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Biomedical subjects

H C Fehmann

Publications and source records attributed to H C Fehmann.

At least 55 records · Page 3Linked to original sources
PubMed1995

Galanin and somatostatin inhibition of substance P-induced airway mucus secretion in the rat.

Substance P is present in several neurons innervating the lung. Tachykinin receptors are expressed on submucosal gland cells. Substance P is known to be a potent stimulator of airway mucus secretion. In the present study we characterized the effects of galanin and somatostatin on basal and substance P-induced mucus secretion. The stimulatory effect of substance P was concentration-dependent (100 pmol/l: 112%, 1 nmol/l: 120%, 10 nmol/l: 153%, 100 nmol/l: 223%, 1 mumol/l: 275%, 10 mumol/l: 172%) and was inhibited by galanin and somatostatin (1 mumol/l substance P: 277%; 1 mumol/l substance P + 1 mumol/l somatostatin: 190%, p < 0.01; 1 mumol/l substance P + 1 mumol/l galanin: 206%, p < 0.05). In the presence of lower concentrations of substance P 1 mumol/l somatostatin and 1 mumol/l galanin did not modify mucus secretion. Lower concentrations of galanin and somatostatin did not significantly change mucus secretion stimulated by 1 mumol/l substance P. Both, galanin and somatostatin at 1 mumol/l left basal airway mucus secretion unaltered. These data suggest that mucus secretion into airways is regulated by a complex network of peptidergic stimulators and inhibitors including substance P, somatostatin and galanin.

Animals↗
PubMed1995

Characterization of GIP(1-30) and GIP(1-42) as stimulators of proinsulin gene transcription.

Originally characterized in terms of its gastric acid inhibitory properties, GIP (gastric inhibitory polypeptide) expressed in the upper small intestine, was subsequently shown to exert strong glucose-dependent insulin-releasing properties. This action is generally attributed to GIP(1-42) and, so far, no evidence for the contribution of other relevant GIP forms exists. In this study, we compared the effects of GIP(1-42) and C-terminally truncated GIP(1-30) on cAMP production and proinsulin gene transcription at clonal insulin-secreting cell lines (RIN 1046-38, beta TC-3). Both peptides were equally potent stimulators of cAMP generation in both cell lines. Insulin release from RIN 1046-38 cells stimulated by both GIP forms was identical. In both B-cell lines GIP(1-42) and GIP(1-30) stimulated proinsulin gene expression equipotently. GIP not only enhances insulin secretion but also insulin gene expression and, therefore, it is a true insulinotropic hormone.

Cell Line↗
PubMed1995

The effects of glucagon-like peptide-I (GLP-I) on hormone secretion from isolated human pancreatic islets.

Glucagon-like peptide-I (GLP-I) is a potent incretin hormone that is now considered as a new therapeutic tool in the treatment of diabetes mellitus. In this study we characterized the effects of GLP-I on peptide hormone release from isolated human pancreatic islets. GLP-I stimulated insulin release in the presence of 10 mM glucose (2.8 mM glucose, 100%; 10 mM glucose, 166%; 10 mM glucose + 10 nM GLP-I, 222%) but had only a weak insulinotropic effect (128%) at 2.8 mM glucose. Glucagon release was inhibited by 10 mM glucose (2.8 mM glucose, 100%; 10 mM glucose, 72%) and by 10 nM GLP-I at 2.8 mM glucose (67%). Somatostatin secretion was increased by 10 mM glucose (2.8 mM glucose, 100%; 10 mM glucose, 166%). GLP-I stimulated somatostatin release in the presence of 2.8 mM glucose (172%). Pancreatic polypeptide (PP) secretion was enhanced by 10 mM glucose (2.8 mM glucose, 100%; 10 mM glucose, 236%). GLP-I induced PP release only in the presence of 2.8 mM glucose (184%).

Culture Techniques↗
PubMed1995

Functional characterization of somatostatin receptors expressed on hamster glucagonoma cells.

