procedure. The internalization assay revealed a lower degree of internalization as well as slower kinetics for the Y2 receptor. Generally, reciprocal exchange of receptor segments did not convey properties of the donor receptor but tended to enhance internalization. Surprisingly, insertion of the Y2 carboxy terminus into Y1 gave almost complete internalization (92%), rather than reduced internalization, while the insertion of both segments resulted in internalization equal to the native Y1 receptor. These findings were confirmed by fluorescence microscopy of immuno-stained receptors tagged with a C-terminal FLAG epitope. However, after exposure to high agonist concentrations (100 nM) Y2 was internalized. Studies of Y2 and the closely related Y7 receptor confirmed low internalization for Y2 from chicken and teleost fishes as well as Y7 from two teleosts. The conservation across species of low internalization at physiological concentrations suggests that this is an ancient feature and of vital importance for Y2 function. We propose that amino acid motifs in the third intracellular loop as well as the C terminus of both Y1 and Y2 are able to drive agonist-promoted internalization and that there may be constraining motifs in the Y2 receptor.

  • 23.
    Monstein, Hans-Jurg
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Molecular Biological Techniques.
    Grahn, Niclas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Truedsson, M.
    Department of Internal Medicine, University Hospital Malmö, S-205 02 Malmö, Sweden.
    Ohlsson, B.
    Department of Internal Medicine, University Hospital Malmö, S-205 02 Malmö, Sweden.
    Oxytocin and oxytocin-receptor mRNA expression in the human gastrointestinal tract: A polymerase chain reaction study2004In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 119, no 1-2, p. 39-44Article in journal (Refereed)
    Abstract [en]

    Background/aim: Oxytocin (OT) has a wide range of effects throughout the body. However, the role of OT on the gastrointestinal (GI) tract has to be settled. So far, the few studies performed reveal no conclusive results. The aim of this study was to examine the expression of OT and OT-receptor mRNA in the human GI tract. Material and methods: Full-thickness biopsies from all segments of the GI tract and the gallbladder were collected during operations at the Department of Surgery, Malmö University Hospital. Biopsies were taken and put immediately into fluid nitrogen and stored at -70°C until total RNA was extracted after mechanical tissue homogenization. Subsequently, poly A + mRNA was isolated from the total RNA extract using an automated nucleic acid extractor and converted into single-stranded cDNA. PCR amplifications were carried out using gene-specific OT and OT-receptor primers. The specificity of the PCR amplicons was further confirmed by Southern blot analyses using gene specific OT and OT-receptor hybridization probes. Results: Expression of OT and OT-receptor mRNA was detected in nearly all segments of the GI tract analyzed. In most of the biopsy specimens analyzed, co-expression of both OT and OT-receptor mRNA appeared to take place. Conclusion: The present study demonstrates that OT and OT-receptor mRNAs are expressed throughout the GI tract. A possible physiological and/or pathophysiological role of OT and OT-receptor expression in the human GI tract and the cellular location of its expression remain to be shown. © 2004 Elsevier B.V. All rights reserved.

  • 24.
    Nilsson, Isabelle
    et al.
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Monstein, Hans-Jurg
    Östergötlands Läns Landsting, LMÖ - Laboratoriemedicin i Östergötland.
    Lindström, Erik
    Department of Pharmacology, Institute of Physiological Sciences, University of Lund, Lund, Sweden.
    Håkanson, Rolf
    Department of Pharmacology, Institute of Physiological Sciences, University of Lund, Lund, Sweden.
    Svensson, Samuel
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Pharmacological analysis of CCK2 receptor ligands using COS-7 and SK-N-MC cells, expressing the human CCK2 receptor2002In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 103, no 1, p. 29-37Article in journal (Refereed)
    Abstract [en]

    A series of CCK2 receptor ligands were analysed with respect to their interaction with binding sites in the membranes of COS-7 cells and SK-N-MC cells transiently expressing the human CCK2 receptor (short isoform). The ligands were YF476, YM022, AG041R, L-740,093, JB93182, PD134308, and PD136450. Their binding was analysed by radioligand competition using [3H]L-365,260 as the labelled ligand. Saturation binding analysis indicated that [3H]L-365,260 interacted with a single class of binding sites. In competition binding experiments using COS-7-cell membranes, all seven ligands were incubated together with 2 nM [3H]L-365,260. The data for four of the compounds fitted a one-site model (pKi values: YM022: 9.2±0.02; YF476: 9.6±0.04; L-740,093: 9.2±0.01; and AG041R: 8.3±0.06), while the data for the three others fitted a two-site model (pKi values: JB93182: 8.8±0.04 and 6.0±0.15; PD134308: 9.0±0.04 and 6.1±0.15; and PD136450: 9.0±0.02 and 5.4±0.41). SK-N-MC cell membranes and 2 nM [3H]L-365,260 were incubated together with YM022, YF476, JB93182, and PD134308. The data for YM022 and YF476 fitted a one-site model (pKi values: YM022: 9.3±0.06; YF476: 9.4±0.02), while the data for JB93182 and PD134308 fitted a two-site model (pKi values: JB93182: 8.7±0.06 and 6.2±0.06; PD134308: 9.1±0.06 and 7.0±0.17). Competition binding experiments in the presence of the GTP-analogue guanylylimidodiphosphate, using either of the two cell types, produced similar binding data for PD134308 and JB93182 as in the absence of GTP-analogue. The human receptor seems to exist in a low and/or high affinity state. The shift from low to high affinity does not seem to reflect the degree of G protein coupling.

