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| 52. |
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| 53. |
- Ludvigsen, Eva, et al.
(författare)
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Regulation of insulin and glucagon secretion from rat pancreatic islets in vitro by somatostatin analogues
- 2007
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Ingår i: Regulatory Peptides. - : Elsevier BV. - 0167-0115 .- 1873-1686. ; 138:1, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- Somatostatin is an inhibitor of hormone secretion through specific receptors (sst1-5). The aim of this study was to investigate the putative regulatory role of somatostatin analogues on the secretion of insulin and glucagon by rat pancreatic islets. After 48 h exposure only the non-selective agonists (somatostatin, octreotide and SOM-230) inhibited insulin accumulation. The inhibition of insulin secretion was accompanied by increased islet insulin contents. None of the analogues showed a consistent effect on the glucagon accumulation in the medium after 48 h. Since we observed a difference in the regulatory effect between the non-selective and selective analogues, combinations of selective analogues were studied. Combination of sst2 + sst5 agonists inhibited the medium insulin accumulation, while combination of sst1 + sst2 analogues caused a decrease in glucagon accumulation. After removal of somatostatin a rebound effect with increased insulin secretion were observed. This effect was reversed after 6 h. For SOM-230 insulin secretion continued to be suppressed even after the analogue was removed and returned to control values after 3 h. As for glucagon secretion there was an initial decline after culture with octreotide, while the other substances failed to induce any changes. In summary, non-selective somatostatin analogues or combinations of receptor selective analogues may cause inhibition of hormone secretion from rat pancreatic islets. For insulin and glucagon, combinations of sst2 + sst5 and sst1 + sst2, respectively may exert this effects. Thus, our data suggest that more than one sst must be involved to down-regulate islet glucagon and insulin secretion.
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| 54. |
- Ludvigsen, Eva, et al.
(författare)
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Somatostatin receptor 1-5; expression profiles during rat development
- 2015
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Ingår i: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 120:3, s. 157-168
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Tidskriftsartikel (refereegranskat)abstract
- Background. Somatostatin acts through five receptor subtypes (SSTRs 1-5). We aimed to investigate SSTRs mRNA expression and protein distribution in whole rat embryos, with special emphasis on the pancreas. Material and methods. Rat embryos were collected on embryonal days 10, 11, 12, 14, 15, 17, 19, 21, and at birth. Presence of SSTRs was investigated with RT-PCR techniques and immunohistochemistry. Results. There was no SSTR5 mRNA expression in the whole rat embryos. All SSTR1-5 proteins were observed at embryonal day 10, but the localization varied between the different subtypes. From day 11 to birth SSTRs protein presence increased with time in major structures such as skin and cartilage. It remained similar over time in the heart and liver. In the fetal pancreas mRNA expression of SSTR2 and 4 was detected at day 14, and there was an increase up to birth. Only SSTR1 protein co-localized to a higher extent with the islet hormones studied. SSTR2 was present in all islet endocrine cells except for beta-cells. In contrast, the immunostaining for SSTR3-4 was co-localized with insulin and PP, and, finally, SSTR5 with glucagon and pancreatic polypeptide. In mRNA isolated from whole rat embryos SSTR1-2 and SSTR4 expression showed a peak at day 14, while SSTR3 mRNA was not present until day 15. Conclusion. The present data suggest a role for SSTRs during the development of the rat embryo. Subsequent functional studies may elucidate regulatory roles of specific SSTRs for the growth and differentiation of the pancreas as well as other organs.
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| 55. |
- Ludvigsen, Eva, 1974-
(författare)
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Somatostatin Receptor Expression and Biological Functions in Endocrine Pancreatic Cells
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Type 1 diabetes is resulting from the selective destruction of insulin-producing beta-cells within the pancreatic islets. Somatostatin acts as an inhibitor of hormone secretion through specific receptors (sst1-5).All ssts were expressed in normal rat and mouse pancreatic islets, although the expression intensity and the co-expression pattern varied between ssts as well as between species. This may reflect a difference in response to somatostatin in islet cells of the two species.The Non-Obese Diabetic (NOD) mouse model is an experimental model of type 1 diabetes, with insulitis accompanied by spontaneous hyperglycaemia. Pancreatic specimens from NOD mice at different age and stage of disease were stained for ssts. The islet cells of diabetic NOD mice showed increased islet expression of sst2-5 compared to normoglycemic NOD mice. The increase in sst2-5 expression in the islets cells may suggest either a contributing factor in the process leading to diabetes, or a defense response against ongoing beta-cell destruction.Somatostatin analogues were tested on a human endocrine pancreatic tumour cell line and cultured pancreatic islets. Somatostatin analogues had an effect on cAMP accumulation, chromogranin A secretion and MAP kinase activity in the cell line. Treatment of rat pancreatic islets with somatostatin analogues with selective receptor affinity was not sufficient to induce an inhibition of insulin and glucagon secretion. However, a combination of selective analogues or non-selective analogues via co-stimulation of receptors can cause inhibition of hormone production. For insulin and glucagon, combinations of sst2 + sst5 and sst1 + sst2, respectively, showed a biological effect.In summary, knowledge of islet cell ssts expression and the effect of somatostatin analogues with high affinity to ssts may be valuable in the future attempts to influence beta-cell function in type 1 diabetes mellitus, since down-regulation of beta-cell function may promote survival of these cells during the autoimmune attack.
