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1
المؤلفون: Krogvold, Lars, Mynarek, Ida Maria, Ponzi, Erica, Mork, Freja Barrett, Hessel, Trine Witzner, Roald, Trine, Lindblom, Nina, Westman, Jacob, Barker, Peter, Hyoety, Heikki, Ludvigsson, Johnny, Hanssen, Kristian F., Johannesen, Jesper, Dahl-Jorgensen, Knut
المصدر: Nature Medicine. 29:2902-2908
الوصف: Previous studies showed a low-grade enterovirus infection in the pancreatic islets of patients with newly diagnosed type 1 diabetes (T1D). In the Diabetes Virus Detection (DiViD) Intervention, a phase 2, placebo-controlled, randomized, parallel group, double-blind trial, 96 children and adolescents (aged 6-15 years) with new-onset T1D received antiviral treatment with pleconaril and ribavirin (n = 47) or placebo (n = 49) for 6 months, with the aim of preserving beta cell function. The primary endpoint was the mean stimulated C-peptide area under the curve (AUC) 12 months after the initiation of treatment (less than 3 weeks after diagnosis) using a mixed linear model. The model used longitudinal log-transformed serum C-peptide AUCs at baseline, at 3 months, 6 months and 1 year. The primary endpoint was met with the serum C-peptide AUC being higher in the pleconaril and ribavirin treatment group compared to the placebo group at 12 months (average marginal effect = 0.057 in the linear mixed model; 95% confidence interval = 0.004-0.11, P = 0.037). The treatment was well tolerated. The results show that antiviral treatment may preserve residual insulin production in children and adolescent with new-onset T1D. This provides a rationale for further evaluating antiviral strategies in the prevention and treatment of T1D. European Union Drug Regulating Authorities Clinical Trials identifier: 2015-003350-41. Results from the DiViD Intervention, a phase 2 randomized, placebo-controlled trial, showed that antiviral treatment with pleconaril and ribavirin for 6 months resulted in higher endogenous insulin production in children and adolescents with new-onset type 1 diabetes.
وصف الملف: electronic
الوصول الحر: https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-198659Test
https://doi.org/10.1038/s41591-023-02576-1Test
https://liu.diva-portal.org/smash/get/diva2:1806609/FULLTEXT01.pdfTest -
2دورية أكاديمية
المؤلفون: Buschard, Karsten, Josefsen, Knud, Krogvold, Lars, Gerling, Ivan, Dahl‐Jørgensen, Knut, Pociot, Flemming
المصدر: Diabetes/Metabolism Research and Reviews ; volume 40, issue 3 ; ISSN 1520-7552 1520-7560
الوصف: Aims Sulfatide is a chaperone for insulin manufacturing in beta cells. Here we explore whether the blood glucose values normally could be associated with this sphingolipid and especially two of its building enzymes CERS2 and CERS6. Both T1D and T2D have low blood sulfatide levels, and insulin resistance on beta cells at clinical diagnosis. Furthermore, we examined islet pericytes for sulfatide, and beta‐cell receptors for GLP‐1, both of which are related to the insulin production. Materials and Methods We examined mRNA levels in islets from the DiViD and nPOD studies, performed genetic association analyses, and histologically investigated pericytes in the islets for sulfatide. Results Polymorphisms of the gene encoding the CERS6 enzyme responsible for synthesising dihydroceramide, a precursor to sulfatide, are associated with random blood glucose values in non‐diabetic persons. This fits well with our finding of sulfatide in pericytes in the islets, which regulates the capillary blood flow in the islets of Langerhans, which is important for oxygen supply to insulin production. In the islets of newly diagnosed T1D patients, we observed low levels of GLP‐1 receptors; this may explain the insulin resistance in their beta cells and their low insulin production. In T2D patients, we identified associated polymorphisms in both CERS2 and CERS6 . Conclusions Here, we describe several polymorphisms in sulfatide enzymes related to blood glucose levels and HbA1c in non‐diabetic individuals. Islet pericytes from such persons contain sulfatide. Furthermore, low insulin secretion in newly diagnosed T1D may be explained by beta‐cell insulin resistance due to low levels of GLP‐1 receptors.
