| 1. |
- Andersson, Sofia A, et al.
(författare)
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Reduced insulin secretion correlates with decreased expression of exocytotic genes in pancreatic islets from patients with type 2 diabetes.
- 2012
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Ingår i: Molecular and Cellular Endocrinology. - : Elsevier BV. - 1872-8057 .- 0303-7207. ; 364:1-2, s. 36-45
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Tidskriftsartikel (refereegranskat)abstract
- Reduced insulin release has been linked to defect exocytosis in β-cells. However, whether expression of genes suggested to be involved in the exocytotic process (exocytotic genes) is altered in pancreatic islets from patients with type 2 diabetes (T2D), and correlate to insulin secretion, needs to be further investigated. Analysing expression levels of 23 exocytotic genes using microarray revealed reduced expression of five genes in human T2D islets (χ(2)=13.25; p<0.001). Gene expression of STX1A, SYT4, SYT7, SYT11, SYT13, SNAP25 and STXBP1 correlated negatively to in vivo measurements of HbA1c levels and positively to glucose stimulated insulin secretion (GSIS) in vitro in human islets. STX1A, SYT4 and SYT11 protein levels correspondingly decreased in human T2D islets. Moreover, silencing of SYT4 and SYT13 reduced GSIS in INS1-832/13 cells. Our data support that reduced expression of exocytotic genes contributes to impaired insulin secretion, and suggest decreased expression of these genes as part of T2D pathogenesis.
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| 2. |
- Heimann, Emilia, et al.
(författare)
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Branched short-chain fatty acids modulate glucose and lipid metabolism in primary adipocytes
- 2016
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Ingår i: Adipocyte. - : Informa UK Limited. - 2162-3945 .- 2162-397X. ; 5:4, s. 359-368
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Tidskriftsartikel (refereegranskat)abstract
- Short-chain fatty acids (SCFAs), e.g. acetic acid, propionic acid and butyric acid, generated through colonic fermentation of dietary fibers, have been shown to reach the systemic circulation at micromolar concentrations. Moreover, SCFAs have been conferred anti-obesity properties in both animal models and human subjects. Branched SCFAs (BSCFAs), e.g., isobutyric and isovaleric acid, are generated by fermentation of branched amino acids, generated from undigested protein reaching colon. However, BSCFAs have been sparsely investigated when referring to effects on energy metabolism. Here we primarily investigate the effects of isobutyric acid and isovaleric acid on glucose and lipid metabolism in primary rat and human adipocytes. BSCFAs inhibited both cAMP-mediated lipolysis and insulin-stimulated de novo lipogenesis at 10 mM, whereas isobutyric acid potentiated insulin-stimulated glucose uptake by all concentrations (1, 3 and 10 mM) in rat adipocytes. For human adipocytes, only SCFAs inhibited lipolysis at 10 mM. In both in vitro models, BSCFAs and SCFAs reduced phosphorylation of hormone sensitive lipase, a rate limiting enzyme in lipolysis. In addition, BSCFAs and SCFAs, in contrast to insulin, inhibited lipolysis in the presence of wortmannin, a phosphatidylinositide 3-kinase inhibitor and OPC3911, a phosphodiesterase 3 inhibitor in rat adipocytes. Furthermore, BSCFAs and SCFAs reduced insulin-mediated phosphorylation of protein kinase B. To conclude, BSCFAs have effects on adipocyte lipid and glucose metabolism that can contribute to improved insulin sensitivity in individuals with disturbed metabolism.
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| 3. |
- Heimann, Emilia, et al.
(författare)
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Expression and regulation of cyclic nucleotide phosphodiesterases in human and rat pancreatic islets.
- 2010
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 5:12
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Tidskriftsartikel (refereegranskat)abstract
- As shown by transgenic mouse models and by using phosphodiesterase 3 (PDE3) inhibitors, PDE3B has an important role in the regulation of insulin secretion in pancreatic β-cells. However, very little is known about the regulation of the enzyme. Here, we show that PDE3B is activated in response to high glucose, insulin and cAMP elevation in rat pancreatic islets and INS-1 (832/13) cells. Activation by glucose was not affected by the presence of diazoxide. PDE3B activation was coupled to an increase as well as a decrease in total phosphorylation of the enzyme. In addition to PDE3B, several other PDEs were detected in human pancreatic islets: PDE1, PDE3, PDE4C, PDE7A, PDE8A and PDE10A. We conclude that PDE3B is activated in response to agents relevant for β-cell function and that activation is linked to increased as well as decreased phosphorylation of the enzyme. Moreover, we conclude that several PDEs are present in human pancreatic islets.
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| 4. |
- Heimann, Emilia, et al.
(författare)
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Propionic acid and butyric acid inhibit lipolysis and de novo lipogenesis and increase insulin-stimulated glucose uptake in primary rat adipocytes.