  • 25.
    Nilsson, Isabelle
    et al.
    Östergötlands Läns Landsting, LMÖ - Laboratoriemedicin i Östergötland. Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Svensson, Samuel
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Monstein, Hans-Jürg
    Östergötlands Läns Landsting, LMÖ - Laboratoriemedicin i Östergötland. Linköping University, Department of Biomedicine and Surgery. Linköping University, Faculty of Health Sciences.
    Molecular cloning of an unusual bicistronic cholecystokinin receptor mRNA expressed in chicken brain: a structural and functional expression study2003In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 114, no 1, p. 37-43Article in journal (Refereed)
    Abstract [en]

    This report describes the molecular cloning and pharmacological characterization of a transiently expressed chicken brain cholecystokinin receptor (CCK-CHR) in COS-7 cells. A polymerase chain reaction (PCR)-based cloning strategy was applied using: (1) an initial PCR with deoxyinosine-containing primers designed to target conserved regions in CCK receptors, followed by (2) rapid amplification of cDNA ends (RACE), and (3) full-length PCR of the CCK-CHR cDNA. The full-length cloned bicistronic CCK-CHR cDNA contained a short upstream open reading frame (uORF) coding for a putative six-amino-acid-long peptide of unknown function, followed by a long open reading frame (lORF) encoding the 436-amino-acid-long CCK-CHR receptor protein. At the amino acid level, the CCK-CHR shared ∼50% homology with mammalian and Xenopus laevis CCK receptors. The pharmacological profile of CCK-CHR resembled that of CCK-B receptors using agonists (CCK-8, CCK-4, gastrin-17), whereas CCK-CHR showed higher affinity for the CCK-A receptor antagonist, devazepide, than for the CCK-B receptor antagonist, l-365,260. To the best of our knowledge, this is the first description and functional expression study of a cloned chicken CCK receptor cDNA.

  • 26.
    Nässel, Dick
    et al.
    Stockholm University, Faculty of Science, Department of Zoology, Functional Morphology.
    Passier, Paul CCM
    Utrecht University.
    Elekes, Karoly
    Balaton Limnological Research Institute of the Hungarian Academy of Sciences,Tihany.
    Dircksen, Heinrich
    Institute of Zoophysiology, University of Bonn, Germany.
    Vullings, Henk G.B.
    Utrecht University.
    Cantera, Rafael
    Stockholm University, Faculty of Science, Department of Zoology.
    Evidence that locustatachykinin I is involved in release of adipokinetic hormone from locust corpora cardiaca1995In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 57, no 3, p. 297-310Article in journal (Refereed)
    Abstract [en]

    The glandular cells of the corpus cardiacum of the locust Locusta migratoria, known to synthesize and release adipokinetic hormones (AKH), are contacted by axons immunoreactive to an antiserum raised against the locust neuropeptide locustatachykinin I (LomTK I). Electron-microscopical immunocytochemistry reveals LomTK immunoreactive axon terminals, containing granular vesicles, in close contact with the glandular cells cells. Release of AKH I from isolated corpora cardiaca of the locust has been monitored in an in vitro system where the amount of AKH I released into the incubation saline is determined by reversed phase high performance liquid chromatography with fluorometric detection. We could show that LomTK I induces release of AKH from corpora cardiaca in a dose-dependent manner when tested in a range of 10-200 microM. This is thus the first clear demonstration of a substance inducing release of AKH, correlated with the presence of the substance in fibers innervating the AKH-synthesizing glandular cells, in the insect corpora cardiaca.

  • 27.
    Portela-Gomes, G. M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Gayen, J. R.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Mahata, S. K.
    The importance of chromogranin A in the development and function of endocrine pancreas2008In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 151, no 1-3, p. 19-25Article in journal (Refereed)
    Abstract [en]

    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.