We characterized somatostatin receptors expressed in hamster glucagonoma INR1G9 cells and the effects of somatostatin on glucagon secretion, proglucagon gene expression, and the adenosine 3',5'-cyclic monophosphate (cAMP)-dependent signal-transduction cascade. 125I-labeled somatostatin was displaced by somatostatin-14 and somatostatin-28 with a dissociation constant of 2 nmol/l. Stable GTP analogues decreased binding of 125I-somatostatin to its receptors, suggesting an interaction of somatostatin receptors with G proteins. Chemical cross-linking of 125I-somatostatin to its receptor revealed a molecular mass of the ligand-receptor complex of 47 kDa. Somatostatin inhibited forskolin-stimulated activation of adenylate cyclase [2.5 microM forskolin (161%) + 1 microM somatostatin (128%); P < 0.05] and protein kinase A [10 microM forskolin (143%) + 1 microM somatostatin (114%); P < 0.05] but did not influence basal activities of these enzymes. Forskolin-induced stimulation of cAMP generation was reduced by somatostatin [2.5 microM forskolin (306%) + 1 microM somatostatin (145%); P < 0.05]. Somatostatin inhibited forskolin, theophylline, and arginine stimulation of glucagon secretion. Basal as well as forskolin-, theophylline-, and isobutyl methylxanthine-induced proglucagon gene expression was significantly reduced by somatostatin. Our data show that, in INR1G9 cells, somatostatin receptors are at least in part coupled to the adenylate cyclase system. Somatostatin is a potent negative regulator of both basal and forskolin-stimulated proglucagon gene expression. The interaction with forskolin occurs at the level of adenylate cyclase. The effect of somatostatin on basal proglucagon gene transcription is most probably mediated by an unrelated second messenger system. Somatostatin may influence several functions of the pancreatic A cell.

Adenylyl Cyclases↗
PubMed1995

Glucagon-like peptide-1 and glucose-dependent insulin-releasing polypeptide plasma levels in response to nutrients.

The nutrient-dependent glucagon-like peptide-1 (7-36) amide (GLP-1) release was studied in comparison to the glucose-dependent insulin-releasing polypeptide (GIP) response in 10 healthy volunteers each undergoing various protocols. Plasma samples were saved up to 120 min after challenges by oral, intravenous or intraduodenal administration of nutrients. Basal plasma-GLP-1 concentrations ranged between 0.4 and 1.4 pM, maximal postprandial GLP-1 levels peaked between 10 and 12 pM. Intravenous glucose (25 g i.v.) did not change basal GLP-1 levels. Oral administration of glucose (50 g) induced a biphasic GLP-1 release peaking at 30-60 min and a biphasic GIP release peaking at 5 and 45 min. This increase paralleled the secretion of insulin. Oral galactose (100 g) and amino acids (25 g) also induced a rapid plasma GLP-1 response. After fat (67 g corn oil) a strong and long-lasting (> 120 min) increase of GLP-1 plasma levels occurred. When a mixed liquid meal was given (6 g soybean oil, 5 g casein, 13 g glucose) immunoreactive (IR)-GLP-1 rapidly increased and peaked after 5 min with declining levels after 30 min. In response to an intraduodenal infusion of a small glucose load (5.34 g within 120 min) a rapid, short-lasting GLP-1 response occurred whereas plasma GIP and insulin levels remained unaltered. Luminal perfusion of an isolated vascularly perfused rat ileum with a polydiet induced a rapid rise of portally released IR-GLP-1 which was followed by a sustained release. Glucose evoked sodium-dependently a sharp increase of IR-GLP-1 levels followed by a plateau release. The intraluminal infusion of a mixture of amino acids or fat was without any effect on IR-GLP-1. We hypothesize that in contrast to GIP the GLP-1 release from L cells is triggered by nervous reflexes, by putative humoral factor(s) being released from the upper small intestine in addition to nutrient stimuli acting at the luminal surface of the gut.

Adult↗
PubMed1995

Reduction of the incretin effect in rats by the glucagon-like peptide 1 receptor antagonist exendin (9-39) amide.

Glucagon-like peptide 1 (7-37)/(7-36) amide (GLP-1) is derived from the intestinal proglucagon processing. It is considered an important insulin-releasing gut hormone. This study uses exendin (9-39) amide as a GLP-1 receptor antagonist to evaluate the contribution of GLP-1 to the incretin effect. Anesthetized rats were challenged by an intraduodenal glucose infusion to evaluate maximally occurring GLP-1 and gastric inhibitory polypeptide (GIP) plasma levels. Maximal immunoreactive (IR) GLP-1 plasma levels amounted to 10 pmol/l (IR-GIP 11 pmol/l). Exendin (9-39) amide abolished the insulin-stimulatory effect of 60 pmol of GLP-1 or of the GLP-1 agonist exendin-4 (0.5 nmol) injected as bolus, respectively. An intravenous bolus injection of 5.94 nmol of exendin (9-39) amide 3 min before enteral glucose infusion grossly reduced the total insulin secretory response (by 60%) and significantly increased circulating blood glucose levels (P < 0.05). In contrast, the GLP-1 antagonist left the insulin response after an intravenous glucose or glucose plus GIP (60 pmol) load unaltered. Our data support the concept that GLP-1 is an important incretin factor. Exendin (9-39) amide is a useful GLP-1 antagonist for in vivo studies.

