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P Zabel

Publications and source records attributed to P Zabel.

At least 55 records · Page 3Linked to original sources
PubMed1997

Tumour necrosis factor alpha promoter gene polymorphism in sarcoidosis.

Biallelic polymorphisms in the promoter region of the TNF-alpha gene (TNFA) and in the first intron of the TNF-beta gene (TNFB) have been associated with variation in TNF-alpha production and with susceptibility to severe diseases. Among other functions, TNF-alpha plays a pivotal role in regulatory aspects of granuloma formation and sustenance. In sarcoidosis, a systemic granulomatous disorder of unknown aetiology, the clinical course of the disease has been associated with the patient's individual capacity of spontaneous TNF-alpha production by alveolar macrophages. We determined the TNFA and TNFB polymorphisms in 101 patients with pulmonary sarcoidosis and 216 healthy blood donors. A highly significant shift to the more uncommon TNFA2 allele was found in the Löfgren syndrome patient group, which represents the acute form of the disease with frequent spontaneous remission. The results show that gene frequencies of the TNFA gene variation are significantly different within the clinical forms of sarcoidosis, indicating that genetic predisposition for TNF-alpha production may play a role in the pathogenesis of the disease.

Humans↗
PubMed1997

Antiinflammatory and antifibrotic properties of colchicine: implications for idiopathic pulmonary fibrosis.

The ancient drug colchicine has repeatedly been proposed as a novel drug for therapy of pulmonary fibrosis. The present study was undertaken to add to the knowledge on colchicine's antiinflammatory and antifibrotic properties and thus help determine its actual rank in the treatment of pulmonary fibrosis. In vitro cell culture experiments with stimulated and unstimulated normal donor peripheral blood mononuclear cells (PMNC) and a human lung fibroblast cell line (WI-38) were used to determine the effects of colchicine on PMNC cytokine release (interleukin-6 and tumor necrosis factor-alpha) as well as on fibroblast proliferation and collagen synthesis rates. Reverse transcriptase polymerase chain amplifications of alpha 1 (III) collagen were done to detect collagen messenger ribonucleic acid (mRNA) expression. Colchicine did not significantly modulate tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) release of PMNC. Colchicine inhibited fibroblast proliferation and total collagen synthesis significantly at concentrations obtainable in serum in vivo. Transcription of the alpha 1 (III) collagen gene into mRNA continued under colchicine. We conclude that colchicine is a potent in vitro inhibitor of fibroblast functions in terms of proliferation and collagen synthesis. The mechanism of collagen inhibition is more likely an inhibition of cellular collagen secretion than a switch off of collagen mRNA transcription. On the other hand, although colchicine is known to inhibit many leukocyte functions, it is a poor inhibitor of cytokines known to be important for fibrogenesis (e.g. IL-6, TNF-alpha, IL-1, platelet-derived growth factor, and transforming growth factor-beta). This makes colchicine, at least from a theoretical standpoint and as concluded from in vitro studies, a preferable candidate for a combined therapeutic strategy.

Cells, Cultured↗
PubMed1997

Pentoxifylline in treatment of sarcoidosis.

The optimal therapy for sarcoidosis remains unclear. Most patients show a short-term response to corticosteroid therapy, but they have to face the risk of significant side effects. Because tumor necrosis factor alpha (TNF) plays a critical role in granuloma formation and sustenance as well as in the progression of sarcoidosis, we investigated pentoxifylline (POF), which exerts TNF-inhibitory activity, as a therapeutic agent in active pulmonary sarcoidosis. Twenty-three previously untreated patients with documented disease progression during the preceding 3 mo were treated with POF (25 mg/kg daily) and followed for 6 mo of therapy. Two patients were lost to follow-up, and three patients discontinued POF therapy because of gastrointestinal side effects; 18 patients were thus evaluated. Eleven patients improved, seven remained stable and, most importantly, none deteriorated. Lung function tests-DL(CO), Pa(O2) and Pa(O2)[exercise]-were significantly improved in the patient group as a whole and increased in a highly significant manner in those who improved. Three patients with corticosteroid-resistant disease progression were additionally treated with a combination of corticosteroids with POF. In all three patients the combination therapy resulted in an immediate complete decrease of disease activity, even after tapering prednisone to 7.5 mg daily or tapering off corticosteroids. These promising results suggest that POF may improve therapeutic regimens in pulmonary sarcoidosis either by sparing or replacing corticosteroids.