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| 56. |
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| 58. |
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| 59. |
- Luo, Zhengkang, 1994-
(författare)
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Immunological strategies for counteracting type 1 diabetes focusing on IL-35 producing regulatory immune cells
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Type 1 diabetes (T1D) is an autoimmune disease where pancreatic β-cells are attacked by immune cells. Regulatory T (Treg) cells play critical roles in suppressing immune responses and their involvement have been intensively studied in T1D. Low dose IL-2 has been proposed to selectively boost Treg cells in T1D, with only limited success. We thus further decreased the IL-2 dosage and treated multiple low dose streptozotocin (MLDSTZ) mice with an ultra-low dose IL-2, but it did not protect STZ mice from hyperglycemia. Similarly, low dose IL-2 only partially prevented diabetes. Treg cells’ phenotype was not protected by either dose. These data suggest that alternative IL-2 therapies might be considered. Regulatory B (Breg) cells suppress pro-inflammatory immune responses by producing anti-inflammatory cytokines IL-10 and IL-35. Decreased IL-35+ and increased IFN-γ+ Breg cell proportions were found in T1D patients, and in diabetic mice. IL-35 treatment prevented increased IFN-γ+ Breg cell proportions in STZ mice. These data illustrate Breg cells’ involvement in T1D, and IL-35 treatment prevents hyperglycemia by maintaining Breg cells’ phenotype.Treg cells’ involvement in diabetic nephropathy (DN) has not been studied. Lower plasma IL-35 was found in DN patients than in T1D patients without DN and healthy controls, and was strongly correlated with kidney function. Decreased IL-35+ and increased IL-17+ Treg cells were found in DN patients. Moreover, Foxp3+ cell infiltration was found in the kidneys of diabetic mice, but it failed to counteract mononuclear cell infiltration. IL-35 treatment prevented DN and Treg cells’ phenotypic shift in STZ mice by maintaining the transcription factor Eos. These results demonstrate that IL-35 may be used to prevent DN. Given the instability of IL-35, we explored the effect of IL-6 signaling blockade. Anti-IL-6R completely protected STZ mice from diabetes. Proteomics indicated enhanced metabolism and down-regulated pro-inflammatory pathways. It maintained Treg cells’ phenotype by increasing IL-35 and decreasing IFN-γ production. It also reduced the number of macrophages and conventional dendritic cells type 2 and their CD80 expression. STZ mice remained normoglycemic despite the discontinuation of anti-IL-6R treatment. Therefore, our results illustrate the outcomes of several potential T1D immunotherapies and highlight the involvement of IL-35 producing immune cells in controlling the disease.
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| 60. |
- Luo, Zhengkang, et al.
(författare)
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Interleukin-35 Prevents Development of Autoimmune Diabetes Possibly by Maintaining the Phenotype of Regulatory B Cells
- 2021
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 22:23
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Tidskriftsartikel (refereegranskat)abstract
- The anti-inflammatory role of regulatory B cells (Breg cells) has been associated with IL-35 based on studies of experimental autoimmune uveitis and encephalitis. The role of Breg cells and IL-35(+) Breg cells for type 1 diabetes (T1D) remains to be investigated. We studied PBMCs from T1D subjects and healthy controls (HC) and found lowered proportions of Breg cells and IL-35(+) Breg cells in T1D. To elucidate the role of Breg cells, the lymphoid organs of two mouse models of T1D were examined. Lower proportions of Breg cells and IL-35(+) Breg cells were found in the animal models of T1D compared with control mice. In addition, the systemic administration of recombinant mouse IL-35 prevented hyperglycemia after multiple low dose streptozotocin (MLDSTZ) injections and increased the proportions of Breg cells and IL-35(+) Breg cells. A higher proportion of IFN-gamma(+) cells among Breg cells were found in the PBMCs of the T1D subjects. In the MLDSTZ mice, IL-35 administration decreased the proportions of IFN-gamma(+) cells among the Breg cells. Our data illustrate that Breg cells may play an important role in the development of T1D and that IL-35 treatment prevents the development of hyperglycemia by maintaining the phenotype of the Breg cells under an experimental T1D condition.
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