PubMed Health⌕ Search

Biomedical subjects

H C Fehmann

Publications and source records attributed to H C Fehmann.

At least 91 records · Page 5Linked to original sources
PubMed1992

Galanin inhibits proinsulin gene expression stimulated by the insulinotropic hormone glucagon-like peptide-I(7-37) in mouse insulinoma beta TC-1 cells.

The neuropeptide hormone galanin, released by sympathetic stimulation of nerve terminals in the endocrine pancreas, inhibits insulin secretion via a receptor-linked pertussis toxin-sensitive (Gi) transmembrane signaling pathway. Glucagon-like peptide-I(7-37) [GLP-I(7-37)] is an intestinal hormone shown to have potent insulin-releasing activities in pancreatic B-cells and is believed to serve a physiological role in the augmentation of nutrient-induced insulin release. GLP-I(7-37) binds to specific Gs- and adenylate cyclase-coupled receptors on pancreatic B-cells and directly stimulates proinsulin gene transcription, thereby increasing cellular levels of proinsulin messenger RNA (mRNA) and proinsulin biosynthesis. This study examines the effects of galanin on GLP-I(7-37)-stimulated proinsulin gene expression in mouse beta TC1 cells. The degree of proinsulin gene transcription was assessed by measuring the activity of chloramphenicol acetyl transferase (CAT) expressed from a CAT reporter plasmid linked to the rat insulin-1 gene promoter transferred to beta TC1 cells and by measuring proinsulin mRNA levels by Northern blot analysis. Galanin inhibited both CAT activity and the rise in proinsulin mRNA levels stimulated by either GLP-I(7-37) or forskolin (0.1 microM). Notably, galanin was without effect on CAT activity induced by the cAMP analog, 8-bromo-cAMP, the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine, or higher concentrations of forskolin. The inhibitory effects of galanin on GLP-I(7-37) and forskolin-induced CAT activity were reversed by the addition of pertussis toxin, a toxin that inactivates inhibitory G-proteins (Gi). We conclude that galanin inhibits GLP-I(7-37)-stimulated proinsulin gene expression by inhibiting the activation of adenylate cyclase by GLP-I(7-37) and subsequently the production of cAMP in B-cells. Further, our data suggest that these actions of galanin are mediated by a pertussis toxin sensitive pathway involving one or more Gis that inhibit adenylate cyclase. Thus, in addition to its well known inhibitory effects on insulin secretion galanin can inhibit proinsulin gene expression stimulated by GLP-I(7-37) activation of the cAMP signaling pathway. These findings may be a unique demonstration of the inhibition of proinsulin gene expression by a substance (galanin) released endogenously within the pancreas.

Adenylate Cyclase Toxin↗
PubMed1991

Functional receptors for the insulinotropic hormone glucagon-like peptide-I(7-37) on a somatostatin secreting cell line.

Glucagon-like peptide-I(7-37) [(GLP-I(7-37)] is an intestinal peptide hormone that has potent insulinotropic activities in vivo in response to oral nutrients, in the isolated perfused pancreas, and in vitro in cultured B cells. GLP-I(7-37) receptor binding and GLP-I(7-37)-induced cAMP generation and hormone secretion was studied using cell lines producing insulin/B cell (beta TC-1), glucagon/A cell (INR1G9) and somatostatin/D cell (RIN 1027-B2). [125I]GLP-I(7-37) bound specifically to both B and D cells but not to A cells. GLP-I(7-37) induced cAMP-formation in B and D cells with a maximum response at 10 nmol/l (B cells) or at 100 nmol/l (D cells). Insulin secretion from perifused B cells was stimulated by GLP-I(7-37) (maximum at 10 nmol/l) and 10 nmol/l GLP-I(7-37) released somatostatin from perifused D cells. GLP-I(7-37) did not influence cAMP or glucagon secretion from A cells. These data indicate that pancreatic B and D cells, but not the A cells are influenced directly by GLP-I(7-37) via binding to specific receptors. Our findings support a model of physiologic regulation of insulin secretion whereby GLP-I(7-37) released from the intestine in response to oral nutrients potently stimulates insulin secretion via an endocrine mechanism that in turn may be dampened by a feed-back suppression by the release of somatostatin. In addition, suppression of the secretion of glucagon, a hormone whose actions are counter-regulatory to those of insulin, may occur by paracrine mechanisms involving GLP-I(7-37)-mediated stimulation of both insulin and somatostatin secretion.