Adult↗
PubMed1997

Sarcoidosis: TNF-alpha release from alveolar macrophages and serum level of sIL-2R are prognostic markers.

At the time of diagnosis, many sarcoidosis patients have no clinical indication for corticosteroid therapy, and prognostic parameters predicting deterioration are missing. In the present study, we investigated parameters derived from bronchoalveolar lavage (BAL) and serum in 77 patients with recently diagnosed sarcoidosis to test their predictive value. Patients were divided into a group with (Group A, n = 37) and a group without (Group B, n = 40) indications for therapy, and the course of the disease was evaluated after 5.7 +/- 0.4 mo. The CD4+/CD8+ lymphocyte ratio and percentage of BAL lymphocytes were of no predictive value. Release of tumor necrosis factor-alpha (TNF-alpha) from cultured alveolar macrophages (AM) was significantly increased in both groups (Group A = 1,872 +/- 428 pg/ml; Group B = 1,561 +/- 449 pg/ml) as compared with controls (220 +/- 37 pg/ml). In Group B, however, patients with a high level of TNF-alpha release had a significantly greater risk of disease progression than did those with normal TNF-alpha release (43.8% versus 8.3%, respectively). From the serologic parameters investigated, consisting of neopterin, angiotensin converting enzyme (ACE), and soluble interleukin-2 receptor (sIL-2R), only the last was of significant predictive value; 42.1% of sarcoidosis patients in Group B with a high level of sIL-2R experienced disease progression, whereas none of those with a normal level did. We conclude that TNF-alpha release and sIL-2R are suitable parameters for predicting disease progression in sarcoid patients who have no indication for therapy at the time of disease diagnosis.

Adult↗
PubMed1997

[Pentoxifylline inhibits experimental bleomycin-induced fibrosing alveolitis].

Therapy of idiopathic pulmonary fibrosis (IPF) is directed at 1) inhibition of alveolitis and tissue damage, and 2) inhibition of matrix deposition. We and others have identified pentoxifylline (POF) as a promising drug in achieving these aims. For further clarification, we established a model of bleomycin-induced fibrosing alveolitis. Fisher 344 rats (n = 7 per group) were given bleomycin intratracheally once (0.7 U/100 g bw) and treated with POF (1.5 or 3 mg/kg bw per day i.p.), prednisolone (15 mg/kg bw i.m. per day), or sodium chloride solution (NaCL). The extent of inflammatory reactions was determined after 8 days by differentiation of cells of broncho-alveolar lavage (BAL) and by quantification of proliferating cells in lung interstitium subsequent to staining of the Ki-67 antigen. POF inhibited neutrophil alveolitis in BAL and reduced the amount of proliferating cells in the lungs significantly while prednisolone and NaCL did not. Both POF and prednisolone exerted a positive influence on postoperative weight loss as well as on lung weight increase subsequent to bleomycin instillation. The postoperative body weight loss and the lung weight increase after bleomycin instillation are most likely due to an inflammatory reaction subsequent to operation and bleomycin deposition. Tumor necrosis factor alpha (TNF-alpha) has been shown to be a key cytokine in bleomycin-induced fibrosing alveolitis as well as in IPF; it also exerts catabolizing effects. Since both POF and prednisolone are known to effectively inhibit proinflammatory cytokines and, among those, TNF-alpha, nonspecific antiinflammatory effects probably explain the benefits. Additionally, however, this study proved POF to be more effective in inhibition of BAL neutrophils and number of proliferating cells in lung interstitium. Further, it has been shown that POF, but not prednisolone, inhibits activation of neutrophil granulocytes and formation of reactive oxygen species. Thus we believe that the mechanism of action of xanthines might contribute to therapy of IPF. For further clarification, a prospective clinical study of POF in IPF therapy has been initiated.

Animals↗
PubMed1996

Preparation of tomato meiotic pachytene and mitotic metaphase chromosomes suitable for fluorescence in situ hybridization (FISH).

Fluorescence in situ hybridization (FISH) is an increasingly powerful tool with a variety of applications in both basic and applied research. With excellent genetic, cytogenetic and molecular maps available, the tomato genome provides a good model to benefit from the full potential of FISH. Tomato chromosomes at mitotic metaphase are small and not particularly suitable for high-resolution FISH. In contrast, chromosomes at meiotic pachytene are about 15 times longer, and easier to identify by their differences in chromosome arm lengths and chromomere pattern. We have developed a technique for preparing chromosomal spreads of young pollen mother cells at mid-prophase I which is suitable for FISH. In a first series of experiments, the hybridization patterns of three classes of repetitive DNA sequences were studied in single and multicolour FISH.