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3
المؤلفون: Oikarinen, Sami, Krogvold, Lars, Edwin, Bjorn, Buanes, Trond, Korsgren, Olle, Laiho, Jutta E., Oikarinen, Maarit, Ludvigsson, Johnny, Skog, Oskar, Docent, PhD, 1981, Anagandula, Mahesh, 1982, Frisk, Gun, Hyoty, Heikki, Dahl-Jorgensen, Knut
المصدر: Diabetologia. 64(11):2491-2501
مصطلحات موضوعية: Enterovirus, Laparoscopy, Organs, Pancreas, Persistent infection, RT-qPCR, Sequence, Type 1 diabetes, Viral RNA
الوصف: Aims/hypothesis The Diabetes Virus Detection (DiViD) study is the first study to laparoscopically collect pancreatic tissue and purified pancreatic islets together with duodenal mucosa, serum, peripheral blood mononuclear cells (PBMCs) and stools from six live adult patients (age 24-35 years) with newly diagnosed type 1 diabetes. The presence of enterovirus (EV) in the pancreatic islets of these patients has previously been reported. Methods In the present study we used reverse transcription quantitative real-time PCR (RT-qPCR) and sequencing to characterise EV genomes present in different tissues to understand the nature of infection in these individuals. Results All six patients were found to be EV-positive by RT-qPCR in at least one of the tested sample types. Four patients were EV-positive in purified islet culture medium, three in PBMCs, one in duodenal biopsy and two in stool, while serum was EVnegative in all individuals. Sequencing the 5' untranslated region of these EVs suggested that all but one belonged to enterovirus B species. One patient was EV-positive in all these sample types except for serum. Sequence analysis revealed that the virus strain present in the isolated islets of this patient was different from the strain found in other sample types. None of the islet-resident viruses could be isolated using EV-permissive cell lines. Conclusions/interpretation EV RNA can be frequently detected in various tissues of patients with type 1 diabetes. At least in some patients, the EV strain in the pancreatic islets may represent a slowly replicating persisting virus.
وصف الملف: electronic
الوصول الحر: https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-470067Test
https://doi.org/10.1007/s00125-021-05525-0Test
https://uu.diva-portal.org/smash/get/diva2:1649910/FULLTEXT01.pdfTest -
4دورية أكاديمية
المؤلفون: Svalastoga, Pernille, Kaci, Alba, Molnes, Janne, Solheim, Marie Holm, Johansson, Bente Berg, Krogvold, Lars, Skrivarhaug, Torild, Valen, Eivind, Johansson, Stefan, Molven, Anders, Sagen, Jørn Vegard, Søfteland, Eirik, Bjørkhaug, Lise, Tjora, Erling, Aukrust, Ingvild, Njølstad, Pål Rasmus
المصدر: Diabetologia ; 2226–2237 ; 66
الوصف: Aims/hypothesis Correctly diagnosing MODY is important, as individuals with this diagnosis can discontinue insulin injections; however, many people are misdiagnosed. We aimed to develop a robust approach for determining the pathogenicity of variants of uncertain significance in hepatocyte nuclear factor-1 alpha (HNF1A)-MODY and to obtain an accurate estimate of the prevalence of HNF1A-MODY in paediatric cases of diabetes. Methods We extended our previous screening of the Norwegian Childhood Diabetes Registry by 830 additional samples and comprehensively genotyped HNF1A variants in autoantibody-negative participants using next-generation sequencing. Carriers of pathogenic variants were treated by local healthcare providers, and participants with novel likely pathogenic variants and variants of uncertain significance were enrolled in an investigator-initiated, non-randomised, open-label pilot study (ClinicalTrials.gov registration no. NCT04239586). To identify variants associated with HNF1A-MODY, we functionally characterised their pathogenicity and assessed the carriers’ phenotype and treatment response to sulfonylurea. Results In total, 615 autoantibody-negative participants among 4712 cases of paediatric diabetes underwent genetic sequencing, revealing 19 with HNF1A variants. We identified nine carriers with novel variants classified as variants of uncertain significance or likely to be pathogenic, while the remaining ten participants carried five pathogenic variants previously reported. Of the nine carriers with novel variants, six responded favourably to sulfonylurea. Functional investigations revealed their variants to be dysfunctional and demonstrated a correlation with the resulting phenotype, providing evidence for reclassifying these variants as pathogenic. Conclusions/interpretation Based on this robust classification, we estimate that the prevalence of HNF1A-MODY is 0.3% in paediatric diabetes. Clinical phenotyping is challenging and functional investigations provide a strong complementary line of ...