Animals↗
PubMed1991

Priming effect of glucagon-like peptide-1 (7-36) amide, glucose-dependent insulinotropic polypeptide and cholecystokinin-8 at the isolated perfused rat pancreas.

The priming effect of glucagon-like peptide-1 (7-36) amide (GLP-1 (7-36) amide), glucose-dependent insulin-releasing polypeptide (GIP) and cholecystokinin-8 (CCK-8) on glucose-induced insulin secretion from rat pancreas was investigated. The isolated pancreas was perfused in vitro with Krebs-Ringer bicarbonate buffer containing 2.8 mmol/l glucose. After 10 min this medium was supplemented with GLP-1 (7-36) amide, GIP or CCK-8 (10, 100, 1000 pmol/l) for 10 min. After an additional 10 min period with 2.8 mmol/l glucose alone, insulin secretion was stimulated with buffer containing 10 mmol/l glucose for 44 min. In control experiments the typical biphasic insulin response to 10 mmol/l glucose occurred. Pretreatment of the pancreas with GIP augmented insulin secretion: 10 pmol/l GIP enhanced only the first phase of the secretory response to 10 mmol/l glucose; 100 and 1000 pmol/l GIP stimulated both phases of hormone secretion. After exposure to CCK-8, enhanced insulin release during the first (at 10 and 1000 pmol/l CCK-8) and the second phase (at 1000 pmol/l) was observed. Priming with 100 pmol/l GLP-1 (7-36) amide significantly amplified the first and 1000 pmol/l GLP-1 (7-36) amide both secretion periods, 10 pmol/l GLP-1 (7-36) amide had no significant effect. All three peptide hormones influenced the first, quickly arising secretory response more than the second phase. Priming with forskolin (30 mM) enhanced the secretory response to 10 mM glucose plus 0.5 nM GLP-1 (7-36) amide 4-fold. With a glucose-responsive B-cell line (HIT cells), we investigated the hypothesis that the priming effect of GLP-1 (7-36) amide is mediated by the adenylate cyclase system. Priming with either IBMX (0.1 mM) or forskolin (2.5 microM) enhanced the insulin release after a consecutive glucose stimulation (5 mM). This effect was pronounced when GLP-1 (7-36) amide (100 pM) was added during glucose stimulation. Priming capacities of intestinal peptide hormones may be involved in the regulation of postprandial insulin release. The incretin action of these hormones can probably, at least in part, be explained by these effects. The priming effect of GLP-1 (7-36) amide is most likely mediated by the adenylate cyclase system.

1-Methyl-3-isobutylxanthine↗
PubMed1991

Helodermin and islet hormone release in isolated rat pancreas.

The effect of helodermin (1,10,100 pmol/L), a new member of the VIP/secretin/glucagon peptide family, was investigated in glucose- (10 mmol/L) and arginine- (10 mmol/L) induced insulin, glucagon, and somatostatin secretion from the isolated perfused rat pancreas. Helodermin stimulated the somatostatin release in a concentration-dependent manner during the first (controls, 100%; 1 pmol/L, 113%, ns; 10 pmol/L, 175%, p less than 0.05; 100 pmol/L, 233%, p less than 0.05) and the second secretion phases (controls, 100%; 1 pmol/L, 117%, ns; 10 pmol/L, 210%, p less than 0.05; 100 pmol/L, 362%, p less than 0.05). There was a biphasic glucagon response with an inhibition during the first phase (controls, 100%; 1 pmol/L, 92%; 10 pmol/L, 63%, p less than 0.05; 100 pmol/L, 52%, p less than 0.05%) and a stimulation during the second phase (controls, 100%; 1 pmol/L, 117%, ns; 10 pmol/L, 210%, p less than 0.05; 100 pmol/L, 362%, p less than 0.05). Helodermin had weak stimulatory effects on pancreatic beta cells with a maximum at 10 pmol/L (first phase: controls, 100%; 1 pmol/L, 96%, ns; 10 pmol/L, 148%, p less than 0.05; 100 pmol/L, 136%, ns; second phase: controls, 100%; 1 pmol/L, 104%, ns; 10 pmol/L, 170%, p less than 0.05; 100 pmol/L, 136%, ns).

Animals↗
PubMed1991

Homologous desensitization of the insulinotropic glucagon-like peptide-I (7-37) receptor on insulinoma (HIT-T15) cells.