Chromosomes↗
PubMed1996

An improved method of partially digesting plant megabase DNA suitable for YAC cloning: application to the construction of a 5.5 genome equivalent YAC library of tomato.

An improved method for preparing partially digested tomato DNA has been developed, that is suitable for YAC cloning. It involves (i) isolation of high molecular-weight DNA from agarose-embedded leaf protoplasts, (ii) controlled partial digestion in situ using EcoRl endonuclease in the presence of EcoRI methylase (M. EcoRl), and (iii) fractionation of the partial digest on a Clamped Homogeneous Electric Fields (CHEF) gel. Unlike methods commonly used for generating partial digests, the present method allows one to produce digests in which the bulk of restriction fragments are of the desired size. Use of these partial digests in constructing YAC libraries of the tomato lines Moneymaker-Cf4 and VFNT Cherry resulted in libraries (total 21,060 clones, 5.5 genome equivalents) in which 80% of the YACs have inserts between 200 and 600 kb. Both libraries have been screened with selected RFLP markers linked to the Cladosporium fulvum Cf4 locus on chromosome 1, using a three-dimensional PCR-based screening technique. To this end, the RFLP markers have been sequenced to allow for the synthesis of specific primers. Thus, for each marker tested several YAC clones have been isolated, including a family of clones that carry leucine-rich repeat sequences located around the Cf4/Cf9 locus.

Base Sequence↗
PubMed1996

High-resolution physical mapping in Arabidopsis thaliana and tomato by fluorescence in situ hybridization to extended DNA fibres.

A technique to detect DNA sequences on extended DNA fibres (EDF) prepared from interphase nuclei from tomato (Lycopersicon esculentum) and Arabidopsis thaliana leaves by fluorescence in situ hybridization (FISH) is described. Three nuclear lysis procedures have been tested for their ability to decondense chromatin and to generate highly extended intact DNA fibres on microscopic slides. DNA probes of various sizes have been used in FISH experiments to EDFs to establish the resolution and sensitivity of the technique. The fluorescent signals of a 5S rDNA probe hybridized to tomato EDFs revealed continuous strings of about 200 microns, that corresponded to a molecular size of about 660 kb. In A. thaliana, a contig of three cosmids spanning a genomic region with a total length of about 89 kb was analysed. By means of multicolour hybridization the physical positions of the cosmids were visualized as red and green fluorescence strings with overlapping regions in yellow. Comparison of the length of the fluorescent signals with the molecular data revealed a stretching degree of the DNA fibres at 3.27 kb microns-1, which is close to the Watson-Crick DNA length estimate of 2.9 kb microns-1. Other experiments on small size molecular probes with both lambda clones (13.5-17 kb insert sizes) and plasmids (4.2 and 5 kb) in a contig of A. thaliana, and the 5S rDNA region in tomato showed close agreement with molecular data. The lower limit of the detection, which was established in a hybridization experiment with two DNA probes from the 45S ribosomal gene on extended fibres of tomato, was about 0.7 kb. Consistent patterns of alternating fluorescent red and green spots were obtained reflecting the tandemly repeated arrangement of the 18S and 25S ribosomal sequences. On the basis of the microscopic distance between these hybridization spots the size of the ribosomal unit was estimated at 8.2 kb. This implies a drastic improvement of high-resolution physical mapping of DNA sequences by FISH on plant DNA.

Arabidopsis↗
PubMed1996

Obstructive sleep apnea syndrome and circadian rhythms of hormones and cytokines.

Several cytokines exhibit a high degree of temporal regulation as well as somnogenic potency (e.g., interleukin-1 [IL-1], tumor necrosis factor-alpha [TNF-alpha]). Seeking the underlying cause of obstructive sleep apnea syndrome (OSAS), we investigated whether circadian rhythms of cytokine release were altered in 10 patients with OSAS. Ten healthy volunteers served as the control population. Seven of the 10 OSAS patients were reexamined after 3 mo of therapy with nasal continuous positive airway pressure (nCPAP) mask ventilation. Circadian cytokine release (IL-1, IL-6, gamma-interferon [gamma-IFN], TNF-alpha) was investigated ex vivo by short-term culture of blood samples. The circadian rhythm of TNF-alpha release was significantly disturbed in OSAS patients: nocturnal physiologic peaks in this cytokine had almost disappeared and an additional daytime peak had developed. Circadian variations in IL-1, IL-6, and gamma-IFN, and in the immunoregulatory hormones melatonin and cortisol, did not differ from those in the controls. Because TNF-alpha is a known modulator of sleep, and nCPAP therapy did not normalize TNF rhythms, we assume that TNF-alpha could well play a pathophysiologic role in OSAS. Further studies should be directed at whether a physiopathologic and/or pathogenic link exists between TNF-alpha and OSAS.