  • 28. Portela-Gomes, G. M.
    et al.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Selective processing of chromogranin A in rectal carcinoid tumours: An immunohistochemical study with region-specific antibodies2010In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 164, no 1, p. 37-37Article in journal (Other academic)
  • 29.
    Portela-Gomes, Guida M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Johansson, H.
    Co-localization of chromogranins and neuroendocrine hormones in the human gastrointestinal mucosa1996In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 64, no 1, p. 154-154Article, book review (Refereed)
    Abstract [en]

    Co-localization of chromogranin (Cg) A, B and C has been studied in different neuroendocrine cell types in histologically normal mucosa from human gastrointestinal (GI) tract (corpus, antrum, duodenum, ileum and colon). Single, double and triple immunofluorescence stains were used, including appropriate controls. The results showed that whereas CgA cells predominated in all GI-regions, CgB cells were numerous in antrum, few in duodenum (only villi), and almost non-existent in corpus, ileum and colon. CgC cells were sparse in antrum and duodenum (only crypts). Concerning co-localization, gastrin cells harboured CgA and B, some also CgC. All EC cells displayed CgA-immunoreactivity. The EC cells localized in the luminal 23 of the antral mucosa and those in the duodenal villi also contained CgB. Occasionally the EC cells in the duodenal crypts displayed CgC. Almost all cells showing immunoreaction to enteroglucagon/PYY, secretin, neurotensin, or GIP were positive for CgA. Somatostatin cells were with few exceptions CgA-negative, and displayed neither CgB nor C immunoreactivity. CCK cells, indirectly identified, were negative for CgB and C, probably also for CgA.Regarding intracellular localization, CgA and C were seen closer to the basal cell regions, whereas CgB was found more diffusely spread throughout the cytoplasm. This difference in localization between chromogranins suggests that not all secretory granules contain CgA or that CgB may appear in a non-granular form. The results confirm previous findings that CgA occurs in most neuroendocrine cell types of the GI-tract. In most gastrin cells there were two sets of chromogranins, CgA and B, a minority all three chromogranins. All EC cells were CgA immunoreactive, a minority also contained CgB (antrum + duodenal villi) or CgC (duodenal crypts), but not both. All CCK cells seem to be devoid of chromogranins. With few exceptions the same was true of the somatostatin cells. An interesting question posed by the present study is why the chromogranins occur in varying extent and composition in the different cell types.

  • 30. Portela-Gomes, Guida M.
    et al.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wilander, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Granins and granin-related peptides in neuroendocrine tumours2010In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 165, no 1, p. 12-20Article, review/survey (Refereed)
    Abstract [en]

    This review focus on neuroendocrine tumours (NETs), with special reference to the immunohistochemical analysis of granins and granin-related peptides and their usefulness in identifying and characterizing the great diversity of NET types. Granins, their derived peptides, and complex protein-processing enzyme systems that cleave granins and prohormones, have to some extent cell-specific expression patterns in normal and neoplastic NE cells. The marker most commonly used in routine histopathology to differentiate between non-NETs and NETs is chromogranin (Cg) A, to some extent CgB. Other members of the granin family may also be of diagnostic value by identifying special NET types, e.g. secretogranin (Sg) VI was only found in pancreatic NETs and phaeochromocytomas. SgIII has recently arisen as an important NET marker; it was strongly expressed in NETs, with some exceptions - phaeochromocytomas expressed few cells and parathyroid adenomas none. Some expression patterns of granin-related peptides seem valuable in differentiating between some benign and malignant NETs, some may also provide prognostic information, among which: well-differentiated NET types expressed more CgA epitopes than the poorly differentiated ones, except insulinomas, where the opposite was noted; medullary thyroid carcinomas containing few cells immunoreactive to a CgB antibody were related to a bad prognosis; C-terminal secretoneurin visualized a cell type related to malignancy in phaeochromocytomas. Further research will probably establish new staining patterns with marker functions for granins in NETs which may be of histopathological diagnostic value.

  • 31.
    Portela-Gomes, Guida Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Prohormone convertases 1/3, 2, furin and protein 7B2 (Secretogranin V) in endocrine cells of the human pancreas2008In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 146, no 1-3, p. 117-124Article in journal (Refereed)
    Abstract [en]

    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.

