| 51. |
- De Marinis, Yang, et al.
(författare)
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Enhancement of glucagon secretion in mouse and human pancreatic alpha cells by protein kinase C (PKC) involves intracellular trafficking of PKCalpha and PKCdelta.
- 2010
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 53:4, s. 717-729
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: Protein kinase C (PKC) regulates exocytosis in various secretory cells. Here we studied intracellular translocation of the PKC isoenzymes PKCalpha and PKCdelta, and investigated how activation of PKC influences glucagon secretion in mouse and human pancreatic alpha cells. METHODS: Glucagon release from intact islets was measured in static incubations, and the amounts released were determined by RIA. Exocytosis was monitored as increases in membrane capacitance using the patch-clamp technique. The expression of genes encoding PKC isoforms was analysed by real-time PCR. Intracellular PKC distribution was assessed by confocal microscopy. RESULTS: The PKC activator phorbol 12-myristate 13-acetate (PMA) stimulated glucagon secretion from mouse and human islets about fivefold (p < 0.01). This stimulation was abolished by the PKC inhibitor bisindolylmaleimide (BIM). Whereas PMA potentiated exocytosis more than threefold (p < 0.001), BIM inhibited alpha cell exocytosis by 60% (p < 0.05). In mouse islets, the PKC isoenzymes, PKCalpha and PKCbeta1, were highly abundant, while in human islets PKCeta, PKCepsilon and PKCzeta were the dominant variants. PMA stimulation of human alpha cells correlated with the translocation of PKCalpha and PKCdelta from the cytosol to the cell periphery. In the mouse alpha cells, PKCdelta was similarly affected by PMA, whereas PKCalpha was already present at the cell membrane in the absence of PMA. This association of PKCalpha in alpha cells was principally dependent on Ca(2+) influx through the L-type Ca(2+) channel. CONCLUSIONS/INTERPRETATION: PKC activation augments glucagon secretion in mouse and human alpha cells. This effect involves translocation of PKCalpha and PKCdelta to the plasma membrane, culminating in increased Ca(2+)-dependent exocytosis. In addition, we demonstrated that PKCalpha translocation and exocytosis exhibit differential Ca(2+) channel dependence.
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| 52. |
- De Marinis, Yang, et al.
(författare)
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GLP-1 inhibits and adrenaline stimulates glucagon release by differential modulation of N- and L-type Ca2+ channel-dependent exocytosis.
- 2010
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Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131. ; 11:6, s. 543-553
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Tidskriftsartikel (refereegranskat)abstract
- Glucagon secretion is inhibited by glucagon-like peptide-1 (GLP-1) and stimulated by adrenaline. These opposing effects on glucagon secretion are mimicked by low (1-10 nM) and high (10 muM) concentrations of forskolin, respectively. The expression of GLP-1 receptors in alpha cells is <0.2% of that in beta cells. The GLP-1-induced suppression of glucagon secretion is PKA dependent, is glucose independent, and does not involve paracrine effects mediated by insulin or somatostatin. GLP-1 is without much effect on alpha cell electrical activity but selectively inhibits N-type Ca(2+) channels and exocytosis. Adrenaline stimulates alpha cell electrical activity, increases [Ca(2+)](i), enhances L-type Ca(2+) channel activity, and accelerates exocytosis. The stimulatory effect is partially PKA independent and reduced in Epac2-deficient islets. We propose that GLP-1 inhibits glucagon secretion by PKA-dependent inhibition of the N-type Ca(2+) channels via a small increase in intracellular cAMP ([cAMP](i)). Adrenaline stimulates L-type Ca(2+) channel-dependent exocytosis by activation of the low-affinity cAMP sensor Epac2 via a large increase in [cAMP](i).
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| 53. |
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| 54. |
- Degerman, Eva, et al.