Glucagon-like peptide-I(7-37) [GLP-I(7-37)] is an intestinal peptide with potent insulinotropic activities on pancreatic beta-cells in vivo and in vitro. In earlier studies elevated concentrations GLP-I(7-37) inhibited insulin release and cAMP generation in beta-cells. We now show that the GLP-I(7-37) receptor in the glucose-responsive B-cell line HIT-T15 undergoes rapid and reversible homologous desensitization in response to supraphysiological concentrations of GLP-I(7-37). GLP-I(7-37) stimulated insulin release and cAMP generation in a glucose-dependent biphasic manner with a maximum stimulation at 10 nmol/liter. The first-phase insulin secretory response was reduced by 41% at doses of GLP-I(7-37) of 100 nmol/liter and higher. Preperifusion of B-cells with 100 nmol/liter GLP-I(7-37) for 5 or 10 min reduced a subsequent insulin secretory response to 10 nmol/liter GLP-I(7-37) after hormone washout and recovery periods of 10 min (52% and 55% reduction) or 30 min (33% reduction or full recovery). Preperifusion of HIT-T15 cells with 100 nmol/liter glucagon (10 min) or 100 nmol/liter gastric inhibitory peptide (GIP) (10 min) had no effect on the insulin secretory response to 10 nmol/liter GLP-(7-37). Prior exposure of cells to 100 nmol/liter GLP-(7-37) (10 min) did not alter the GIP-induced (10 nmol/liter) insulin release, but 100 nmol/liter GIP (10 min) reduced the insulin secretion during stimulation with 10 nmol/liter GIP by 56%. These data indicate that: 1) the GLP-I(7-37) receptor is subject to rapid and reversible homologous desensitization and, 2) the GLP-I(7-37) receptor on beta-cells is distinct from that of GIP. The recent finding of elevated GLP-I(7-36)amide levels in subjects with noninsulin-dependent diabetes suggest the possibility that a homologous desensitization of the GLP-I(7-37) receptor might contribute to the impaired insulin secretion in this disorder.

Cyclic AMP↗
PubMed1990

Islet amyloid polypeptide (IAPP;amylin) influences the endocrine but not the exocrine rat pancreas.

The effect of synthetic rat amylin (10,100,1000 pmol/l) on glucose (10 mmol/) and arginine (10 mmol/l) -stimulated islet hormone release from the isolated perfused rat pancreas and on amylase release from isolated pancreatic acini was investigated. Amylin stimulated the insulin release during the first (+76%) and the second secretion period (+42%) at 1 nmol/l. The first phase of the glucagon release was inhibited concentration dependently by amylin and completely suppressed during the second phase. Amylin diminished the somatostatin release in a concentration dependent manner. This effect was more pronounced at the first than the second secretion period (1 nmol amylin: 1 phase: -60%, 2.phase: -22%). Amylin was without any effect on basal and CCK stimulated amylase release from isolated rat pancreatic acini. Our data suggest amylin, a secretory product of pancreatic B-cells, as a peptide with approximately strong paracrine effects within the Langerhans islet. Therefore, amylin might be involved in the regulation of glucose homeostasis.

Amylases↗
PubMed1990

Cosecretion of amylin and insulin from isolated rat pancreas.

Amylin, a 37 amino acid C-terminal amidated peptide is an integral part of secretory granules of pancreatic beta-cells. Utilizing a specific radioimmunoassay system we demonstrate in the present study a cosecretion of amylin and insulin from the isolated rat pancreas. The secretion pattern of both peptides during glucose or glucose plus arginine stimulation is identical. The molar ratio of amylin amounts to 10% of that of insulin. The biological significance of amylin is still unknown, but a paracrine/endocrine role in glucose homeostasis is speculated.

Amyloid↗
PubMed1990

Atrial natriuretic factor has a weak insulinotropic action in the isolated perfused rat pancreas.

The effect of atrial natriuretic factor (ANF; 1, 10, 100, 1000 pmol/l) on insulin release from the isolated perfused rat pancreas was studied. ANF weakly augmented the glucose (10 mmol/l)-stimulated insulin release during the second (controls: 100%; 1 pmol/l: 99%; 10 pmol/l: 149%, P less than 0.05; 100 pmol/l: 111%; 1000 pmol/l 135%), but not the first phase of the secretory response. In contrast, the first, but not the second phase of arginine (10 mmol/l)-stimulated insulin release was significantly enhanced by ANF (1000 pmol/l; controls: 100%; 1000 pmol/l: 235%, P less than 0.05). The hormone did not influence basal insulin secretion. Our data indicate an insulinotropic effect of ANF on the rat pancreas, which is dependent on the utilized background secretagogues.