- 2015
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Ingår i: Adipocyte. - : Informa UK Limited. - 2162-3945 .- 2162-397X. ; 4:2, s. 81-88
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Tidskriftsartikel (refereegranskat)abstract
- Fermentation of dietary fibers by colonic microbiota generates short-chain fatty acids (SCFAs), e.g., propionic acid and butyric acid, which have been described to have "anti-obesity properties" by ameliorating fasting glycaemia, body weight and insulin tolerance in animal models. In the present study, we therefore investigate if propionic acid and butyric acid have effects on lipolysis, de novo lipogenesis and glucose uptake in primary rat adipocytes. We show that both propionic acid and butyric acid inhibit isoproterenol- and adenosine deaminase-stimulated lipolysis as well as isoproterenol-stimulated lipolysis in the presence of a phosphodiesterase (PDE3) inhibitor. In addition, we show that propionic acid and butyric acid inhibit basal and insulin-stimulated de novo lipogenesis, which is associated with increased phosphorylation and thus inhibition of acetyl CoA carboxylase, a rate-limiting enzyme in fatty acid synthesis. Furthermore, we show that propionic acid and butyric acid increase insulin-stimulated glucose uptake. To conclude, our study shows that SCFAs have effects on fat storage and mobilization as well as glucose uptake in rat primary adipocytes. Thus, the SCFAs might contribute to healthier adipocytes and subsequently also to improved energy metabolism with for example less circulating free fatty acids, which is beneficial in the context of obesity and type 2 diabetes.
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| 5. |
- Heimann, Emilia
(författare)
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Studies in beta cells and adipocytes in the context of obesity and T2D - focusing on PDE3B, OPN and SCFAs
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Type 2 diabetes (T2D) is a heterogeneous disease characterized by altered lipid parameters and elevated glucose levels, as a direct consequence of impaired insulin signaling in target tissues and reduced insulin exocytosis from pancreatic β-cells. Obesity, which dramatically increases worldwide, is associated with insulin resistance and T2D. In this thesis, we elucidate the effects of hormones and nutrients on biological responses and regulatory mechanisms in pancreatic β-cells and adipocytes. The information is scarce with regard to the regulation of cyclic nucleotide phosphodiesterase 3B (PDE3B) in pancreatic β-cells. We show that PDE3B is activated in response to glucose, insulin and forskolin, which is coupled to a decrease, no apparent change or an increase in total phosphorylation of the enzyme in rat pancreatic β-cells. Furthermore, PDE1A, PDE3, PDE4C, PDE5A, PDE7A, PDE7B, PDE8A, PDE10A and PDE11A are detected in human pancreatic islets. Islets from RIP-PDE3B mice, exhibiting β-cell specific overexpression of the cAMP-degrading enzyme phosphodiesterase 3B (PDE3B) and dysregulated insulin secretion, show induced OPN protein expression. In addition, in silico and functional approaches demonstrate that PDE3B and OPN are connected and follow a similar protein expression pattern in response to e.g. cAMP-elevating agents and insulin. Little is known regarding the direct effects of short-chain fatty acids (SCFAs), produced through bacterial fermentation of dietary fibers, on glucose and lipid metabolism in adipocytes. We show that the SCFAs propionic acid and butyric acid inhibit cAMP-stimulated lipolysis, a mechanism that is not dependent on the cAMP-degrading enzyme PDE3B. Moreover, both SCFAs inhibit basal and insulin-stimulated de novo lipogenesis, which is associated with increased phosphorylation of acetyl CoA carboxylase, the rate-limiting enzyme in fatty acid synthesis. Propionic acid and butyric acid are also able to potentiate insulin-stimulated glucose uptake. In summary, we demonstrate that agents relevant for β-cell function regulate PDE3B activity and phosphorylation levels. Based on several strategies, we demonstrate a connection between PDE3B and OPN, the latter having a protective role in pancreatic β-cells. Further investigations are required to identify downstream targets of PDE3B that are involved in the regulation of insulin exocytosis and also to elucidate the relationship with OPN. Moreover, several PDEs are present in human pancreatic islets. The majority of these PDEs have been described as insulin secretagogues in animal models and it is thus promising to also confirm their presence in humans, as it can be advantageous for the 8 treatment of T2D. SCFAs inhibit fatty acid mobilization and potentiates insulininduced glucose uptake; observed effects that might be beneficial for preventing ectopic lipid accumulation, lipotoxicity and insulin resistance. Thus, it remains to be verified if anti-obesity properties can be conferred to SCFAs.
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| 6. |
- Karlsson-Parra, Alex, et al.
(författare)
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Ilixadencel - an Allogeneic Cell-Based Anticancer Immune Primer for Intratumoral Administration
- 2018
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Ingår i: Pharmaceutical research. - : Springer Science and Business Media LLC. - 0724-8741 .- 1573-904X. ; 35:8
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Forskningsöversikt (refereegranskat)abstract
- Intratumoral administration of an immune primer is a therapeutic vaccine strategy aimed to trigger dendritic cell (DC)-mediated cross-presentation of cell-associated tumor antigens to cytotoxic CD8(+) T cells without the need for tumor antigen characterization. The prevailing view is that these cross-presenting DCs have to be directly activated by pathogen-associated molecular patterns (PAMPS), including Toll-like receptor ligands or live microbial agents like oncolytic viruses. Emerging data are however challenging this view, indicating that the cross-presenting machinery in DCs is suboptimally activated by direct PAMP recognition, and that endogenous inflammatory factors are the main drivers of DC-mediated cross-presentation within the tumor. Here we present preclinical mode of action data, CMC and regulatory data, as well as initial clinical data on ilixadencel. This cell-based drug product is an off-the-shelf immune primer, consisting of pro-inflammatory allogeneic DCs secreting high amounts of pro-inflammatory chemokines and cytokines at the time of intratumoral administration. The mechanism of action of ilixadencel is to induce recruitment and activation of endogenous immune cells, including NK cells that subsequently promotes cross-presentation of cell-associated tumor antigens by co-recruited DCs.
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