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Biomedical subjects

M Pettersson

Publications and source records attributed to M Pettersson.

At least 55 records · Page 3Linked to original sources
PubMed1990

Failure of islet amyloid polypeptide to inhibit basal and glucose-stimulated insulin secretion in model experiments in mice and rats.

Islet amyloid polypeptide (IAPP), also known as amylin, has previously been demonstrated to occur in amyloid deposits in pancreatic islets in type 2 diabetics, and, therefore, the peptide has been suggested to be involved in the pathogenesis of diabetes. The 37 amino acid peptide shows approximately 50% homology with the intrapancreatic neuropeptide calcitonin gene-related peptide (CGRP), a peptide that inhibits insulin secretion. We therefore examined, in model experiments in mice and rats, if IAPP also exerts this effect. IAPP was given intravenously, at dose levels at which CGRP previously has been shown to inhibit insulin secretion. Thus, in mice, IAPP was injected at 0.85 and 4.25 nmol kg-1, and in rats IAPP was infused at 17 or 68 pmol min-1. However, neither basal nor glucose-stimulated insulin release was inhibited by IAPP under these experimental conditions. We also investigated if IAPP (10(-11) to 10(-6) M), when incubated in vitro with isolated, overnight-cultured rat islets, could affect insulin secretion induced by glucose (3.3, 8.3 or 11.7 mM). However, also in vitro no effect by IAPP on insulin release was observed. Hence, in mice and rats, IAPP does not inhibit insulin secretion under experimental conditions identical to those previously used to demonstrate an inhibition by CGRP. Therefore, we conclude (1) that the homologous amino acid sequence within IAPP and CGRP does not seem to be sufficient for inducing inhibition of insulin release in mice and rats and (2) that the possible involvement of IAPP in the pathogenesis of diabetes type 2 still remains speculative.

Amyloid↗
PubMed1990

Glucose tolerance and insulin secretion in experimental peritonitis in the rat.

The changes in the regulation of insulin secretion that accompany sepsis are yet to be fully established. We therefore examined insulin secretion both in vivo and in vitro in 2 different models of peritonitis/sepsis in the rat. Sepsis was induced by intraperitoneal injection of Escherichia coli either alone or together with bile. Following sepsis induction, an initial hyperglycemia developed. This hyperglycemia was transient and had vanished after 3 h (coli group) or 9 h (bile group). However, after 24 h, a second phase of hyperglycemia developed in both groups. The glucose elimination rate after intravenous glucose injection (0.5 g/kg) at 4 and 10 h after peritonitis/sepsis induction was retarded and the hyperglycemia that occurred during intravenous glucose infusion (10 mg/min for 30 min) was exaggerated. This is consistent with a reduced glucose uptake. Simultaneously, the plasma insulin responses to glucose were markedly exaggerated. This could be due to a true potentiated insulin secretion or simply to an adaptation to the hyperglycemia. However, also during intravenous arginine infusion (7 mg/min) at 4 h after peritonitis/sepsis induction, the plasma insulin responses were markedly exaggerated. Since only a slight change in plasma glucose occurred during this challenge, the results suggest that sepsis is accompanied by a true hypersecretion of insulin. To verify whether this is directly or indirectly mediated, pancreatic islets were isolated from peritonitis/sepsis animals at 4 h after disease induction and incubated for 45 min in a KRB medium supplemented with different concentrations of glucose. The subsequent insulin secretion was the same in islets from the septic animals as in controls. Hence, our results show that experimental peritonitis/sepsis in the rat is accompanied by (1) glucose intolerance and (2) a true hypersecretion of insulin which is indirectly mediated.

Animals↗
PubMed1990

Calcitonin gene-related peptide inhibits insulin secretion studies on ion fluxes and cyclic AMP in isolated rat islets.

