Knut Dahl-Jørgensen

• Haugvik, Severina; Hennekes, Mareille H.C.L.; Wit, Maartje de; Toschi, Elena; Desjardins, Christopher D. & Skrivarhaug, Torild [Show all 9 contributors for this article] (2026). Can the Diabetes Eating Problem Survey-Revised (DEPS-R) reliably identify eating disorder diagnosis in women with type 1 diabetes? Diabetic Medicine. ISSN 0742-3071. 43(5). doi: 10.1111/dme.70207. Full text in Research Archive Show summary

  Aims The objective of this study was to evaluate the Diabetes Eating Problems Survey-Revised (DEPS-R) against the Eating Disorder Diagnostic Interview (EDDI). Specific aims were to (1) assess the ability of the DEPS-R to identify Diagnostic and Statistical Manual-5 (DSM-5) eating disorders, including sensitivity and specificity of the current DEPS-R cutoff ≥20 and (2) report the correlation of each item to the presence of any eating disorder. Methods Baseline data from 293 women (14–35 years) with type 1 diabetes (T1D) and body image concerns enrolled in a multinational randomized controlled trial were examined. Receiver operating characteristic (ROC) analysis, univariate logistic regression and two-sample t-test were performed. Results The ROC analysis demonstrated good accuracy of the DEPS-R with an area under the curve (AUC) of 0.82 (95% CI 0.79–0.94). The cutoff of ≥20 yielded a sensitivity of 87.5% (95% CI 83.6%–91.3%) and a specificity of 60.4% (95% CI 54.8%–66.0%). Univariate logistic regression identified 12 items as significantly correlated with the presence of any eating disorder. The highest odds ratios (OR) were observed for items 9 (OR = 3.64), 8 (OR = 2.85), 13 (OR = 2.36), 14 (OR = 2.23), 15 (OR = 1.99) and 5 (OR = 1.99). Conclusions This is the first study to investigate the ability of the DEPS-R to identify DSM-5 eating disorder diagnosis established via a diagnostic interview using a ROC-analysis. DEPS-R cutoff ≥20 correctly identified most cases with eating disorders but showed moderate specificity, considered acceptable as an initial screening tool for disordered eating. In clinical care, specific DEPS-R items may be emphasized to explore the presence of disordered eating behaviours and eating disorders.

• Haugvik, Severina; Harel, Shiraz; Shaw, Heather; Wit, Maartje de; Toschi, Elena & Hennekes, Mareille H.C.L. [Show all 10 contributors for this article] (2025). Diabetes body project eating disorder prevention program—Descriptive content analysis of participant and facilitator feedback in a multinational randomized controlled trial. Diabetic Medicine. ISSN 0742-3071. 42(10). doi: 10.1111/dme.70108. Full text in Research Archive Show summary

  Aims To examine and describe feedback after participation in a novel eating disorder prevention program for young women with type 1 diabetes (Diabetes Body Project) in a multinational randomised controlled trial. Methods Written feedback from participants (N = 109) and facilitators (N = 19) at four sites (Europe and US) was analysed using descriptive, manifest content analysis. Open-ended questions included motivation for participation, most/less valuable aspects of the program and suggestions for improvement. Results “Community” was the most important motivator and most valued aspect, reported by one-third of participants. When asked about less valued aspects of the program, participants and facilitators most frequently reported “none/not sure/everything was valuable” and “nothing” respectively. Suggestions to improve the program common for participants and facilitators were “more creative exercises”, specific for participants after “none” was “limit homework/obligations” and specific for facilitators was “more flexibility to move away from the script”. The three most frequently perceived barriers for participation reported by participants and facilitators were “requiring personal vulnerability”, “time and energy constraints” and the “group setting”. Conclusions Participants and facilitators expressed overall high satisfaction with the program, specifically the value of T1D community. Additionally, they suggested incorporating more creative exercises. Future research should aim at widespread implementation and addressing barriers to participation.