  • 32. Portela-Gomes, Guida Maria
    et al.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Secretogranin III in human neuroendocrine tumours A comparative immunohistochemical study with chromogranins A and B and secretogranin II2010In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 165, no 1, p. 30-35Article in journal (Refereed)
    Abstract [en]

    Background: Different epitopes of the granin family of proteins, chromogranin (Cg) A, CgB and secretogranin (Sg) II, have been demonstrated in normal human pancreas, gastrointestinal tract, adrenal medulla and in several neuroendocrine tumours (NETs). SgIII has been recently reported in endocrine pancreas. The aim of the present study was to examine the expression of SgIII in different NETs and compare it with the expression of CgA. CgB and SgII epitopes. Material and methods: Tissue specimens from 47 NETs were analyzed. Antibodies to CgA 250-284, CgB 244-255. SgII 172-186 (C-terminal secretoneurin) and SgIII 348-361 were used for immunostaining. Results: SgIII was expressed in 41 of 47 NETs. The expression of SgIII agreed well with that of CgA, CgB and SgII, with exceptions of phaeochromocytomas, where more CgB and SgII immunoreactive cells were observed and parathyroid adenomas, which were only stained by CgA. In rectal NETs more cells expressed SgIII than CgA. Conclusions: This is the first report on SgIII expression in various NETs. A majority of tumours studied displayed SgIII immunostaining, which indicates a functional relationship with the other granins.

  • 33. Rosjo, Helge
    et al.
    Opstad, Per-Kristian
    Hoff, Jon Erik
    Godang, Kristin
    Christensen, Geir
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Omland, Torbjorn
    Effect of short- and long-term physical activities on circulating granin protein levels2013In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 185, p. 14-19Article in journal (Refereed)
    Abstract [en]

    Background: The classic chromogranin-secretogranin (granin) proteins are produced in the myocardium and throughout the neuroendocrine system, but while chromogranin (Cg) A and B levels are high in the adrenal medulla, secretogranin (Sg) II production is higher in the pituitary gland. Whether these differences may influence the response to physical activity is not known. Methods: We measured circulating granin proteins during (1) a short-term maximal bicycle exercise stress test and (2) a 7 day military ranger course of continuous physical activity and sleep and energy deprivation. Results: In 9 healthy subjects performing the exercise stress test (7 male, age 45 +/- 5 y [mean +/- SEM], duration 10.13 +/- 1.14 min), CgB levels increased from before to immediately after the test: 1.20 +/- 0.12 vs. 1.45 +/- 0.09 nmol/L, p = 0.013. Metabolic equivalents, representing an index of performed work, were closely associated with the change (Delta) in CgB levels during stress testing and explained 74% of the variability in (Delta)CgB levels (p = 0.004). CgA and SgII levels were not increased after exercise stress testing. In the second cohort of 8 male subjects (age 25 +/- 1 y) participating in the ranger course, CgB levels increased from day 1 and wire significantly elevated on days 5 and 7. CgA also increased gradually with levels significantly elevated on day 7, while SgII was markedly increased on day 5 whereas levels on days 3 and 7 were unchanged compared to baseline levels. Conclusion: We demonstrate a heterogeneous response to short- and long-term physical activities among circulating granin proteins with the most potent effect on CgB levels.

  • 34. Rudholm Feldreich, Tobias
    et al.
    Wallin, B
    Theodorsson, E
    Näslund, E
    Hellström, P M
    Release of regulatory gut peptides somatostatin, neurotensin and vasoactive intestinal peptide by acid and hyperosmolal solutions in the intestine in conscious rats.2009In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 152, no 1-3Article in journal (Refereed)
    Abstract [en]

    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 NT and 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.

  • 35. Rudholm, T
    et al.
    Wallin, B
    Theodorsson, E
    Näslund, E
    Hellström, Per M.
    Release of regulatory gut peptides somatostatin, neurotensin and vasoactive intestinal peptide by acid and hyperosmolal solutions in the intestine in conscious rats2009In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 152, no 1-3, p. 8-12Article in journal (Refereed)
    Abstract [en]

    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 NT and 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.

  • 36.
    Rudholm, Tobias
    et al.
    Department of Medicine, Gastroenterology and Hepatology unit, Karolinska Institutet, Karolinska University Hospital.
    Wallin, B
    Department of Medicine, Gastroenterology and Hepatology unit, Karolinska Institutet, Karolinska University Hospital.
    Theodorsson, E
    Department of Clinical Chemistry, Linköping University.
    Näslund, E
    Department of Clinical Sciences, Karolinska Institutet, Danderyd Hospital.
    Hellström, P M
    Department of Medicine, Gastroenterology and Hepatology unit, Karolinska Institutet, Karolinska University Hospital.
    Release of regulatory gut peptides somatostatin, neurotensin and vasoactive intestinal peptide by acid and hyperosmolal solutions in the intestine in conscious rats2009In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 152, no 1-3, p. 8-12Article in journal (Refereed)
    Abstract [en]

    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 NT and 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.