Calcitonin gene-related peptide (CGRP) is an intrapancreatic neuropeptide that is known to inhibit glucose-stimulated insulin secretion in rats. To study if this inhibition is a direct islet effect, isolated, overnight cultured, rat islets were incubated together with glucose (3.3 or 8.3 mM) and CGRP (10(-11) to 10(-6) M). It was found that insulin secretion stimulated by glucose (8.3 mM) was inhibited by 77% by CGRP at 10(-6) M (p less than 0.001) and by 48% by the peptide at 10(-7) M (p less than 0.05). To study the possible mechanism(s) behind this inhibition, we investigated the effects of CGRP (10(-6) M) on the efflux of 45Ca2+ and 86Rb+ (reflecting Ca2+ and K+ ion movements, respectively) from isolated, perifused, rat islets. Furthermore, we examined the influence of CGRP on the content of cyclic AMP in overnight cultured isolated rat islets. We found that the initial, immediate 2-8 min peak of glucose (16.7 mM)-stimulated 45Ca(2+)-efflux was not affected by CGRP. In contrast, when the peptide was added at min 20 after glucose introduction, i.e., when the peak 45Ca(2+)-efflux had vanished, a small decrease in 45Ca(2+)-efflux was observed (p less than 0.001). CGRP did not alter the 86Rb(+)-efflux at 8.3 mM glucose neither in the presence nor in the absence of extracellular Ca2+. The islet content of cyclic AMP after 30 min incubation was 19.1 +/- 3.1 fmol/islet at 3.3 mM glucose and increased to 36.0 +/- 5.7 fmol/islet at 16.7 mM glucose (p less than 0.05). CGRP (10(-6) M) completely abolished this increase.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Insulin secretion in rats: effects of neuropeptide Y and noradrenaline.

Neuropeptide Y (NPY) occurs within nerves in the rat pancreas, some of which are adrenergic. Therefore, we examined the influence of NPY alone and together with noradrenaline (NA) on insulin release in the rat. When infused alone for 30 min under basal conditions, NPY increased basal plasma insulin concentrations by 32 +/- 13 microU/ml at the highest dose level tested (68 pmol/min), as compared to +7 +/- 7 microU/ml in the controls (p less than 0.05). In contrast, NPY at 17 pmol/min reduced the plasma insulin response to both glucose (by 11%; p less than 0.001) and to arginine (by 26%; p less than 0.001). Infusion of NA alone (340 pmol/min) significantly elevated the basal plasma insulin levels by 41 +/- 4 microU/ml (p less than 0.001). NPY (17 pmol/min) completely abolished this effect (p less than 0.001). When NA (340 pmol/min) was added to an ongoing glucose infusion, the plasma insulin levels were markedly reduced (by 48%; p less than 0.001). By introducing NPY (17 pmol/min), this inhibitory action occurred more rapidly. However, NPY did not affect the maximal response to NA. In isolated rat islets, both NPY (10(-6) M) and NA (10(-6) M) inhibited glucose-stimulated insulin secretion. However, the maximal inhibitory effect exerted by the two neurotransmitters was not altered by giving them together. We conclude that, in the rat, NPY and NA both elevate basal plasma insulin levels and inhibit stimulated insulin secretion. In combination, NPY also induces a more rapid onset of the inhibitory action of NA on glucose-induced insulin secretion.

Analysis of Variance↗
PubMed1988

Expression of messenger RNAs for platelet-derived growth factor and transforming growth factor-alpha and their receptors in human malignant glioma cell lines.

Formal proof for an involvement of autocrine stimulation in the disturbed growth of malignant cells has been difficult to obtain, in part due to lack of precise methods of assessing growth factor production and receptor occurrence. In this study we have analyzed the mRNA levels for two growth factors and the corresponding receptors in a number of established human malignant glioma cell lines. Twenty-one tested lines all contained transcripts for the platelet-derived growth factor (PDGF) A chain while 16-17 of 21 expressed the c-sis/PDGF B chain gene; these two genes were expressed independently of each other. PDGF receptor transcripts were present in 15-16 of the 21 lines. Transcripts for the epidermal growth factor receptor were found in all 15 tested lines, in 2 of them at high levels, and the corresponding ligand transforming growth factor-alpha was found in 11 of 15 lines. No amplification or structural rearrangements of the genes, as analyzed by Southern blot hybridization, could explain the varying expression of PDGF A and B chain transcripts or the elevated levels of epidermal growth factor receptor mRNA. A correlation was found between cell morphology and expression of growth factor and receptor mRNA in these lines. The highest amount of PDGF receptor transcripts was found in cells with fibroblast-like morphology, and c-sis/B chain transcripts were found in small cell types and in cells with astrocyte-like morphology, while no clear relationship was found between PDGF receptor and A chain transcript levels or between morphology and A chain transcripts. It is possible that the findings reflect a coordinated expression of these genes in the progenitor cells. In conclusion, the data imply the existence of two possible autocrine loops in human malignant glioma lines, affecting the PDGF and epidermal growth factor receptor pathways.