وصف الملف: application/pdf
العلاقة: urn:issn:0012-186X; https://hdl.handle.net/11250/3112394Test; https://doi.org/10.1007/s00125-023-06012-4Test; cristin:2189662; Diabetologia. 2023, 66, 2226–2237.
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5دورية أكاديمية
المؤلفون: Josefsen, Knud, Krogvold, Lars, Gerling, Ivan C., Pociot, Flemming, Dahl-Jørgensen, Knut, Buschard, Karsten
المصدر: 1664-2392.
الوصف: Background At diagnosis of Type 1 Diabetes (T1D), 30% of the beta cells are dormant, i.e. alive, but inactive. This could reduce beta cell destruction, as cellular stress contributes to beta cell damage. However, the beta cells, that are still active, must produce more insulin and are therefore more vulnerable. The inactive beta cells represent a potential for restoring the insulin secretion. Methods We analyzed the expression of selected genes in islets from live, newly diagnosed T1D patients from the DiViD study and organ doners with longer duration of T1D, type 2 diabetes (T2D), or no diabetes from the nPOD study. Additionally, analysis of polymorphisms was performed on all the investigated genes. Findings Various possibilities were considered for the inactivity of the beta cells: secretion defect, fetal state, hibernation, and insulin resistance. We analyzed genes related to the ceramide and sphingomyelin synthesis and degradation, secretion, circadian rhythm and insulin action, and found changes in T1D islets that resemble fetal dedifferentiation and asynchrony. Furthermore, we found low levels of insulin receptor mRNA in the islets. No polymorphisms were found. Interpretation Our findings suggest a secretion defect, but also fetal dedifferentiation and desynchronization in the inactive beta cells. Together with previous evidence, that predisposing factors for T2D are also present for T1D development, we raise the idea to treat individuals with ongoing T1D development prophylactically with T2D medicine like GLP-1 receptor agonists, metformin, or others, combined with anti-inflammatory compounds, in order to reactivate the dormant beta cells, and to prevent autoimmune destruction. T2D mechanisms during T1D development should be investigated further.
العلاقة: Josefsen, Knud Krogvold, Lars Gerling, Ivan C. Pociot, Flemming Dahl-Jørgensen, Knut Buschard, Karsten . Development of Type 1 Diabetes may occur through a Type 2 Diabetes mechanism. Frontiers in Endocrinology. 2022, 13; http://hdl.handle.net/10852/101233Test; 2102439; info:ofi/fmt:kev:mtx:ctx&ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Frontiers in Endocrinology&rft.volume=13&rft.spage=&rft.date=2022; Frontiers in Endocrinology; 13; 10; https://doi.org/10.3389/fendo.2022.1032822Test
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6دورية أكاديمية
المؤلفون: Lyngstadaas, Anne Viktoria, Holm, Jan‐Øivind, Krogvold, Lars, Måløy, Anne Karin, Ingvaldsen, Christoffer Aam
المصدر: Skin Health and Disease ; volume 3, issue 4 ; ISSN 2690-442X 2690-442X
الوصف: Continuous glucose monitors (CGM) and insulin pumps have become the preferred treatment option for most young children and adolescents with type 1 diabetes (T1D), by avoiding fingerstick testing and providing real‐time glucose measurements. These medical devices and their adhesives contain substances which have been identified as being responsible for allergic contact dermatitis. We describe the case of a toddler who developed severe contact dermatitis from her diabetes devices, leading to secondary infections and hospital admissions. This was followed by the development of a symmetrical exanthema with retroauricular and glutaeal distribution. Patch tests were positive for isobornyl acrylate (IBOA) and 4‐tert‐butylcatechol (PTBC). Her symmetrical exanthema was interpreted as systemic contact dermatitis due to IBOA and PTBC in her diabetes devices. We suspect that systemic contact dermatitis is an underreported complication in diabetic patients.