• Buschard, Karsten; Krogvold, Lars; Pociot, Flemming; Gerling, Ivan; Thea, Rikke & Dahl-Jørgensen, Knut [Show all 7 contributors for this article] (2025). TLR5 influences the development of type 1 diabetes. BMJ Open Diabetes Research & Care. 13(5), p. 1–6. doi: 10.1136/bmjdrc-2025-005111. Full text in Research Archive
• Mynarek, Ida Maria; Krogvold, Lars; Mørk, Freja B.; Lawaetz, Trine; Roald, Trine & Fagerland, Morten [Show all 14 contributors for this article] (2025). Three-Year Follow-up After Antiviral Treatment in New-Onset Type 1 Diabetes: Results From the Diabetes Virus Detection and Intervention Trial. Diabetes Care. ISSN 0149-5992. 48(3), p. 481–488. doi: 10.2337/dc24-2121. Full text in Research Archive
• Hennekes, Mareille H. C. L.; Haugvik, Severina; Wit, Maartje de; Toschi, Elena; Desjardins, Christopher D. & Skrivarhaug, Torild [Show all 9 contributors for this article] (2025). Diabetes Body Project: Acute Effects of an Eating Disorder Prevention Program for Young Women With Type 1 Diabetes. A Multinational Randomized Controlled Trial. Diabetes Care. ISSN 0149-5992. 48(2), p. 221–225. doi: 10.2337/dc24-1599. Full text in Research Archive
• Pala, Kaaj; Sun, Kevin Xueying; Krogvold, Lars; Dahl-Jørgensen, Knut & Reddy, Shiva (2025). Distribution of glutathione peroxidase-1 immunoreactive cells in pancreatic islets from type 1 diabetic donors and non-diabetic donors with and without islet cell autoantibodies is variable and independent of disease. Cell and Tissue Research. ISSN 0302-766X. 400(3), p. 255–271. doi: 10.1007/s00441-025-03955-5. Full text in Research Archive
• Rees, Nicolás Verschueren van; Ashwin, Peter; McMullan, Conor; Krogvold, Lars; Dahl-Jørgensen, Knut & Morgan, Noel G. [Show all 8 contributors for this article] (2025). Beyond the loss of beta cells: a quantitative analysis of islet architecture in adults with and without type 1 diabetes. Diabetologia. ISSN 0012-186X. 68(5), p. 1031–1043. doi: 10.1007/s00125-025-06376-9. Full text in Research Archive
• Ravlo, Erlend; Ianevski, Aleksandr; Schjølberg, Jørn-Ove; Solvang, Vanessa; Dumaru, Rabina & Lysvand, Hilde [Show all 31 contributors for this article] (2025). Synergistic combination of orally available safe-in-man pleconaril, AG7404, and mindeudesivir inhibits enterovirus infections in human cell and organoid cultures. Cellular and Molecular Life Sciences (CMLS). ISSN 1420-682X. 82. doi: 10.1007/s00018-025-05581-4. Full text in Research Archive Show summary

  Enteroviruses can infect various human organs, causing diseases such as meningitis, the common cold, hand-foot-and-mouth disease, myocarditis, pancreatitis, hepatitis, poliomyelitis, sepsis, and type 1 diabetes. Currently, there are no approved treatments for enterovirus infections. In this study, we identified a synergistic combination of orally available, safe-in-man pleconaril, AG7404, and mindeudesivir, that at non-toxic concentrations effectively inhibited enterovirus replication in human cell and organoid cultures. Importantly, the cocktail did not alter glucose and insulin levels in the culture medium of pancreatic β-cells and preserved the contraction rhythm of infected heart organoids. These findings highlight a promising drug cocktail for further preclinical studies and clinical trials targeting a broad range of enterovirus-mediated diseases.

• Simeunovic, Aida; Brunborg, Cathrine; Heier, Martin; Berg, Tore Julsrud; Dahl-Jørgensen, Knut & MARGEIRSDOTTIR, HANNA DIS (2025). Early increase in carotid intima-media thickness in women with childhood-onset type 1 diabetes compared with healthy peers: the Norwegian Atherosclerosis and Childhood Diabetes study. BMJ Open Diabetes Research & Care. 13(1). doi: 10.1136/bmjdrc-2024-004505. Full text in Research Archive Show summary