Cell Line↗
PubMed1988

Insulin and glucagon secretion in the rat: effects of gastrin releasing peptide.

Immunoreactive gastrin releasing peptide (GRP) has been shown to occur in intrapancreatic nerve fibers, and to be released from the perfused porcine pancreas during electrical vagal activation. Hence, it could be anticipated that GRP may be of functional importance for the neural control of islet hormone secretion. Therefore, we investigated the effects of intravenous infusion of GRP on basal and stimulated insulin and glucagon secretion in vivo in the rat. We found that GRP, at 4.3 or 17 pmol/min, increased basal plasma concentrations of both insulin and glucagon and induced hyperglycemia. Furthermore, GRP (1.1 or 4.3 pmol/min) potentiated the plasma insulin response to glucose (7 mg/min). In contrast, the peptide (at 4.3 pmol/min) inhibited the insulin response to arginine (8.5 mg/min). Moreover, GRP increased the plasma glucagon levels during infusion of both arginine and glucose. In summary, in the rat GRP 1) stimulates basal insulin and glucagon secretion, 2) potentiates glucose-stimulated insulin secretion, 3) inhibits arginine-stimulated insulin secretion, 4) potentiates arginine-stimulated glucagon secretion, 5) counteracts the glucose-induced suppression of glucagon secretion, and 6) induces hyperglycemia. Though this study can not establish the mechanisms or physiological importance of these effects, we conclude that the intrapancreatic neuropeptide GRP has the capability to affect both insulin and glucagon secretion in vivo in the rat.

Animals↗
PubMed1988

Insulin and glucagon secretion in rats: effects of calcitonin gene-related peptide.

Immunoreactive calcitonin gene-related peptide (CGRP) has been shown to occur in intrapancreatic nerves and islet somatostatin cells in the rat. Therefore, we investigated the effects of CGRP on insulin and glucagon secretion in the rat. CGRP was infused i.v. at one of 3 dose levels (4.3, 17 or 68 pmol/min). Infusion of CGRP alone was found to elevate basal plasma levels of both insulin and glucagon. In contrast, CGRP impaired the plasma insulin responses to both glucose (7 mg/min; P less than 0.001) and arginine (8.5 mg/min; P less than 0.001), and inhibited the arginine-induced increase in plasma glucagon concentrations (P less than 0.001). Since CGRP and somatostatin are colocalized within the D-cells, we also infused CGRP and somatostatin together at equimolar dose levels (17 pmol/min), with glucose (7 mg/min). By that, the increase in plasma insulin concentrations decreased more rapidly than during infusion of either peptide alone. Since alpha 2-adrenoceptor activation is known to inhibit glucose-stimulated insulin secretion, we also infused CGRP together with the specific alpha 2-adrenoceptor antagonist yohimbine (37 nmol/min). In that way, the plasma insulin-lowering effect of CGRP was prevented. We have shown in the rat: (1) that CGRP stimulates basal insulin and glucagon secretion; (2) that CGRP inhibits stimulated insulin and glucagon secretion; (3) that CGRP and somatostatin more rapidly induce a potent inhibitory action on glucose-stimulated insulin secretion when given together; and (4) that the alpha 2-adrenoceptor antagonist, yohimbine, counteracts the inhibitory action of CGRP on glucose-stimulated insulin secretion. We suggest that CGRP is of importance for the regulation of insulin and glucagon secretion in the rat. The mechanisms behind the islet effects of CGRP can not be established by the present results, though they apparently require intact alpha 2-adrenoceptors.

Animals↗
PubMed1987

Evidence for progressional changes in the human malignant glioma line U-343 MGa: analysis of karyotype and expression of genes encoding the subunit chains of platelet-derived growth factor.

