| 1. |
- Abadpour, S., et al.
(författare)
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Inhibition of the prostaglandin D-2-GPR44/DP2 axis improves human islet survival and function
- 2020
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 63, s. 1355-1367
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis Inflammatory signals and increased prostaglandin synthesis play a role during the development of diabetes. The prostaglandin D-2 (PGD(2)) receptor, GPR44/DP2, is highly expressed in human islets and activation of the pathway results in impaired insulin secretion. The role of GPR44 activation on islet function and survival rate during chronic hyperglycaemic conditions is not known. In this study, we investigate GPR44 inhibition by using a selective GPR44 antagonist (AZ8154) in human islets both in vitro and in vivo in diabetic mice transplanted with human islets. Methods Human islets were exposed to PGD(2) or proinflammatory cytokines in vitro to investigate the effect of GPR44 inhibition on islet survival rate. In addition, the molecular mechanisms of GPR44 inhibition were investigated in human islets exposed to high concentrations of glucose (HG) and to IL-1 beta. For the in vivo part of the study, human islets were transplanted under the kidney capsule of immunodeficient diabetic mice and treated with 6, 60 or 100 mg/kg per day of a GPR44 antagonist starting from the transplantation day until day 4 (short-term study) or day 17 (long-term study) post transplantation. IVGTT was performed on mice at day 10 and day 15 post transplantation. After termination of the study, metabolic variables, circulating human proinflammatory cytokines, and hepatocyte growth factor (HGF) were analysed in the grafted human islets. Results PGD(2) or proinflammatory cytokines induced apoptosis in human islets whereas GPR44 inhibition reversed this effect. GPR44 inhibition antagonised the reduction in glucose-stimulated insulin secretion induced by HG and IL-1 beta in human islets. This was accompanied by activation of the Akt-glycogen synthase kinase 3 beta signalling pathway together with phosphorylation and inactivation of forkhead box O-1and upregulation of pancreatic and duodenal homeobox-1 and HGF. Administration of the GPR44 antagonist for up to 17 days to diabetic mice transplanted with a marginal number of human islets resulted in reduced fasting blood glucose and lower glucose excursions during IVGTT. Improved glucose regulation was supported by increased human C-peptide levels compared with the vehicle group at day 4 and throughout the treatment period. GPR44 inhibition reduced plasma levels of TNF-alpha and growth-regulated oncogene-alpha/chemokine (C-X-C motif) ligand 1 and increased the levels of HGF in human islets. Conclusions/interpretation Inhibition of GPR44 in human islets has the potential to improve islet function and survival rate under inflammatory and hyperglycaemic stress. This may have implications for better survival rate of islets following transplantation.
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| 2. |
- Berg, Anna-Karin, et al.
(författare)
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Induction of the chemokine interferon-gamma-inducible protein-10 in human pancreatic islets during enterovirus infection
- 2006
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 49:11, s. 2697-2703
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: Enterovirus infections have long been suspected to be environmental factors that may cause type 1 diabetes, but the pathways leading from infection to beta cell destruction are still unknown. We therefore examined whether enterovirus infection of human islets leads to upregulation of interferon-gamma-inducible protein (IP-10, now known as chemokine [C-X-C motif] ligand 10 [CXCL10]), a chemokine important for the induction of insulitis. Methods: Isolated human islets were infected with three different strains of Coxsackie B4 virus. IP-10 expression and secretion from the infected human islets were then measured using RT-PCR and ELISA at several time points. Results: IP-10 was clearly upregulated in and secreted from human islets during enterovirus infection. This was demonstrated with three different strains of Coxsackie B4 virus, two of which are lytic to islets and one which is non-lytic and can establish a persistent infection in human islets. Conclusions/interpretation: We propose that enterovirus-induced upregulation of IP-10 during infection of the islets in vivo is the first step towards destructive insulitis. Our findings support the idea that enterovirus infection triggers immune-mediated beta cell destruction, and for the first time suggest a possible mechanism behind enterovirus-induced diabetes.
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| 3. |
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| 4. |
- Carlbom, Lina, et al.