  • 37.
    Rudholm, Tobias
    et al.
    Karolinska University Hospital.
    Wallin, B
    Karolinska University Hospital.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Naslund, E
    Karolinska Institute.
    Hellstrom, P H
    Karolinska University Hospital.
    Release of regulatory gut peptides somatostatin, neurotensin and vasoactive intestinal peptide by acid and hyperosmolal solutions in the intestine in conscious rats2009In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 152, no 1-3, p. 8-12Article in journal (Refereed)
    Abstract [en]

    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.

  • 38.
    Rugarn, Olof
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology. Linköping University, Faculty of Health Sciences.
    Hammar, Mats
    Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology. Linköping University, Faculty of Health Sciences.
    Theodorsson, Elvar
    Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Progesterone and norethisterone have different effects on tachykinin-like immunoreactivity in rat cortex and striatum2001In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 101, no 1-3, p. 87-91Article in journal (Refereed)
    Abstract [en]

    Objective: The purpose of this study was to investigate the effects of progesterone and the most commonly prescribed synthetic progestogen, norethisterone, on regional immune-like reactivity of neuropeptide Y (NPY), substance P (SP), neurokinin A (NKA) and neurotensin (NT) in brains of female ovariectomized estradiol-substituted rats.

    Results: Norethisterone+estradiol-treated rats had 44% lower SP levels compared with estradiol-only-treated in frontal cortex and 20% lower NKA levels in comparison with progesterone+estradiol-treated in frontal cortex. Progesterone+estradiol-treated rats had 66% lower SP levels in striatum in comparison with both estradiol-only-treated and norethisterone+estradiol-treated. No significant results were found for NPY and NT.

    Conclusion: Progesterone and the synthetic progestogen, norethisterone, have different effects on SP- and NKA-like immunoreactivity in rat cortex and striatum.

    The effects of NET on SP- and NKA-like immunoreactivity in frontal cortex may contribute to the mood effects ascribed to this progestogen in clinical usage.

  • 39. Salehi, Albert
    et al.
    Qader, Saleem S
    Grapengiesser, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Hellman, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Pulses of somatostatin release are slightly delayed compared with insulin and antisynchronous to glucagon2007In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 144, no 1-3, p. 43-49Article in journal (Refereed)
    Abstract [en]

    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.

  • 40. Sandin, Johan
    et al.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Silberring, Jerzy
    Metabolism of beta-endorphin in plasma studied by liquid chromatography-electrospray ionization mass spectrometry1998In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 73, no 1, p. 67-72Article in journal (Refereed)
    Abstract [en]

    Degradation of synthetic human beta-endorphin by a human plasma proteinase was studied with high-performance liquid chromatography in combination with mass spectrometry. The peptide was metabolized at a rate of 25 pmol/min to the major fragments beta-endorphin (1-19) and (20-31), the latter reported as a potent inhibitor of morphine- and beta-endorphin-induced analgesia in mice. The proteinase responsible for this process was classified as a metal-dependent serine proteinase and was effectively inactivated by phenylmethylsulfonyl fluoride and ethylenediaminetetraacetic acid. Identification of the products formed during the enzymatic reaction was performed by liquid chromatography on-line with electrospray mass spectrometry, using a reversed-phase or a novel size-exclusion column capable of separating molecules between 0.1-7 kilodaltons. Peptide sequences were verified by tandem mass spectrometry experiments. The conversion of beta-endorphin may have physiological implications in the mechanism of pain. The obtained data suggest that several precautions should be considered during recovery and measurement of beta-endorphin in plasma by immunological techniques. The applied strategy may also be useful for studying metabolism of various peptidergic compounds with potential pharmacological significance.

  • 41. Sathanoori, Ramasri
    et al.
    Voss, Ulrikke
    Riva, Matteo
    Sorhede-Winzell, M.
    Ahren, B.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Wierup, Nils
    Cocaine- and amphetamine-regulated transcript (CART) is upregulated in islets of type-2 diabetic patients to stimulate insulin secretion, inhibit glucagon secretion and protect against beta cell death2010In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 164, no 1, p. 45-45Article in journal (Other academic)
  • 42.
    Sjöblom, Markus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Lindqvist, Ramin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Bengtsson, Magnus W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jedstedt, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Flemström, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Cholecystokinin but not ghrelin stimulates mucosal bicarbonate secretion in rat duodenum: Independence of feeding status and cholinergic stimuli2013In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 183, p. 46-53Article in journal (Refereed)
    Abstract [en]