Three cell samples in different passages of the line U-343 MGa, derived from a human malignant glioma biopsy, gave rise to clones with different amounts of platelet-derived growth factor (PDGF)-like activity secreted to extracellular medium, and of 125I-labeled PDGF binding. Sixteen clones were completely karyotyped with the G-banding technique. The unique markers 1p-q+, 16p- found in all clones, as well as in the parallel uncloned line, U-343 MG, provided evidence of their common origin. The deduced early, possibly partly primary, deviations had the formula 44, XY, 1p-q+, -14, 16p-, -22, where loss of one chromosome 22 is in accordance with previous reports on early chromosomal deviations in gliomas. Two clones, the hypodiploid 26L and 5H, represented early progressional changes. The other clones followed two patterns of late progressional changes, probably starting from the karyotype of 5H, with additional markers and doubling of the stemlines. In late progressional line I 12q+ and in II +7 were the most characteristic findings. Northern blot analysis using complementary DNA clones for the A and B chains of PDGF showed that both PDGF chains were expressed in 26L and 5H indicating that activation of the PDGF genes could have been an early event in the development of this glioma. Clones with late progression pattern II had been subjected to the highest selective pressure in vitro, and they secreted the highest amount of PDGF-like activity to the extracellular medium. Among them were the most rapidly and tightly growing cells and some clones with high 125I-labeled epidermal growth factor binding. Possibly these findings reflect progressional changes including defective regulation of the growth factor/growth factor receptor genes, selected for in vitro, without involving gross rearrangements or amplifications of the genes. The possible significance of extra chromosomes 7, with the PDGF A chain and epidermal growth factor receptor genes, and of the 12q+ marker, located near the gamma interferon gene is discussed.

Cell Line↗
PubMed1987

Expression of multiple growth factors in a human lung cancer cell line.

U-1810, a human large-cell lung cancer line, was found to express a PDGF-like growth factor. 35S-cysteine labelling and immunoprecipitation revealed the synthesis and secretion of a 31-kDa PDGF-like protein. Serum-free conditioned medium contained PDGF-receptor-competing and mitogenic activity when tested on human fibroblasts. Whereas the receptor-competing activity was fully neutralized by anti-PDGF antibodies, the mitogenic activity was only partially affected. We therefore probed U-1810 mRNA with a panel of growth-factor DNA clones. We found expression of the genes for PDGF A- and B-chains, TGF-alpha, TGF-beta and IGF-II but not EGF or IGF-I. U-1810 cells lacked specific binding sites for PDGF but showed specific binding of EGF and expressed EGF-receptor transcripts. Thus, U-1810 is an example of a human tumor cell line that expresses multiple growth factor genes; in the intact tumor the corresponding growth factors may operate in autocrine stimulation of the tumor cells as well as in paracrine growth reactions (i.e. stroma recruitment).

Cell Line↗
PubMed1987

Neuropeptide Y: intrapancreatic neuronal localization and effects on insulin secretion in the mouse.

The intrapancreatic localization and the effects on basal and stimulated insulin secretion of neuropeptide Y (NPY) were investigated in the mouse. Immunocytochemistry showed NPY to be confined to intrapancreatic nerve fibers mainly associated with blood vessels. Fine varicose NPY fibers were also detected in the exocrine parenchyma and occasionally also within the islets. Double-staining experiments with the use of antisera for both NPY and tyrosine hydroxylase (TH) indicated that most of the NPY fibers were nonadrenergic in nature. Only a population of the NPY fibers occurring around blood vessels showed TH immunoreactivity. Under in vivo conditions, NPY was found to elevate plasma insulin levels slightly when injected intravenously at the high dose level of 8.5 nmol/kg. At lower dose levels, NPY did not affect basal plasma insulin levels, but instead inhibited glucose-induced insulin secretion. Thus, the glucose-induced increment in plasma insulin levels, which was 120 +/- 7 microU/ml in controls, was reduced to 87 +/- 5 microU/ml by NPY at 4.25 nmol/kg (p less than 0.01) and to 98 +/- 6 microU/ml by NPY at 1.06 nmol/kg (p less than 0.05). In contrast, the insulin secretory response to the cholinergic agonist carbachol was not affected by NPY. We conclude that NPY nerve fibers occur in the mouse pancreas and that most of these NPY nerve fibers are nonadrenergic. Furthermore, in the mouse, NPY enhances basal plasma insulin levels at high dose levels and inhibits glucose-induced, but not cholinergically induced insulin secretion at lower dose levels under in vivo conditions.