  Introduction The risk of cardiovascular disease is increased in individuals with type 1 diabetes, despite good glycemic control. This study aims to evaluate early signs of atherosclerosis and predisposing factors in individuals with childhood-onset type 1 diabetes compared with healthy controls. Research design and methods The Atherosclerosis and Childhood Diabetes study is a prospective population-based cohort study with follow-up every fifth year. The cohort consists of 329 subjects with type 1 diabetes and 173 controls. Carotid intima-media thickness (cIMT) was measured at baseline and 5 and 10 years of follow-up. Data from the Norwegian Childhood Diabetes Registry were used in assessment of traditional risk factors. Results Mean cIMT in young women with type 1 diabetes increased significantly over a 10-year period compared with healthy controls (∆0.019 mm (0.001–0.035), p=0.035). At the 10-year follow-up the group with type 1 diabetes had a mean age of 24.2±2.9 years (13.7±2.8 years at baseline), diabetes duration of 15.6±3.4 years (5.4±3.3 years at baseline) and HbA1c of 8.2±3.6% (66±16 mmol/mol) (8.4±3.4% (68±13 mmol/mol) at baseline). Women with type 1 diabetes had significantly higher mean weight, body mass index, waist circumference, diastolic blood pressure (DBP), serum low-density lipoprotein (LDL)-cholesterol and apolipoprotein B, while men with type 1 diabetes had significantly higher mean DBP and urinary albumin-creatinine ratio compared with the control group. Mean cIMT change over time was not associated with long-term HbA1c or LDL-cholesterol burden in childhood and adolescence. Conclusion Young women with childhood-onset type 1 diabetes of relatively short diabetes duration had a higher mean cIMT over a 10-year period compared with their healthy female controls, with values similar to males.

• Buschard, Karsten; Josefsen, Knud; Krogvold, Lars; Gerling, Ivan; Dahl-Jørgensen, Knut & Pociot, Flemming (2024). Influence of sphingolipid enzymes on blood glucose levels, development of diabetes, and involvement of pericytes. Diabetes/Metabolism Research and Reviews. ISSN 1520-7552. 40(3). doi: 10.1002/dmrr.3792. Full text in Research Archive Show summary

  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.

• Dahl-Jørgensen, Knut (2024). Virus as the cause of type 1 diabetes. Trends in Molecular Medicine. ISSN 1471-4914. 30(11), p. 1020–1027. doi: 10.1016/j.molmed.2024.06.011. Full text in Research Archive Show summary

  Type 1 diabetes (T1D), a severe disease requiring intensive insulin treatment, carries an increased risk for complications and reduced lifespan. Certain viruses have been implicated in T1D’s etiology, with ‘live‘, replicating enteroviruses (EVs) recently found in the pancreas at diagnosis. This discovery prompted a trial to slow down disease progression using antiviral drugs. A 6-month treatment combining pleconaril and ribavirin in new-onset T1D patients preserved residual insulin production after 1 year, unlike placebo. The results support the theory that viruses may cause T1D in genetically susceptible individuals. A low-grade, persistent viral infection may initiate a cascade of pathogenic mechanisms initially involving the innate immune system, inducing β-cell stress and neoantigen release, leading to autoimmunity, and eventually the destruction of insulin-producing β-cells.

• Wisting, Line; Haugvik, Severina; Wennersberg, Anne Louise; Hage, Trine Wiig; Stice, Eric & Olmsted, Marion P. [Show all 11 contributors for this article] (2024). A pilot study of a virtually delivered dissonance-based eating disorder prevention program for young women with type 1 diabetes: within-subject changes over 6-month follow-up. Eating Disorders. ISSN 1064-0266. doi: 10.1080/10640266.2024.2331391. Full text in Research Archive Show summary

  Introduction: In an uncontrolled study, we previously demonstrated the feasibility and preliminary efficacy of our virtual diabetes-specific version (Diabetes Body Project) of the eating disorder (ED) prevention program the Body Project. The aim of the current study was to evaluate further this program for women with type 1 diabetes (T1D) by assessing within-subject changes in outcomes from pretest over 6-month follow-up. Methods: Young women with T1D aged 16–35 years were invited to participate in Diabetes Body Project groups. A total of 35 participants were allocated to five Diabetes Body Project groups (six meetings over 6 weeks). Primary outcome measures included ED risk factors and symptoms, and secondary outcomes included three T1D-specific constructs previously found to be associated with ED pathology: glycemic control as measured by HbA1c level, diabetes distress, and illness perceptions. Results: Within-subject reductions, with medium-to-large effect sizes, were observed for the primary (ED pathology, body dissatisfaction, thin-ideal internalization, and appearance ideals and pressures) and secondary outcomes (within-condition Cohen’s ds ranged from .34 to 1.70). Conclusion: The virtual Diabetes Body Project appears to be a promising intervention worthy of more rigorous evaluation. A randomized controlled trial with at least a 1-year follow-up is warranted to determine its efficacy compared to a control condition.