Adult↗
PubMed1996

Twenty-four-hour analysis of lymphocyte subpopulations and cytokines in healthy subjects.

Fourteen healthy male subjects were studied under resting conditions for 24 or 48 h. The 24-h variations of ACTH and cortisol with peaks in the morning were confirmed. Interleukin-2 release was profoundly reduced at 8: 00. A cosine function could be fitted to lymphocyte subpopulations including populations such as T helper-memory cells (CD4+/CDw29) and HLA-DR-bearing cells displaying peak values during the night and minimal values at 9:00. Numbers of natural killer cells (CD57) were not correlated to other cell populations and no rhythm could be detected. Interleukin- 1 beta was detectable in some plasma samples only with an interleukin- 1 ELISA kit (Quantakine HS(R)), but neither a 24-h rhythm nor reproducible results could be obtained for day 1 and 2 of the study. We conclude that there might be a temporal relation between the parameters analyzed: Higher levels of endogenous cortisol in the morning hours probably inhibit the cellular interleukin-2 synthesis and are responsible for an enhanced migration of lymphocytes from the blood into the tissues of the reticuloendothelial system. These results might be indicative of a circadian organization of the immune system which may play a role in both physiological and pathological functioning.

Adrenocorticotropic Hormone↗
PubMed1996

Rapid clearance of human insulin-like growth factor binding protein-3 from the rat circulation and cellular localization in liver, kidney and stomach.

The gastrointestinal tract represents a major site for the trophic actions of insulin-like growth factors (IGFs), which may be derived in vivo from a large circulating pool. The high capacity binding protein for IGFs in blood is IGF binding protein-3 (IGFBP-3), which is largely complexed with an acid-labile subunit (ALS). However, we and others have shown that IGFBP-3 not complexed with ALS can rapidly leave the circulation, and may carry IGFs to peripheral tissues. In this study we investigated the transfer of recombinant, glycosylated human (h)IGFBP-3 from the rat circulation to the stomach and intestine, compared with liver and kidney. [125I]-labeled IGFBP-3 was administered into the tail vein of conscious male rats, which were killed between 5 min and 2 h later. Blood was taken for the preparation of plasma, and the liver, kidneys, stomach and intestine were removed either for estimation of the associated radioactivity, or fixed for autoradiographic analysis of histological sections. Following injection, [125I]-labeled IGFBP-3 was associated, in part, with a 150 kDa complex in plasma within 10 min when analyzed by gel filtration chromatography. However, 84% of the administered IGFBP-3 had already left the circulation, and 40% of the initial injected dose was accumulated in liver by 5 min, with a further 4% localized in the kidneys. Autoradiographic analysis showed that IGFBP-3 was selectively accumulated within Kupffer cells of the liver, and by the glomeruli and proximal tubules of the kidney. Little radiolabeled IGFBP-3 was recovered from the small intestine, but 14% of the initial injected dose was found within the stomach after 2 h, and a further 12% within the stomach contents. Autoradiographic localization within the stomach showed that the [125I]-labeled IGFBP-3 was primarily associated with the mucosal lining and gastric glands. Separation on sodium dodecyl sulphate polyacrylamide gel electrophoresis showed that the majority of the radioactivity associated with the stomach contents represented small, degraded peptides. These results suggest that while a rapid clearance of IGFBP-3 is achieved by the liver and kidney, a longer term accumulation occurs in the stomach with a luminal secretion. This may represent a delivery system by which circulating IGFs may reach gastric tissue.

Animals↗
PubMed1995

Pentoxifylline exerts synergistic immunomodulatory effects in combination with dexamethasone or cyclosporin A.