(författare)
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Inhibition of phosphodiesterase 3, 4, and 5 induces endolymphatic hydrops in mouse inner ear, as evaluated with repeated 9.4T MRI
- 2017
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Ingår i: Acta Oto-Laryngologica. - : Informa UK Limited. - 0001-6489 .- 1651-2251. ; 137:1, s. 8-15
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Tidskriftsartikel (refereegranskat)abstract
- Conclusion: The data indicate important roles for phosphodiesterase (PDE) 3, 4, 5, and related cAMP and cGMP pools in the regulation of inner ear fluid homeostasis. Thus, dysfunction of these enzymes might contribute to pathologies of the inner ear. Objective: The mechanisms underlying endolymphatic hydrops, a hallmark of inner ear dysfunction, are not known in detail; however, altered balance in cAMP and cGMP signaling systems appears to be involved. Key components of these systems are PDEs, enzymes that modulate the amplitude, duration, termination, and specificity of cAMP and cGMP signaling. Method: To evaluate the role of PDE3, 4, and 5 and associated cAMP and cGMP pools in inner ear function, the effect of cilostamide (PDE3 inhibitor), rolipram (PDE4 inhibitor), and sildenafil (PDE5 inhibitor), administrated via mini-osmotic pumps, on mouse inner ear fluid homeostasis was evaluated using 9.4T in vivo MRI in combination with intraperitoneally administered Gadolinium contrast. Also, using human saccule as a model, the expression of PDEs and related signaling molecules and targets was studied using immunohistochemistry. Results: PDE3, PDE4, as well as PDE5 inhibitors resulted in the development of endolymphatic hydrops. Furthermore, PDE3B, PDE4D, and some related signaling components were shown to be expressed in the human saccule.
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| 55. |
- Dehlin, Eva, et al.
(författare)
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Nio förstelärares arbete i grundsärskola och gymnasiesärskola : resultat från en forskningscirkel
- 2017
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Samlingsverk (redaktörskap) (övrigt vetenskapligt/konstnärligt)abstract
- Forskningscirkeln har genomförts tillsammans med nio förstelärare från två kommuner som arbetar inom grundsärskola och gymnasiesärskola. Inom ramen forskningscirkeln har de drivit utvecklingsprojekt under läsåret 2016/2017. Grundsärskola och gymnasiesärskola utgör arenan för deltagarna i forskningscirkeln och de nio förstelärarna har drivit egna utvecklingsprojekt inom sina respektive verksamheter. Trots att de nio förstelärarna arbetar på olika stadier, med olika elevgrupper och utifrån olika förutsättningar samlades de kring några centrala teman. I de olika utvecklingsprojekten har skolutveckling utifrån elevernas delaktighet och inflytande, bedömning för lärande, elevhälsa, kommunikation och kollegialt lärande stått i förgrunden.
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| 56. |
- Dekker Nitert, Marloes, et al.
(författare)
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CaV1.2 rather than CaV1.3 is coupled to glucose-stimulated insulin secretion in INS-1 832/13 cells.
- 2008
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Ingår i: Journal of Molecular Endocrinology. - 1479-6813. ; 41:1, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- In clonal beta-cell lines and islets from different species, a variety of calcium channels are coupled to glucose-stimulated insulin secretion. The aim of this study was to identify the voltage-gated calcium channels that control insulin secretion in insulinoma (INS)-1 832/13 cells. The mRNA level of Ca(V)1.2 exceeded that of Ca(V)1.3 and Ca(V)2.3 two-fold. Insulin secretion, which rose tenfold in response to 16.7 mM glucose, was completely abolished by 5 microM isradipine that blocks Ca(V)1.2 and Ca(V)1.3. Similarly, the increase in intracellular calcium in response to 15 mM glucose was decreased in the presence of 5 microM isradipine, and the frequency of calcium spikes was decreased to the level seen at 2.8 mM glucose. By contrast, inhibition of Ca(V)2.3 with 100 nM SNX-482 did not significantly affect insulin secretion or intracellular calcium. Using RNA interference, Ca(V)1.2 mRNA and protein levels were knocked down by approximately 65% and approximately 34% respectively, which reduced insulin secretion in response to 16.7 mM glucose by 50%. Similar reductions in calcium currents and cell capacitance were seen in standard whole-cell patch-clamp experiments. The remaining secretion of insulin could be reduced to the basal level by 5 microM isradipine. Calcium influx underlying this residual insulin secretion could result from persisting Ca(V)1.2 expression in transfected cells since knock-down of Ca(V)1.3 did not affect glucose-stimulated insulin secretion. In summary, our results suggest that Ca(V)1.2 is critical for insulin secretion in INS-1 832/13 cells.