(författare)
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Pancreatic perfusion and subsequent response to glucose in healthy individuals and patients with type 1 diabetes
- 2016
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 59:9, s. 1968-1972
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: The aim of this study was to investigate pancreatic perfusion and its response to a glucose load in patients with type 1 diabetes mellitus compared with non-diabetic ('healthy') individuals.METHODS: Eight individuals with longstanding type 1 diabetes and ten sex-, age- and BMI-matched healthy controls underwent dynamic positron emission tomography scanning with (15)O-labelled water before and after intravenous administration of glucose. Perfusion in the pancreas was measured. Portal and arterial hepatic perfusion were recorded as references.RESULTS: Under fasting conditions, total pancreatic perfusion was on average 23% lower in the individuals with diabetes compared with healthy individuals. Glucose increased total pancreatic and portal hepatic blood perfusion in healthy individuals by 48% and 38%, respectively. In individuals with diabetes there was no significant increase in either total pancreatic or portal hepatic perfusion.CONCLUSIONS/INTERPRETATION: Individuals with type 1 diabetes have reduced basal pancreatic perfusion and a severely impaired pancreatic and splanchnic perfusion response to intravenous glucose stimulation.
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| 5. |
- Gotthardt, Martin, et al.
(författare)
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Detection and quantification of beta cells by PET imaging : why clinical implementation has never been closer
- 2018
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Ingår i: Diabetologia. - : SPRINGER. - 0012-186X .- 1432-0428. ; 61:12, s. 2516-2519
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Tidskriftsartikel (refereegranskat)abstract
- In this issue of Diabetologia, Alavi and Werner (10.1007/s00125-018-4676-1) criticise the attempts to use positron emission tomography (PET) for in vivo imaging of pancreatic beta cells, which they consider as futile'. In support of this strong statement, they point out the limitations of PET imaging, which they believe render beta cell mass impossible to estimate using this method. In our view, the Alavi and Werner presentation of the technical limitations of PET imaging does not reflect the current state of the art, which leads them to questionable conclusions towards the feasibility of beta cell imaging using this approach. Here, we put forward arguments in favour of continuing the development of innovative technologies enabling in vivo imaging of pancreatic beta cells and concisely present the current state of the art regarding putative technical limitations of PET imaging. Indeed, far from being a futile' effort, we demonstrate that beta cell imaging is now closer than ever to becoming a long-awaited clinical reality.
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| 6. |
- Granlund, Louise, et al.
(författare)
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Loss of insulin-expressing extra-islet cells in type 1 diabetes is accompanied with increased number of glucagon-expressing extra-islet cells
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Ingår i: Diabetologia. - 0012-186X .- 1432-0428.
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Aims: The presence of a limited number of insulin-positive cells remaining in type 1 diabetes (T1D) is well-known. These cells are part of islets or appear as extra-islet insulin-positive cells scattered in the exocrine parenchyma. Pancreatic endocrine cells not located within islets are poorly described and the presence of scattered endocrine cells expressing other islet hormones than insulin has not been explored and quantified. The aim of this study was to compare the extra-islet insulin- or glucagon-positive cells with regard to their density, transcription-factor expression, and mitotic activity in subjects with or without T1D.Methods: Multispectral imaging was used to examine extra-islet cells by staining for insulin, glucagon, ARX, PDX1 and Ki67. This was done in well-preserved pancreatic tissue obtained from heart-beating organ donors with or without T1D.Results: Decreased density of insulin-positive (median 0.44 cells/mm2 and 20 cells/mm2 in donors with and without type T1D respectively, p=<0.0001) and increased density of glucagon-positive (median 51 cells/mm2 and 14 cells/mm2 in donors with and without T1D respectively, p=0.008) extra-islet cells were observed in donors with T1D. The combined density of extra-islet cells expressing either insulin or glucagon was similar in donors with or without T1D. Proliferating endocrine cells were present both in donors with, and in donors without T1D, as demonstrated by Ki67-positive staining (0-3% of the cells expressing insulin or glucagon). Regardless of disease status, many of the extra-islet insulin-positive cells lacked PDX1-expression and many of the glucagon-positive cells lacked ARX-expression.Conclusions: We report a decrease in extra-islet insulin-positive cells and an increase in extra-islet glucagon-positive cells in T1D. The increase of glucagon-positive cells could be a compensatory effect in response to impaired alpha-cell function, or a sign of beta- to alpha-cell conversion. The latter notion is an intriguing mechanism, possibly contributing to the loss of beta cells in T1D.
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| 9. |
- Korsgren, Olle, et al.
(författare)
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Optimising islet engraftment is critical for successful clinical islet transplantation
- 2008
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 51:2, s. 227-32
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Tidskriftsartikel (refereegranskat)abstract
- Clinical islet transplantation is currently being explored as a treatment for persons with type 1 diabetes and hypoglycaemia unawareness. Although 'proof-of-principle' has been established in recent clinical studies, the procedure suffers from low efficacy. At the time of transplantation, the isolated islets are allowed to embolise the liver after injection in the portal vein, a procedure that is unique in the area of transplantation. A novel view on the engraftment of intraportally transplanted islets is presented that could explain the low efficacy of the procedure.
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