The methylxanthine derivative pentoxifylline (PTX) is an immunomodulatory agent with incompletely characterized effects on cytokine production. To analyse these effects and to delineate new combination strategies in immunotherapy, we have investigated immunomodulatory properties of PTX in combination with dexamethasone (DEX) or cyclosporin A (CsA). Stimulated human peripheral blood mononuclear cells were treated with clinically relevant concentrations of PTX (12.5-100 micrograms/ml), DEX (0.01-10 microM) or CsA (12.5-50 ng/ml), alone or in combination. With increasing doses of PTX the maximum supernatant titres of tumour necrosis factor (TNF)-alpha, interleukin (IL)-2 and interferon (IFN)-gamma decreased concomitantly, and all cultures co-treated with DEX showed synergism. Release of IL-6 was not consistently altered under PTX treatment. Similarly, PTX and CsA synergistically inhibited the release of IL-2, IFN-gamma and, to a lesser degree, TNF-alpha. Although PTX alone did not significantly reduce lymphoproliferation, both combinations of drugs synergistically inhibited this process. Furthermore, to demonstrate that the key mechanism of PTX-induced effects is an increase in intracellular cyclic adenosine 3':5'-monophosphate (cAMP) levels, identical experiments were performed using dibutyryl-cAMP instead of PTX. In cultures treated with PTX and DEX, expression of different cell receptors was analysed. Expression of IL-2 receptor (IL-2R) was reduced in cultures treated with PTX, and combination with DEX led to further reduction. Expression of intercellular adhesion molecule (ICAM)-1 and of leucocyte function antigen (LFA)-1 alpha was also synergistically reduced, though to a lesser degree. HLA-DR expression remained unchanged. In conclusion, we demonstrate that clinically relevant levels of PTX exert profound immunomodulatory effects in vitro, and that the combined treatment with DEX or CsA has synergistic effects.

Adjuvants, Immunologic↗
PubMed1995

Glucagon-like peptide I reduces postprandial glycemic excursions in IDDM.

Effects of human glucagon-like peptide I (GLP-I)(7-36)amide were examined in volunteers having insulin-dependent diabetes mellitus (IDDM) with residual C-peptide (CP) secretion (n = 8, 7 men and 1 woman; age, 31 +/- 1.4 years; body mass index, 24.7 +/- 0.7 kg/m2; duration of diabetes, 3.2 +/- 0.8 years; insulin dose, 0.41 +/- 0.05 U.kg-1.day-1; meal-stimulated CP, 1.0 +/- 0.2 nmol/l [means +/- SE]). After a mixed meal (Sustacal, 30 kJ/kg body wt), intravenous injection of GLP-I, 1.2 pmol.kg-1.min-1 through 120 min, virtually abolished increments of plasma glucose, CP, pancreatic polypeptide (PP), and glucagon concentrations, with no significant effect on plasma gastrin levels during the infusions. At reduced dosage (0.75 pmol.kg-1.min-1), GLP-I had lesser effects on plasma glucose and CP levels. On cessation of intravenous GLP-I infusions after the meals, plasma glucose, CP, PP, and glucagon concentrations rebounded toward control levels by 180 min, and the response of plasma gastrin was prolonged. These rebound responses are consistent with intestinal delivery of food retained in the stomach on escape from inhibition of gastric emptying by GLP-I. Infusion of 1.2 pmol.kg-1.min-1 GLP-I with 20 g glucose (10% dextrose in water) injected intravenously over 60 min enhanced plasma responses of immunoreactive CP; the mean incremental areas under concentration curves (0-60 min) increased sixfold, but the glycemic excursion was not affected. Thus, in CP-positive IDDM, pharmacological doses of GLP-I reduce glycemic excursions after meals by a mechanism(s) not dependent on stimulation of insulin secretion, presumably involving delayed gastric emptying.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

[Pathogenesis of interstitial pulmonary changes with collagen diseases--therapeutic implications].

Autoantibodies, immune complexes and autoreactive lymphocytes represent the initial steps in the pathogenic events leading to interstitial pulmonary manifestations of collagen vascular diseases. Vascular damage caused by deposition of immune complexes in the vascular wall and chemotactic factors result in an influx of neutrophils and mononuclear cells leading to inflammatory phenomena like vasculitis and alveolitis. Finally, persistent activation of lung fibroblasts may result in interstitial pulmonary fibrosis characterized by nearly identical histopathological findings independent of the underlying disease. Several inflammatory mediators, e.g. cytokines, are markedly involved in the regulation of different pathogenic mechanisms. Furthermore, different pathogenic mechanisms exert variable roles depending on the specificity of the underlying disease. Therefore, disease-specific effective pharmacotherapy, which in most cases will be a combination therapy, has to take into consideration not only the predominant pathogenic mechanisms but also drug-specific efficacy.