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| 57. |
- Demarin, Eva-Lena, et al.
(författare)
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Samhällsvetenskapliga perspektiv på risk och kris : Uppfattning, kommunikation och organisation.
- 2010
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Forskargruppen KRIHS, Kris och risk i det heterogena samhället, har fått uppdraget att skriva en kunskapsöversikt inom ramen för MSB:s verksamhetsområden skydd mot olyckor, krishantering och civil beredskap. Uppdraget har gjorts i samarbete med Eva-Lena Demarin som stått för stora delar av sammanställningen av tidigare forskning samt delar av övriga avsnitt. Undertecknad ansvarar för översiktens vetenskapliga kvalitet. Kunskapsöversikten är dock ett resultat av forskargruppens gemensamma ansträngningar. Tillsammans med Eva-Lena har gruppen träffats vid fem tillfällen varav vid ett seminarium där texten diskuterats och reviderats. De som varit med och diskuterat, samlat in material och/eller skrivit delar av översikten är förutom ovan nämnda, Erna Danielsson, Sara Ekholm, Linda Eliasson, Roine Johansson, Jörgen Sparf, Erika Wall och Susanna Öhman.Då både tiden och utrymmet har varit begränsat gör vi inga anspråk på att kunskapsöversikten är heltäckande. Den ska snarare ses som en ganska grovkorning bild av de senaste tio årens risk- och krisforskning rörande uppfattningar, kommunikation och organisation. Det huvudsakliga bidraget är att översikten identifierar vissa områden där kunskapsuppbyggnad behövs. På så sätt kan översikten ses som en karta där vissa kompassriktningar markerats utifrån vilka MSB kan välja vilka som passar myndighetens framtida verksamhet.
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| 58. |
- Dos Santos, Cristiane, et al.
(författare)
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Glucocorticoids and glucolipotoxicity alter the DNA methylome and function of human EndoC-βH1 cells
- 2022
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Ingår i: Life Sciences. - : Elsevier BV. - 1879-0631 .- 0024-3205. ; 307
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Synthetic glucocorticoids, including dexamethasone (DEX), are clinically prescribed due to their immunoregulatory properties. In excess they can perturb glucose homeostasis, with individuals predisposed to glucose intolerance more sensitive to these negative effects. While DEX is known to negatively impact β-cell function, it is unclear how. Hence, our aim was to investigate the effect of DEX on β-cell function, both alone and in combination with a diabetogenic milieu in the form of elevated glucose and palmitate.MAIN METHODS: Human pancreatic EndoC-βH1 cells were cultured in the presence of high glucose and palmitate (glucolipotoxicity) and/or a pharmacological concentration of DEX, before functional and molecular analyses.KEY FINDINGS: Either treatment alone resulted in reduced insulin content and secretion, while the combination of DEX and glucolipotoxicity promoted a strong synergistic effect. These effects were associated with reduced insulin biosynthesis, likely due to downregulation of PDX1, MAFA, and the proinsulin converting enzymes, as well as reduced ATP response upon glucose stimulation. Genome-wide DNA methylation analysis found changes on PDE4D, MBNL1 and TMEM178B, all implicated in β-cell function, after all three treatments. DEX alone caused very strong demethylation of the glucocorticoid-regulated gene ZBTB16, also known to influence the β-cell, while the combined treatment caused altered methylation of many known β-cell regulators and diabetes candidate genes.SIGNIFICANCE: DEX treatment and glucolipotoxic conditions separately alter the β-cell epigenome and function. The combination of both treatments exacerbates these changes, showing that caution is needed when prescribing potent glucocorticoids in patients with dysregulated metabolism.
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| 59. |
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| 60. |
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