Animals↗
PubMed1990

The effects of two FMRFamide related peptides (A-18-F-amide and F-8-F-amide; 'morphine modulating peptides') on the endocrine and exocrine rat pancreas.

The effects of two recently isolated mammalian FMRFamide related peptides (A-18-F-amide and F-8-F-amide) on the encocrine and exocrine rat pancreas were investigated. A-18-F-amide (10, 100, 1000 pM) inhibited concentration dependently glucose (10 mM)- and arginine (10 mM)-induced insulin secretion from the isolated perfused rat pancreas during the first (controls: 100%; 10 pM: 114%; 100 pM: 63%, p less than 0.05; 1000 pM: 31%, p less than 0.05) and the second secretion phase (controls: 100%; 10 pM: 102%; 100 pM: 78%; 1000 pM: 27%, p less than 0.05). The inhibitory actions of A-18-F-amide on pancreatic D-cell secretion were more pronounced during the first than the second phase (first phase: controls: 100%; 10 pM: 95%; 100 pM: 37%, p less than 0.05; 1000 pM: 39%, p less than 0.05%; second phase: controls: 100%; 10 pM: 113%; 100 pM: 72%; 1000 pM: 59%, p less than 0.05). F-8-F-amide (at 1000 pM) inhibited stimulated insulin (controls: 100%; first phase: 26%, p less than 0.05%; second phase: 20%, p less than 0.05) and somatostatin release (controls: 100%; first phase: 14%, p less than 0.05; second phase: 29%, p less than 0.05). Both peptides were without effect on basal and CCK-8-stimulated amylase release from isolated incubated rat pancreatic acini.

Amino Acid Sequence↗
PubMed1990

Interaction of glucagon-like peptide-1 (7-36)amide and cholecystokinin-8 in the endocrine and exocrine rat pancreas.

The synergistic impact of glucagon-like peptide-1 (GLP-1) (7-36)amide and cholecystokinin-8 (CCK-8) was studied in the rat pancreas. The GLP-1 (7-36)amide (1 pM-1 microM) had no effect on the basal or CCK-stimulated (1 nM-1 pM) amylase release from isolated pancreatic acini. The insulinotropic action of 0.5 nM GLP-1 (7-36)amide, which weakly stimulated the glucose-induced (6.7 mM) insulin release from the isolated perfused rat pancreas, was strongly potentiated by the addition of CCK-8 (20, 50, and 100 pM) to the perfusate. In concentrations as they occur physiologically after a meal, CCK-8 alone had no significant effect on basal or glucose-stimulated (6.7 mM) insulin secretion. Our data support the assumption that the nutrient-regulated intestinal release of various peptides represents a regulatory system to ensure an adequate insulin response to food intake, at least in rats.

Amylases↗
PubMed1990

Carbachol priming increases glucose- and glucagon-like peptide-1 (7-36)amide-, but not arginine-induced insulin secretion from the isolated perfused rat pancreas.

The priming effect of carbachol on glucose-, arginine- and glucose plus GLP-1 (7-36)amide induced insulin secretion was investigated. The isolated rat pancreas was perfused in vitro during a basal period of 10 min with Krebs-Ringer-bicarbonate buffer containing 2.8 mmol/l glucose. This medium was then supplemented with carbachol (10,1.0.1 mumol/l, respectively). After an additional 10 min period at 2.8 mmol/l glucose insulin secretion was stimulated for 44 min with 10 mmol/l glucose, or glucose plus GLP-1 (7-36)amide (0.5 nmol/l), or arginine (10 mmol/l). Pretreatment with carbachol resulted in a concentration dependent sensitization of B-cells to a consecutive glucose load (10 mmol/l). Both phases of the biphasic insulin secretory response were significantly enhanced. Priming experiments followed by a subsequent combined glucose / GLP-1 (7-36)amide or arginine stimulation were performed with 10 mumol/l carbachol. Prior exposure of the pancrease to carbachol enhanced the glucose / GLP-1 (7-36)amide induced insulin release, but left the arginine stimulated secretion unaltered. Our data suggest that in the regulation of postprandial insulin release cholinergic sensitizing effects might be involved which are mediated by muscarinic receptors.