• Tegehall, Angie; Ingvast, Sofie; Krogvold, Lars; Dahl-Jørgensen, Knut & Korsgren, Olle (2024). Reduced expression of central innate defense molecules in pancreatic biopsies from subjects with Type 1 diabetes. Acta Diabetologica. ISSN 0940-5429. 61, p. 1117–1127. doi: 10.1007/s00592-024-02286-1. Full text in Research Archive Show summary

  Aims/Hypothesis Defensins play a crucial role in the innate immune system's first defense against microbial threats. However, little is known about the defensin system in the pancreas, especially in relation to Type 1 diabetes. We explore the expression of defensins in different disease stages of Type 1 diabetes and correlated obtained findings to the degree of inflammation, providing new insights into the disease and the innate immune system. Material and methods Pancreases from non-diabetic human organ donors of different age groups and donors with Type 1 diabetes with different disease duration were examined. Sections from head, body and tail of the pancreas were stained for eight different defensins and for immune cells; CD3+, CD45+, CD68+ and NES+ (granulocytes). Results In non-diabetic adult controls the level of expression for defensins Beta-1,Alpha-1, Cathelicidin and REG3A correlated with the level of inflammation. In contrast, individuals with Type 1 diabetes exhibit a reduction or absence of several central defensins regardless of the level of inflammation in their pancreas. The expression of Cathelicidin is present in neutrophils and macrophages but not in T-cells in subjects with Type 1 diabetes. Conclusions Obtained findings suggest a pancreatic dysfunction in the innate immune system and the bridging to the adaptive system in Type 1 diabetes. Further studies on the role of the local innate immune system in Type 1 diabetes is needed.

• Simeunovic, Aida; Brunborg, Cathrine; Heier, Martin; Seljeflot, Ingebjørg; Dahl-Jørgensen, Knut & MARGEIRSDOTTIR, HANNA DIS (2023). Sustained low-grade inflammation in young participants with childhood onset type 1 diabetes: The Norwegian atherosclerosis and childhood diabetes (ACD) study. Atherosclerosis. ISSN 0021-9150. 379. doi: 10.1016/j.atherosclerosis.2023.05.020. Full text in Research Archive
• Krogvold, Lars; Mynarek, Ida Maria; Ponzi, Erica; Mørk, Freja Barrett; Hessel, Trine Witzner & Roald, Trine [Show all 14 contributors for this article] (2023). Pleconaril and ribavirin in new-onset type 1 diabetes: a phase 2 randomized trial. Nature Medicine. ISSN 1078-8956. 29(4), p. 2902-2908–2902-2908. doi: 10.1038/s41591-023-02576-1. Full text in Research Archive Show summary

  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 β 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.

• Buschard, Karsten; Jensen, Mathias Høj; Krogvold, Lars; Gerling, Ivan C.; Dahl-Jørgensen, Knut & Pedersen, Kristina [Show all 7 contributors for this article] (2023). Type 1 diabetes could begin with alterations in innate anti-viral immunity, which are already at this stage associated with HLA risk haplotypes. Diabetes/Metabolism Research and Reviews. ISSN 1520-7552. 39(7). doi: 10.1002/dmrr.3678. Full text in Research Archive Show summary

  Abstract 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.

• Krogvold, Lars; Genoni, Angelo; Puggioni, Anna; Campani, Daniela; Richardson, Sarah J. & Flaxman, Christine S. [Show all 10 contributors for this article] (2022). Live enteroviruses, but not other viruses, detected in human pancreas at the onset of type 1 diabetes in the DiViD study. Diabetologia. ISSN 0012-186X. 65, p. 2108–2120. doi: 10.1007/s00125-022-05779-2. Full text in Research Archive Show summary