الإتاحة: https://doi.org/10.1002/ski2.234Test
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7دورية أكاديمية
المؤلفون: Buschard, Karsten, Jensen, Mathias Høj, Krogvold, Lars, Gerling, Ivan C., Dahl‐Jørgensen, Knut, Pedersen, Kristina, Haupt‐Jorgensen, Martin
المصدر: Diabetes/Metabolism Research and Reviews ; volume 39, issue 7 ; ISSN 1520-7552 1520-7560
الوصف: Aims To investigate if HLA risk haplotypes and HbA1c levels are associated with the expression levels of innate anti‐viral immune pathway genes in type 1 diabetes. Materials and Methods We investigated RNA expression levels of innate anti‐viral immune pathway genes in laser‐dissected islets from two to five tissue sections per donor from the Diabetes Virus Detection study and the network of Pancreatic Organ Donors in relation to HLA risk haplotypes (non‐predisposed and predisposed) and HbA1c levels (normal, elevated, and high). Results The expression of innate anti‐viral immune genes (TLR7, OAS1, OAS3 etc.) was significantly increased in individuals with predisposing vs non‐predisposing HLA haplotypes. Also, the expression of several of the innate anti‐viral immune genes from the HLA risk haplotype analysis was significantly increased in the group with high vs normal HbA1c. Furthermore, the gene expression of OAS2 was significantly increased in the group with high HbA1c vs elevated HbA1c. Conclusions Expression of innate anti‐viral immune pathway genes was increased in individuals with predisposing HLA risk haplotypes and those with high HbA1c. This indicates that type 1 diabetes might well begin with alterations in innate anti‐viral immunity, and already at this stage be associated with HLA risk haplotypes.
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8
المؤلفون: Seiron, Peter, Wiberg, Anna, Kuric, Enida, Krogvold, Lars, Jahnsen, Frode L., Dahl-Jorgensen, Knut, Skog, Oskar, Docent, PhD, 1981, Korsgren, Olle
المصدر: EXODIAB (Excellence of Diabetes Research in Sweden) The journal of pathology. Clinical research. 5(4):248-255
مصطلحات موضوعية: type 1 diabetes, human, pancreas
الوصف: Insulin deficiency in type 1 diabetes (T1D) is generally considered a consequence of immune-mediated specific beta-cell loss. Since healthy pancreatic islets consist of similar to 65% beta cells, this would lead to reduced islet size, while the number of islets per pancreas volume (islet density) would not be affected. In this study, we compared the islet density, size, and size distribution in biopsies from subjects with recent-onset or long-standing T1D, with that in matched non-diabetic subjects. The results presented show preserved islet size and islet size distribution, but a marked reduction in islet density in subjects with recent onset T1D compared with non-diabetic subjects. No further reduction in islet density occurred with increased disease duration. Insulin-negative islets in T1D subjects were dominated by glucagon-positive cells that often had lost the alpha-cell transcription factor ARX while instead expressing PDX1, normally only expressed in beta cells within the islets. Based on our findings, we propose that failure to establish a sufficient islet number to reach the beta-cell mass needed to cope with episodes of increased insulin demand contributes to T1D susceptibility. Exhaustion induced by relative lack of beta cells could then potentially drive beta-cell dedifferentiation to alpha-cells, explaining the preserved islet size observed in T1D compared to controls.
وصف الملف: electronic
الوصول الحر: https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-397132Test
https://doi.org/10.1002/cjp2.140Test
https://uu.diva-portal.org/smash/get/diva2:1374044/FULLTEXT01.pdfTest -
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10مؤتمر
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