Animals↗
PubMed1989

Synergistic stimulatory effect of glucagon-like peptide-1 (7-36) amide and glucose-dependent insulin-releasing polypeptide on the endocrine rat pancreas.

The interaction of glucagon-like peptide-1 (7-36)amide (GLP-1) and glucose-dependent insulin-releasing polypeptide (GIP) on insulin release from the perfused rat pancreas was studied. The GLP-1 stimulated (0.5 nmol/l), glucose-induced (6.7 mmol/l) insulin secretory answer was enhanced by GIP (0.1, 1.0 and 10.0 nmol/l) to the arterial perfusate. This effect was maximal at 1 nmol/l GIP and smaller but still significant at 0.1 nmol/l GIP. The high GIP concentration of 10 nmol/l GIP did not further increase insulin secretion compared to the stimulation by 1 nmol/l GIP. Our data demonstrate an additive synergistic effect of GLP-1 and GIP on the glucose-induced insulin release. This supports the concept of an action "in concert' of gastrointestinal incretin hormones postprandially released on the endocrine pancreas to guarantee adequate insulin answers after meals.

Animals↗
PubMed1989

The effect of cyclosporin A on rat pancreatic B-cell: interaction with the calcium-antagonist diltiazem.

Cyclosporin A (CyA) was fed to male Wistar rats in a dose of 5, 10 or 50 mg/kg b.wt. for 7 days. In another experimental procedure 10 mg/kg b.wt. CyA was given for 7 days combined with Diltiazem (DIL) 6.25 mg/kg b.wt. once daily ip. Glucose stimulated insulin secretion from the isolated perfused pancreas was investigated in these animals. Total insulin secretion (ng/50 min) was not affected after feeding 5 mg/kg b.wt. CyA, but was significantly decreased with 10 and 50 mg/kg b.wt. CyA. The biphasic insulin secretion was reduced after 5 mg/kg b.wt. CyA during the initial peak (0-10 min) but not during the second peak (10-50 min), whereas after 10 and 50 mg/kg b.wt. CyA both peaks nearly reached base-line levels. DIL markedly increased the initial peak (0-10 min) after feeding CyA 10 mg/kg b.wt., whereas the second peak was not affected. Our results demonstrate a toxic effect of CyA on the pancreatic B-cell, which might be partly abolished by calcium-antagonists.

Animals↗
PubMed1989

Interaction of glucagon-like peptide-1(7-36)amide and somatostatin-14 in RINm5F cells and in the perfused rat pancreas.

Glucagon-like peptide-1(7-36)amide [GLP-1(7-36)amide], a new important incretin candidate, binds to specific high-affinity receptors on rat insulinoma-derived beta-cells (RINm5F). In the present study, the effect of somatostatin-14 on the GLP-1(7-36)amide-induced insulin release and cAMP generation in this cell line was investigated. Somatostatin did not decrease basal insulin release of RINm5F cells. The GLP-1(7-36)amide-induced insulin release was decreased concentration dependently by somatostatin. Somatostatin, 1 microM reduced the maximally GLP-1(7-36)amide-stimulated (0.1 microM) insulin release to basal insulin levels. The GLP-1(7-36)amide-induced cAMP production was significantly decreased by somatostatin in a concentration-dependent manner. The GLP-1(7-36)amide concentration causing half-maximal cAMP production was 2.98 +/- 1.56 nM. Somatostatin left the EC50 unaltered but decreased the maximal GLP-1(7-36)amide effect for 32% in the presence of 1 nM somatostatin and for 50% at 1 microM. In additional experiments, the interaction of both hormones was evaluated in the perfused pancreas as a nontumor model. Somatostatin (1 nM, 1 microM) inhibited the glucose-induced (6.7 mM) and GLP-1(7-36)amide-potentiated (0.05, 0.5, and 5 nM) insulin release dose dependently. The biphasic pattern of insulin release remained preserved. The GLP-1(7-36)amide-induced insulin release is potently inhibited by somatostatin-14. This effect was demonstrated in different model systems for beta-cell function studies. The present data allow the conclusion that the somatostatin action upon GLP-1(7-36)amide effects is at least partly related to regulation of intracellular cyclic nucleotides.

Adenoma, Islet Cell↗