  Abstract Aims/hypothesis Enterovirus (EV) infection of pancreatic islet cells is one possible factor contributing to type 1 diabetes development. We have reported the presence of EV genome by PCR and of EV proteins by immunohistochemistry in pancreatic sections. Here we explore multiple human virus species in the Diabetes Virus Detection (DiViD) study cases using innovative methods, including virus passage in cell cultures. Methods Six recent-onset type 1 diabetes patients (age 24–35) were included in the DiViD study. Minimal pancreatic tail resection was performed under sterile conditions. Eleven live cases (age 43–83) of pancreatic carcinoma without diabetes served as control cases. In the present study, we used EV detection methods that combine virus growth in cell culture, gene amplification and detection of virus-coded proteins by immunofluorescence. Pancreas homogenates in cell culture medium were incubated with EV-susceptible cell lines for 3 days. Two to three blind passages were performed. DNA and RNA were extracted from both pancreas tissue and cell cultures. Real-time PCR was used for detecting 20 different viral agents other than EVs (six herpesviruses, human polyomavirus [BK virus and JC virus], parvovirus B19, hepatitis B virus, hepatitis C virus, hepatitis A virus, mumps, rubella, influenza A/B, parainfluenza 1–4, respiratory syncytial virus, astrovirus, norovirus, rotavirus). EV genomes were detected by endpoint PCR using five primer pairs targeting the partially conserved 5′ untranslated region genome region of the A, B, C and D species. Amplicons were sequenced. The expression of EV capsid proteins was evaluated in cultured cells using a panel of EV antibodies. Results Samples from six of six individuals with type 1 diabetes (cases) and two of 11 individuals without diabetes (control cases) contained EV genomes ( p <0.05). In contrast, genomes of 20 human viruses other than EVs could be detected only once in an individual with diabetes (Epstein–Barr virus) and once in an individual without diabetes (parvovirus B19). EV detection was confirmed by immunofluorescence of cultured cells incubated with pancreatic extracts: viral antigens were expressed in the cytoplasm of approximately 1% of cells. Notably, infection could be transmitted from EV-positive cell cultures to uninfected cell cultures using supernatants filtered through 100 nm membranes, indicating that infectious agents of less than 100 nm were present in pancreases. Due to the slow progression of infection in EV-carrying cell cultures, cytopathic effects were not observed by standard microscopy but were recognised by measuring cell viability. Sequences of 5′ untranslated region amplicons were compatible with EVs of the B, A and C species. Compared with control cell cultures exposed to EV-negative pancreatic extracts, EV-carrying cell cultures produced significantly higher levels of IL-6, IL-8 and monocyte chemoattractant protein-1 (MCP1). Conclusions/interpretation Sensitive assays confirm that the pancreases of all DiViD cases contain EVs but no other viruses. Analogous EV strains have been found in pancreases of two of 11 individuals without diabetes. The detected EV strains can be passaged in series from one cell culture to another in the form of poorly replicating live viruses encoding antigenic proteins recognised by multiple EV-specific antibodies. Thus, the early phase of type 1 diabetes is associated with a low-grade infection by EVs, but not by other viral agents. Graphical abstract

• Nigi, Laura; Brusco, Noemi; Grieco, Giuseppina E.; Fignani, Daniela; Licata, Giada & Formichi, Caterina [Show all 13 contributors for this article] (2022). Increased Expression of Viral Sensor MDA5 in Pancreatic Islets and in Hormone-Negative Endocrine Cells in Recent Onset Type 1 Diabetic Donors. Frontiers in Immunology. 13, p. 1–12. doi: 10.3389/fimmu.2022.833141. Full text in Research Archive Show summary

  The interaction between genetic and environmental factors determines the development of type 1 diabetes (T1D). Some viruses are capable of infecting and damaging pancreatic β-cells, whose antiviral response could be modulated by specific viral RNA receptors and sensors such as melanoma differentiation associated gene 5 (MDA5), encoded by the IFIH1 gene. MDA5 has been shown to be involved in pro-inflammatory and immunoregulatory outcomes, thus determining the response of pancreatic islets to viral infections. Although the function of MDA5 has been previously well explored, a detailed immunohistochemical characterization of MDA5 in pancreatic tissues of nondiabetic and T1D donors is still missing. In the present study, we used multiplex immunofluorescence imaging analysis to characterize MDA5 expression and distribution in pancreatic tissues obtained from 22 organ donors (10 nondiabetic autoantibody-negative, 2 nondiabetic autoantibody-positive, 8 recent-onset, and 2 long-standing T1D). In nondiabetic control donors, MDA5 was expressed both in α- and β-cells. The colocalization rate imaging analysis showed that MDA5 was preferentially expressed in α-cells. In T1D donors, we observed an increased colocalization rate of MDA5-glucagon with respect to MDA5-insulin in comparison to nondiabetic controls; such increase was more pronounced in recent-onset with respect to long-standing T1D donors. Of note, an increased colocalization rate of MDA5-glucagon was found in insulin-deficient-islets (IDIs) with respect to insulin-containing-islets (ICIs). Strikingly, we detected the presence of MDA5-positive/hormone-negative endocrine islet-like clusters in T1D donors, presumably due to dedifferentiation or neogenesis phenomena. These clusters were identified exclusively in donors with recent disease onset and not in autoantibody-positive nondiabetic donors or donors with long-standing T1D. In conclusion, we showed that MDA5 is preferentially expressed in α-cells, and its expression is increased in recent-onset T1D donors. Finally, we observed that MDA5 may also characterize the phenotype of dedifferentiated or newly forming islet cells, thus opening to novel roles for MDA5 in pancreatic endocrine cells.