Animals↗
PubMed1994

Spontaneous calcium oscillations in clonal endocrine pancreatic glucagon-secreting cells.

Measurements of the cytosolic calcium concentration in single cells of the clonal endocrine pancreatic glucagon-secreting cell line INR1 G9 revealed the existence of spontaneous calcium oscillations in 20-70% of these cells. Inhibition of these spontaneous oscillations by thapsigargin as well as the phospholipase C inhibitor U 73122 demonstrated involvement of calcium release from intracellular stores, probably mediated by a high basal activity of phospholipase C. Removal of extracellular calcium but not the L-type calcium channel antagonists verapamil or nifedipine terminated the spontaneous oscillations, suggesting that calcium influx by a pathway distinct from L-type channels contributed to the oscillations. Similar spontaneous calcium oscillations could be the pacemaker of pulsatile glucagon release in endocrine pancreatic A-cells.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1994

Ras antagonizes cAMP stimulated glucagon gene transcription in pancreatic islet cell lines.

Ras, a GTP-binding protein, converts membrane tyrosine kinase signalling to changes in gene expression patterns. Utilising a rat glucagon promoter-CAT construct (p[-1.1]GLU-CAT) we demonstrate in transient transfection experiments that the oncogenic Ras inhibits cAMP-dependent activation of p[-1.1]GLU-CAT in both glucagonoma InR1-G9 and insulinoma beta-TC1 cells. Conversely, the expression of a dominant negative mutant of Ras enhances the cAMP-induced activation of p[-1.1]GLU-CAT transcription in these cells. Our data suggests a functional interference of Ras with the cAMP-dependent transcription of the glucagon gene.

Adenoma, Islet Cell↗
PubMed1994

Expression, intracellular localization, and gene transcription regulation of the secretory protein 7B2 in endocrine pancreatic cell lines and human insulinomas.

7B2 is a 23-kDa protein encoded by a single gene that is expressed in a variety of neuroendocrine tissues. Although its physiological role has not yet been elucidated, its presence in secretory granules suggests a function in the secretory machinery of certain neuronal and endocrine cells in various species. The present study characterizes the expression of 7B2 in endocrine pancreatic cells. We demonstrate that: (i) 7B2 is highly expressed in human insulinomas; (ii) its ultrastructural localization, associated with secretory granules of A and B cells of the islets, suggests a participation of 7B2 in the secretion of insulin and glucagon; (iii) sequences located in the first intron of the 7B2 gene are required for its transcription in either insulinoma or glucagonoma cell lines; and (iv) in a B cell-like insulinoma cell line, the transcription of 7B2 is regulated by protein kinase A and protein kinase C activators, while in an A-like insulinoma cell line, 7B2 gene transcription seems to be constitutively activated.

Animals↗
PubMed1994

Glucagon-like peptide 1 immunoreactivity in gastroentero-pancreatic endocrine tumors: a light- and electron-microscopic study.

The preproglucagon gene encodes, in addition to glucagon, two smaller peptides with structural similarity: glucagon-like peptides 1 and 2. Glucagon-like peptide 1 (GLP-1) 7-36 amide is the most powerful incretin candidate. In the present study, GLP-1 immunoreactivity was investigated in tissue specimens of various types of gastroenteropancreatic tumors, and the serum-levels of GLP-1 were assayed. Immunohistochemical staining of 88 tumors revealed GLP-1 immunoreactivity in 17 neoplasias (19.3%), viz., in 7 out of 33 non-functioning tumors, 4 out of 20 gastrinomas, 4 out of 13 insulinomas, 1 out of 3 vasoactive-intestinal-polypeptide (VIP)omas and 1 adrenocorticotropic-hormone (ACTH)-producing tumor. In these tumors, GLP-1-immunoreactive cells were distributed either diffusely, arranged in clusters, or as single cells. All GLP-1-positive tumors were immunoreactive for glucagon or glicentin, 10 tumors were immunoreactive for pancreatic polypeptide, and 8 tumors for insulin. Ultrastructural analysis of 8 GLP-1-positive tumors, with the immunogold technique, demonstrated GLP-1 immunoreactivity mainly in cells resembling the A-cells of the pancreas or the L-cells of the gut. Of the 17 GLP-1-immunoreactive tumors, 15 were primarily located in the pancreas. Additionally, 2 non-functioning tumors of the rectum were GLP-1 immunoreactive. Five tumors were GLP-1 immunoreactive from 9 patients with multiple endocrine neoplasia I syndrome. Patients with GLP-1-immunoreactive tumors were characterized by a significantly lower rate of distant metastases (P < 0.01) and a higher rate of curative resections (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