    Cholecystokinin (CCK) is an important regulator of food digestion but its influence on small intestinal secretion has received little attention. We characterized effects of CCK-8, ghrelin and some related peptides on duodenal HCO3- secretion in vivo and demonstrated CCK-induced calcium signaling in acutely isolated enterocytes. A segment of proximal duodenum with intact blood supply was cannulated in situ in anaesthetized rats. Mucosal HCO3- secretion was continuously recorded (pH-stat). Peptides were administrated to the duodenum by close intra-arterial infusion. Clusters of duodenal enterocytes were attached to the bottom of a perfusion chamber. The intracellular calcium concentration ([Ca2+](i)) was examined by dual-wavelength imaging. CCK-8 (3.0, 15 and 60 pmol/kg,h) caused dose-dependent increases (p < 0.01) in duodenal alkaline secretion in both overnight fasted and continuously fed animals. The CCK1R-antagonist devazepide but neither the CCK2R-antagonist YMM022 nor the melatonin MT2-selective antagonist luzindole inhibited the rise in secretion. Atropine decreased sensitivity to CCK-8. The appetite-related peptide ghrelin was without effect on the duodenal secretion in fasted as well as fed animals. Superfusion with CCK-8 (1.0-50 nM) induced [Ca2+](i) signaling in acutely isolated duodenal enterocytes. After an initial peak response, [Ca2+](i) returned to near basal values within 3-5 min. Devazepide but not YMM022 inhibited this [Ca2+](i) response. Low doses of CCK-8 stimulate duodenal alkaline secretion and induce enterocyte [Ca2+](i) signaling by an action at CCK1 receptors. The results point to importance of CCK in the rapid postprandial rise in mucosa-protective duodenal secretion.

  • 43. Spegel, Peter
    et al.
    Lindqvist, Andreas
    Sandberg, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Wierup, Nils
    Glucose-dependent insulinotropic polypeptide lowers branched chain amino acids in hyperglycemic rats2014In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 189, p. 11-16Article in journal (Refereed)
    Abstract [en]

    Hypersecretion of the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) has been associated with obesity and glucose intolerance. This condition has been suggested to be linked to GIP resistance. Besides its insulinotropic effect, GIP also directly affects glucose uptake and lipid metabolism. This notwithstanding, effects of GIP on other circulating metabolites than glucose have not been thoroughly investigated. Here, we examined effects of infusion of various concentrations of GIP in normo- and hyperglycemic rats on serum metabolite profiles. We found that, despite a decrease in serum glucose levels (-26%, p < 0.01), the serum metabolite profile was largely unaffected by GIP infusion in normoglycemic rats. Interestingly, levels of branched chain amino acids and the ketone body beta-hydroxybutyrate were decreased by 21% (p < 0.05) and 27% (p < 0.001), respectively, in hyperglycemic rats infused with 60 ng/ml GIP. Hence, our data suggest that GIP provokes a decrease in BCAA levels and ketone body production. Increased concentrations of these metabolites have been associated with obesity and T2D.

  • 44.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Region-specific expression of granins in neuroendocrine tissue and measurements of circulating concentrations2010In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 164, no 1, p. 21-21Article in journal (Refereed)
  • 45.
    Stridsberg, Mats
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kristiansson, Gudjon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Janson, Eva Tiensuu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Measurements of chromogranin B can serve as a complement to chromogranin A2007In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 139, no 1-3, p. 80-83Article in journal (Refereed)
    Abstract [en]

    Objective

    CgA has been shown to be an excellent marker for neuroendocrine tumours. However, there are two major drawbacks with CgA measurements; elevated levels are common in patients with decreased renal function and in patients on treatment with proton pump inhibitors. These problems are not seen with CgB measurements. We have recently presented the development of 13 region-specific radioimmunoassays for measurements of CgB. A region-specific assay was identified, which measured higher concentrations of CgB than the other assays and seemed to be very useful as a marker for neuroendocrine tumours. The aim of the present study was therefore to further explore the diagnostic potential of this assay in the clinical management of patients with neuroendocrine tumours.

    Methods

    Measurements of CgB with two methods were compared with CgA in plasma samples from patients investigated for neuroendocrine tumours (N = 86), patients with decreased renal function (N = 35) and patients on treatment with proton pump inhibitors (N = 29).

    Results

    The diagnostic sensitivity for the new CgB assay was almost as good as that for CgA. Furthermore, with CgB measurements we could avoid the falsely elevated levels of CgA found in patients with decreased renal function and treatment with proton pump inhibitors.

    Conclusions

    We conclude that the new CgB assay can serve as a complement to CgA measurements as an important tumour marker for neuroendocrine tumours.