• Josefsen, Knud; Krogvold, Lars; Gerling, Ivan C.; Pociot, Flemming; Dahl-Jørgensen, Knut & Buschard, Karsten (2022). Development of Type 1 Diabetes may occur through a Type 2 Diabetes mechanism. Frontiers in Endocrinology. 13. doi: 10.3389/fendo.2022.1032822. Full text in Research Archive Show summary

  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.

• Välikangas, Tommi; Lietzén, Niina; Jaakkola, Maria K.; Krogvold, Lars; Eike, Morten Christoph & Kallionpää, Henna [Show all 14 contributors for this article] (2022). Pancreas whole tissue transcriptomics highlights the role of the exocrine pancreas in patients with recently diagnosed type 1 diabetes. Frontiers in Endocrinology. 13:881985, p. 1–12. doi: 10.3389/fendo.2022.861985. Full text in Research Archive Show summary

  Although type 1 diabetes (T1D) is primarily a disease of the pancreatic beta-cells, understanding of the disease-associated alterations in the whole pancreas could be important for the improved treatment or the prevention of the disease. We have characterized the whole-pancreas gene expression of patients with recently diagnosed T1D from the Diabetes Virus Detection (DiViD) study and non-diabetic controls. Furthermore, another parallel dataset of the whole pancreas and an additional dataset from the laser-captured pancreatic islets of the DiViD patients and non-diabetic organ donors were analyzed together with the original dataset to confirm the results and to get further insights into the potential disease-associated differences between the exocrine and the endocrine pancreas. First, higher expression of the core acinar cell genes, encoding for digestive enzymes, was detected in the whole pancreas of the DiViD patients when compared to non-diabetic controls. Second, In the pancreatic islets, upregulation of immune and inflammation related genes was observed in the DiViD patients when compared to non-diabetic controls, in line with earlier publications, while an opposite trend was observed for several immune and inflammation related genes at the whole pancreas tissue level. Third, strong downregulation of the regenerating gene family ( REG ) genes, linked to pancreatic islet growth and regeneration, was observed in the exocrine acinar cell dominated whole-pancreas data of the DiViD patients when compared with the non-diabetic controls. Fourth, analysis of unique features in the transcriptomes of each DiViD patient compared with the other DiViD patients, revealed elevated expression of central antiviral immune response genes in the whole-pancreas samples, but not in the pancreatic islets, of one DiViD patient. This difference in the extent of antiviral gene expression suggests different statuses of infection in the pancreas at the time of sampling between the DiViD patients, who were all enterovirus VP1 + in the islets by immunohistochemistry based on earlier studies. The observed features, indicating differences in the function, status and interplay between the exocrine and the endocrine pancreas of recent onset T1D patients, highlight the importance of studying both compartments for better understanding of the molecular mechanisms of T1D.

• Krogvold, Lars; Leete, Pia; Mynarek, Ida Maria; Russell, Mark A.; Gerling, Ivan C. & Lenchik, Nataliya I. [Show all 10 contributors for this article] (2022). Detection of Antiviral Tissue Responses and Increased Cell Stress in the Pancreatic Islets of Newly Diagnosed Type 1 Diabetes Patients: Results From the DiViD Study. Frontiers in Endocrinology. 13, p. 1–10. doi: 10.3389/fendo.2022.881997. Full text in Research Archive Show summary