Animals↗
PubMed1987

Neuropeptide Y and calcitonin gene-related peptide: effects on glucagon and insulin secretion in the mouse.

Neuropeptide Y (NPY) and calcitonin gene-related peptide (CGRP) are both intrapancreatic neuropeptides that are known to inhibit stimulated insulin secretion. In the present study, we examined their influences on basal and stimulated glucagon and insulin secretion in the mouse. Either NPY or CGRP was injected intravenously at two dose levels (0.85 or 4.25 nmol/kg). When injected alone, neither of them did affect basal plasma glucagon levels but CGRP reduced basal plasma insulin levels. Glucagon secretion stimulated by the cholinergic agonist carbachol was modestly inhibited by NPY at 4.25 nmol/kg (P less than 0.01) but not affected by CGRP. In contrast, glucagon secretion stimulated by the beta 2-adrenoceptor agonist terbutaline was markedly inhibited by NPY already at the lower dose level (P less than 0.01) and potentiated by CGRP (P less than 0.01). Insulin secretion stimulated by carbachol was inhibited by CGRP (P less than 0.01) but not affected by NPY, whereas terbutaline-induced insulin secretion was inhibited by both NPY (P less than 0.05) and CGRP (P less than 0.01). We conclude that the two intrapancreatic neuropeptides NPY and CGRP have opposite actions on stimulated glucagon secretion in the mouse: NPY in an inhibitory and CGRP in a potentiatory direction. Both peptides, however, inhibit insulin secretion stimulated by terbutaline.

Animals↗
PubMed1986

Calcitonin gene-related peptide: occurrence in pancreatic islets in the mouse and the rat and inhibition of insulin secretion in the mouse.

The intrapancreatic cellular distribution and effects on basal and stimulated insulin secretion of the 37-amino-acid polypeptide, calcitonin gene-related peptide (CGRP), were investigated in the mouse. The cellular localization of CGRP was also studied in the rat pancreas. In both species, CGRP was demonstrated in pancreatic islet cells and nerve fibers. Immunocytochemical double staining experiments revealed the CGRP-immunoreactive cells in the mouse to be identical with a majority population of the insulin cells. In the rat, on the other hand, CGRP-immunoreactive cells were identical with somatostatin cells. CGRP-immunoreactive nerve fibers were observed, in both species, running in the exocrine parenchyma, particularly around blood vessels, and they were occasionally seen also within the islets. In in vivo experiments, CGRP was found to inhibit both basal and stimulated insulin secretion in the mouse. Thus, 6 min after the iv injection of CGRP (0.85 nmol/kg), plasma insulin levels were 13 +/- 2 (SE) microU/ml compared to 30 +/- 4 microU/ml in controls (P less than 0.01). At this dose level, CGRP inhibited the insulin secretory response to carbachol, leaving that to glucose unaffected. However, at a higher dose level (4.25 nmol/kg), CGRP inhibited glucose-induced insulin secretion as well. We conclude that CGRP occurs in islet cells and in intrapancreatic nerve fibers of both the mouse and the rat, and inhibits both basal and stimulated insulin secretion in vivo in the mouse.

Animals↗
PubMed1984

The gene for the adenovirus 2 hexon polypeptide.

The nucleotide sequence of the gene for the adenovirus type 2 hexon has been determined. The hexon polypeptide consists of 967 amino acid residues and has a molecular weight of 109,058. Several tentative parts in the previously reported amino acid sequence were resolved from the DNA sequence. The existence of regions with unusual properties in the hexon protein was confirmed, including a region consisting of 16 consecutive acidic residues in the N-terminal part of the protein. In conjunction with previously published sequences and sequences reported in the accompanying papers (Aleström, P., Akusjärvi, G., Lager, M., Yeh-Kai, L., and Petterson, U. (1984) J. Biol. Chem. 259, 13980-13985; Roberts, R. J., O'Neill, K. E., and Yen, C. E. (1984) J. Biol. Chem. 259, 13965-13975) a complete sequence of the 35,937-base pairs-long adenovirus type 2 genome can now be reconstructed.

Adenoviruses, Human↗