  • 46.
    Stridsberg, Mats
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Janson, Eva Tiensuu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Measurements of secretogranins II, III, V and proconvertases 1/3 and 2 in plasma from patients with neuroendocrine tumours2008In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 148, no 1-3, p. 95-98Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION:

    Chromogranin (Cg) and secretogranin (Sg) are members of the granin family of proteins, which are expressed in neuroendocrine and nervous tissue. In recent publications we have presented generation of region-specific antibodies against CgA and CgB and also development of several region-specific radioimmunoassays for measurements of specific parts of the Cgs. In this study we describe generation of antibodies against SgII, SgIII, SgV and the proconvertases PC1/3 and PC2 and development of radioimmunoassays for measurements of these proteins.

    MATERIALS AND METHODS:

    Peptides homologous to defined parts of the secretogranin and proconvertase molecules were selected and synthesised. Antibodies were raised, radioimmunoassays were developed and circulating levels of the proteins in plasma samples from 22 patients with neuroendocrine tumours were measured in the assays.

    RESULTS:

    Increased plasma concentrations were recorded in 11, 4 and 3 of the patients with the SgII 154-165 (N-terminal secretoneurin), the SgII 172-186 (C-terminal Secretoneurin) and the SgII 225-242 assays respectively. The SgIII, SgV, PC1/3 and PC2 assays failed to detect increased concentrations in any of the patients.

    CONCLUSION:

    Increased concentrations of SgII, especially the N-terminal part of secretoneurin could be measured in plasma from patients with endocrine pancreatic tumours and in this case this assay was quite comparable to measurements of CgA and CgB. Even though secretoneurin was not as frequently increased as CgA and CgB in patients with carcinoid tumours or pheochromocytoma it may be a useful marker for endocrine pancreatic tumours.

  • 47.
    Stridsberg, Mats
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Lundqvist, Gudmar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Wilander, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Molecular and Morphological Pathology.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Islet amyloid polypeptide (IAPP) in patients with neuroendocrine tumours1995In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 55, no 2, p. 119-131Article in journal (Refereed)
    Abstract [en]

    Although IAPP was first discovered and isolated from amyloid deposits in an endocrine pancreatic tumour (EPT), surprisingly few reports have investigated the potential use of IAPP as a marker for neuroendocrine tumour growth. In this study we present results from plasma measurements of IAPP in 102 patients with neuroendocrine tumours. Four of 35 patients (11%) with midgut carcinoid tumours, but none of the patients (4 and 5, respectively) with lung carcinoids or with rectal carcinoids displayed elevated plasma levels of IAPP. Five of 31 patients (16%) with sporadic EPT and 3 of 27 patients (11%) with EPT and multiple endocrine neoplasia type 1 syndrome disclosed elevated IAPP levels. Within the different syndromes, 1/11 individuals with insulinoma, 2/16 with gastrinoma, 0/2 with glucagonoma, 0/3 with VIPoma and 5/26 with non-functioning tumours showed elevated plasma levels of IAPP. In two patients, the plasma IAPP levels were extremely elevated. These patients also exhibited altered glucose homeostasis. In response to a standardised mixed meal test, IAPP increased in parallel to the insulin, pancreatic polypeptide, gastrin and glucose responses. In MEN1 patients with hypercalcaemia due to increased secretion of parathyroid hormone, the plasma levels of IAPP were significantly higher before than after surgical removal of the parathyroid adenomas. However in normocalcaemic patients, no correlation between the blood calcium and plasma IAPP levels was found. Immunocytochemical staining of tumour tissue showed that 9/13 (69%) of insulin producing tumours, 4/14 (29%) of non-functioning tumours and 1/9 (11%) of gastrin producing tumours were IAPP immunoreactive. Amyloid deposits were always IAPP immunoreactive. In conclusion, increased circulating levels of IAPP occurred in 12% of 102 patients with neuroendocrine tumours. In 2 patients with extremely elevated plasma levels of IAPP, effects on glucose homeostasis were recorded. Thus, IAPP may be useful as an additional marker for neuroendocrine tumour growth in selected cases.

  • 48.
    Thorsell, Annika
    et al.
    Magnus Huss Clinic, Karolinska Hospital, S-17176 Stockholm, Sweden.
    Blomqvist, Anders G
    Department of Medical Genetics, Uppsala University, Uppsala, Sweden.
    Heilig, Markus
    Magnus Huss Clinic, Karolinska Hospital, S-17176 Stockholm, Sweden.
    Cationic lipid-mediated delivery and expression of prepro-neuropeptide Y cDNA after intraventricular administration in rat: feasibility and limitations.1996In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 61, no 3, p. 205-211Article in journal (Refereed)
    Abstract [en]