Adrenal Cortex Hormones↗
PubMed1994

Blood-brain barrier permeability in rats is altered by exposure to magnetic fields associated with magnetic resonance imaging at 1.5 T.

We have previously reported that exposure of rats to low-field (0.15 T) magnetic resonance imaging (MRI) increases blood-brain barrier (BBB) permeability. However, a number of investigators have failed to observe this effect when high-field MRI (1.5 T or higher) is used. Therefore, we investigated whether or not we would observe changes using our technique at these higher fields. Adult male Sprague-Dawley rats were anaesthetised and then exposed to a 22.5 min imaging or sham procedure. Immediately following exposure, rats were injected with 1 MBq of 153Gd-DTPA intracardially and then immediately re-exposed for an additional 22.5 min. The rats were killed 1h following the second MRI exposure, at which time the brain was resected and 3 ml of venous blood collected. The ratio of radioactivity per gram of brain to radioactivity per milliliter of blood, known as the brain-blood partition coefficient, was determined and used as a measure of BBB permeability. Groups of animals had different exposures. Group 1 (n = 9) was exposed to a clinically relevant MRI procedure. Group 2 (n = 20) was exposed to the same procedure except the rf specific absorption rate (SAR) was reduced to 25% and the animals were positioned 15 cm from imager centre to increase the time-varying magnetic field from 0.4 to 2.8 T/s. For the sham exposures (n = 21), the animals were placed in the imager with the static field ramped down to zero and exposed to a sound recording simulating a MRI examination.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Effect of renal function on cytokine secretion of monocytes and lymphocytes.

The effect of renal function on cytokine secretion capacity of mononuclear cells was analysed in patients who had not been subjected to any form of renal replacement therapy. The aim of the study was especially to determine whether there is a defect of monocyte function. The patients were divided into three groups of 12 on the basis of renal function: group I, serum creatinine 1.5-3 mg/dl; group II, 3-6 mg/dl; and group III, > 6 mg/dl. Serving as controls were 36 age- and sex-matched healthy volunteers. IL-1 beta, IL-6, TNF-alpha, IL-2 and IF-gamma concentrations were measured in the supernatants of stimulated and unstimulated cells isolated from the blood. Renal function was not found to have any effect on the secretion capacity of IL-2 and IF-gamma. However, the secretion capacity of IL-1 beta of lipopolysaccharide (LPS)-stimulated monocytes was reduced in patients of group III to 214 +/- 290 pg/ml, compared with 501 +/- 327 pg/ml in controls (P = 0.047). The effect was even more accentuated for IL-6 (group III: 5422 +/- 5116 pg/ml; controls: 16,319 +/- 12,474 pg/ml; P = 0.019). Spontaneous secretion levels did not change for any of the cytokines, and LPS-stimulated TNF-alpha secretion was also normal. Highly purified blood monocytes/macrophages were stained for CD14, HLA-DR, CD11c, and CD4. Neither the percentage of positive cells nor the fluorescence intensity, as measured by FACS, was influenced by renal function, and no correlation could be established between function and phenotype.(ABSTRACT TRUNCATED AT 250 WORDS)

Cells, Cultured↗
PubMed1994

Canine, human, and rat plasma insulin responses to galanin administration: species response differences.

Previous studies demonstrated that porcine galanin is a potent inhibitor of insulin secretion in many species but fails to alter human insulin secretion. To resolve whether this discrepancy was due to the use of a heterologous peptide or to a true species response difference, we studied the effect of a synthetic replicate of human galanin on glucose-stimulated insulin secretion in rats, dogs, and humans. On administration into rats, human and rat galanin significantly inhibited glucose-induced insulin responses to a similar degree. Similarly, porcine and human galanin significantly elevated canine plasma glucose and inhibited canine plasma insulin responses. In contrast, plasma glucose and insulin responses to glucose administration in humans were unaltered by the addition of human galanin at or above the maximum effective dose employed in dogs. Possible effects of galanin administration were seen on human glucagon and pancreatic polypeptide responses to glucose at the highest dose of human galanin infused. We conclude that galanin probably does not play a major role in modulating human beta-cell function.

Adult↗