  Aims/hypothesis: The Diabetes Virus Detection (DiViD) study has suggested the presence of low-grade enteroviral infection in pancreatic tissue collected from six of six live adult patients newly diagnosed with type 1 diabetes. The present study aimed to compare the gene and protein expression of selected virally induced pathogen recognition receptors and interferon stimulated genes in islets from these newly diagnosed type 1 diabetes (DiViD) subjects vs age-matched non-diabetic (ND) controls. Methods: RNA was extracted from laser-captured islets and Affymetrix Human Gene 2.0 ST arrays used to obtain gene expression profiles. Lists of differentially expressed genes were subjected to a data-mining pipeline searching for enrichment of canonical pathways, KEGG pathways, Gene Ontologies, transcription factor binding sites and other upstream regulators. In addition, the presence and localisation of specific viral response proteins (PKR, MxA and MDA5) were examined by combined immunofluorescent labelling in sections of pancreatic tissue. Results: The data analysis and data mining process revealed a significant enrichment of gene ontologies covering viral reproduction and infectious cycles; peptide translation, elongation and initiation, as well as oxidoreductase activity. Enrichment was identified in the KEGG pathways for oxidative phosphorylation; ribosomal and metabolic activity; antigen processing and presentation and in canonical pathways for mitochondrial dysfunction, oxidative phosphorylation and EIF2 signaling. Protein Kinase R (PKR) expression did not differ between newly diagnosed type 1 diabetes and ND islets at the level of total RNA, but a small subset of β-cells displayed markedly increased PKR protein levels. These PKR+ β-cells correspond to those previously shown to contain the viral protein, VP1. RNA encoding MDA5 was increased significantly in newly diagnosed type 1 diabetes islets, and immunostaining of MDA5 protein was seen in α- and certain β-cells in both newly diagnosed type 1 diabetes and ND islets, but the expression was increased in β-cells in type 1 diabetes. In addition, an uncharacterised subset of synaptophysin positive, but islet hormone negative, cells expressed intense MDA5 staining and these were more prevalent in DiViD cases. MxA RNA was upregulated in newly diagnosed type 1 diabetes vs ND islets and MxA protein was detected exclusively in newly diagnosed type 1 diabetes β-cells. Conclusion/interpretation: The gene expression signatures reveal that pathways associated with cellular stress and increased immunological activity are enhanced in islets from newly diagnosed type 1 diabetes patients compared to controls. The increases in viral response proteins seen in β-cells in newly diagnosed type 1 diabetes provide clear evidence for the activation of IFN signalling pathways. As such, these data strengthen the hypothesis that an enteroviral infection of islet β-cells contributes to the pathogenesis of type 1 diabetes.

• Tekin, Hasim; Josefsen, Knud; Krogvold, Lars; Dahl-Jørgensen, Knut; Gerling, Ivan & Pociot, Flemming [Show all 7 contributors for this article] (2022). PDE12 in type 1 diabetes. Scientific Reports. 12:18149, p. 1–5. doi: 10.1038/s41598-022-22890-x. Full text in Research Archive Show summary

  Abstract Type 1 diabetes (T1D) incidence is increased after COVID-19 infection in children under 18 years of age. Interferon-α-activated oligoadenylate synthetase and downstream RNAseL activation degrade pathogen RNA, but can also damage host RNA when RNAseL activity is poorly regulated. One such regulator is PDE12 which degrades 2′-5′ oligoadenylate units, thereby decreasing RNAseL activity. We analyzed PDE12 expression in islets from non-diabetic donors, individuals with newly (median disease duration 35 days) and recently (5 years) diagnosed T1D, and individuals with type 2 diabetes (T2D). We also analyzed PDE12 single-nucleotide polymorphisms (SNPs) relative to T1D incidence. PDE12 expression was decreased in individuals with recently diagnosed T1D, in three of five individuals with newly diagnosed T1D, but not in individuals with T2D. Two rare PDE12 SNPs were found to have odds ratios of 1.80 and 1.74 for T1D development. We discuss whether decreased PDE12 expression after COVID-19 infection might be part of the up to 2.5-fold increase in T1D incidence.

• Weider, Therese; Genoni, Angelo; Broccolo, Francesco; Paulsen, Trond Harder; Dahl-Jørgensen, Knut & Toniolo, Antonio [Show all 7 contributors for this article] (2022). High prevalence of common human viruses in thyroid tissue. Frontiers in Endocrinology. 13, p. 1–11. doi: 10.3389/fendo.2022.938633. Full text in Research Archive Show summary