    The utility of in vivo lipofection for delivery and expression of a neuropeptide gene in the adult rat brain was explored. Prepro-neuropeptide Y (NPY) cDNA was cloned into the episomal eucaryotic expression vector pCEP4. This construct was complexed to lipofectamine or lipofectin. Complexed DNA was injected into the lateral ventricles of adult rats. Brains were removed for analysis following various time intervals. Polymerase chain reaction (PCR) reactions were designed for specific detection of endogenous and vector derived NPY sequence, respectively. PCR of DNA preparations from 5 major brain regions (frontal and parietal cortex, striatum, hypothalamus, brain stem) demonstrated presence of vector DNA up to 1 month (longest interval studied) in all brain regions. Reverse-transcription (RT-) PCR of DNase treated RNA-preparations from brain tissue demonstrated presence of both vector-derived and endogenous NPY mRNA in treated animals, while only endogenous mRNA was detected in controls. In situ hybridization histochemistry indicated scattered patches of vector uptake into tissue in the vicinity of the CSF compartment, but not into deeper located structures. Weight gain was not affected, indicating that the expression levels achieved may not be sufficient to play a functional role, and/or may need to be targeted to specific brain areas. These findings suggest a potential for cationic lipid mediated gene transfer in the brain as an experimental tool and as a possible future therapeutic principle, but also indicate the need for optimization of delivery strategies in order to achieve functionally relevant expression levels.

  • 49.
    Trulsson, Lena
    et al.
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    Gasslander, Thomas
    Department of Surgery, Vrinnevi Hospital, Norrköping, Sweden.
    Sundqvist, Tommy
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Svanvik, Joar
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    The influence of nitric oxide on basal and cholecystokinin-8-induced proliferation and apoptosis in the rat pancreas2002In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 106, no 1-3, p. 97-104Article in journal (Refereed)
    Abstract [en]

    Nitric oxide (NO) is formed by different cell types in the pancreas. In this study, inhibition of endogenous nitric oxide by Nω-nitro-l-arginine (l-NNA) reduced the urinary excretion of NO2/NO3 and raised serum l-arginine and the NO donator S-nitroso-N-acetylpenicillamine (SNAP) increased the urinary excretion of NO2/NO3. The peptide cholecystokinin-8 (CCK-8) has a strong influence on exocrine pancreatic proliferation. Rat pancreas was excised and studied with regard to tissue weight, protein and DNA contents after 3 days of treatment with saline, l-NNA or SNAP given separately or combined with CCK-8. Further, proliferation of different pancreatic cells was studied with [3H]-thymidine incorporation and apoptotic activity was studied by analysing caspase-3 activity and histone-associated DNA fragments. The effects of l-NNA indicate that endogenous nitric oxide formation has a tonic inhibition on apoptosis in the pancreas during both basal condition and growth stimulation by CCK-8. In CCK-induced hyperplasia, NO inhibits the proliferation of acinar cells but stimulates ductal cells. Endogenous NO may regulate the balance between proliferation and apoptosis and in a situation of growth stimulation by CCK-8, it has a tonic inhibition on both mitogenesis and apoptosis thus slowing down the acinar cell turnover in the pancreas.

  • 50.
    Trulsson, Lena M.
    et al.
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    Svanvik, Joar
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    Permert, Johan
    Department of Surgery, Karolinska Institute at Huddinge, Huddinge University Hospital, Stockholm, Sweden.
    Gasslander, Thomas
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    Cholecystokinin octapeptide induces both proliferation and apoptosis in the rat pancreas2001In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 98, no 1-2, p. 41-48Article in journal (Refereed)
    Abstract [en]

    Cholecystokinin-8 (CCK-8) causes exocrine pancreatic hypertrophy and hyperplasia. High doses of the CCK analogue cerulein causes necrosis and an inflammatory response in the pancreas. We have studied the pancreatic growth response in rats after administration of CCK-8 for 3 days, given either intermittently (20–80 μg/kg) twice a day, or continuously (2.4–48 μg/kg per 24 h). Plasma CCK-8 levels, pancreatic wet weight, water, protein and DNA contents and the pancreatic caspase-3 activity were measured. Cell proliferation was visualized by [3H]thymidine incorporation and apoptosis by TUNEL reaction. Continuous administration of CCK-8 dose-dependently increased the plasma CCK levels, the pancreatic wet weight, protein and DNA contents as well as thymidine labeling index, apoptotic index and caspase-3 activity. Intermittent injections of CCK-8 caused transient raises in plasma CCK, increased apoptotic index and caspase-3 activity, a dose-dependent increase in thymidine labeling but caused a dose-dependent reduction of pancreatic wet weight, protein, and DNA contents. It is concluded that CCK-8 causes both increased proliferation and apoptosis in the pancreas. In case of continuous administration of CCK-8, the proliferation outweighs the apoptosis causing hyperplasia but in the case of intermittent administration the opposite effect is seen.

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