  Introduction: Evidence points to viral infections as possible triggers of autoimmune thyroid disease (AITD), but little is known about the prevalence of common viruses in the thyroid gland. Using a novel approach based on virus enrichment in multiple cell lines followed by detection of the viral genome and visualization of viral proteins, we investigated the presence of multiple human viruses in thyroid tissue from AITD patients and controls. Methods: Thyroid tissue was collected by core needle biopsy or during thyroid surgery from 35 patients with AITD (20 Graves’ disease and 15 Hashimoto’s thyroiditis). Eighteen thyroid tissue specimens from patients undergoing neck surgery for reasons other than thyroid autoimmunity served as controls. Specimens were tested for the presence of ten different viruses. Enteroviruses and human herpesvirus 6 were enriched in cell culture before detection by PCR and immunofluorescence, while the remaining viruses were detected by PCR of biopsied tissue. Results: Forty of 53 cases (75%) carried an infectious virus. Notably, 43% of all cases had a single virus, whereas 32% were coinfected by two or more virus types. An enterovirus was found in 27/53 cases (51%), human herpesvirus 6 in 16/53 cases (30%) and parvovirus B19 in 12/53 cases (22%). Epstein-Barr virus and cytomegalovirus were found in a few cases only. Of five gastroenteric virus groups examined, only one was detected in a single specimen. Virus distribution was not statistically different between AITD cases and controls. Conclusion: Common human viruses are highly prevalent in the thyroid gland. This is the first study in which multiple viral agents have been explored in thyroid. It remains to be established whether the detected viruses represent causal agents, possible cofactors or simple bystanders.

• Veiby, Nina; Simeunovic, Aida; Heier, Martin; Brunborg, Cathrine; Saddique, Naila & Moe, Morten C. [Show all 9 contributors for this article] (2021). Retinal venular oxygen saturation is associated with non-proliferative diabetic retinopathy in young patients with type 1 diabetes. Acta Ophthalmologica. ISSN 1755-375X. doi: 10.1111/aos.15018. Full text in Research Archive Show summary

  Purpose To determine the contribution of retinal vessel density (VD), central retinal vessel diameter and retinal oxygen (O2) saturation independently of other known risk factors in the development of non-proliferative diabetic retinopathy (NPDR). Methods Macular optical coherence tomography angiography (OCTA), central retinal artery/vein equivalent diameter (CRAE/CRVE) measurements and retinal oximetry were performed in a cross-sectional study of 166 eyes from 166 individuals with type 1 diabetes (T1D) aged 14–30 years. Multiple logistic regression analysis was used to investigate whether O2 saturation, retinal vessel diameters and vessel density in the deep capillary plexus (VD-DCP) were associated with NPDR, when adjusting for known risk factors. The individuals were allocated to one group without and one group with NPDR. Results Multiple logistic regression analysis showed that age (OR = 1.25, 95% CI: 1.04–1.49) and AV-difference in O2 saturation (OR = 0.85, 95% CI 0.77–0.93) were significantly associated with NPDR. Conclusion Our findings suggest that age and lower AV-O2 saturation difference contribute to explaining the grade of NPDR independently of other well-known risk factors. Reduced delivery of O2 to the retinal tissue is associated with the development of NPDR in young patients with T1D and should be given appropriate weight in the risk stratification at early stages of the disease.

• Reddy, Shiva; Krogvold, Lars; Martin, Charlton; Sun, Kevin Xueying; Martin, Owen & Al-Ani, Aamenah [Show all 7 contributors for this article] (2021). Expression of immunoreactive inducible nitric oxide synthase in pancreatic islet cells from newly diagnosed and long-term type 1 diabetic donors is heterogeneous and not disease-associated. Cell and Tissue Research. ISSN 0302-766X. 384, p. 655–674. doi: 10.1007/s00441-020-03340-4. Full text in Research Archive
• Sever, Dror; Hershko-Moshe, Anat; Srivastava, Rohit; Eldor, Roy; Hibsher, Daniel & Keren-Shaul, Hadas [Show all 13 contributors for this article] (2021). NF-κB activity during pancreas development regulates adult β-cell mass by modulating neonatal β-cell proliferation and apoptosis. Cell death discovery. 7(1), p. 1–16. doi: 10.1038/s41420-020-00386-9. Full text in Research Archive
• Weider, Therese; Richardson, Sarah J.; Morgan, Noel G.; Paulsen, Trond Harder; Dahl-Jørgensen, Knut & Hammerstad, Sara Salehi (2021). HLA Class I Upregulation and Antiviral Immune Responses in Graves Disease. Journal of Clinical Endocrinology and Metabolism (JCEM). ISSN 0021-972X. 106(4), p. 1763–1774. doi: 10.1210/clinem/dgaa958. Full text in Research Archive Show summary

  Abstract Context The origin of Graves disease (GD) remains elusive. However, evidence of an association between GD and viral infections is emerging. Human leukocyte antigen (HLA) class I presents viral antigens to circulating immune cells and plays a crucial role in the defense against viral infections. Objective This work aimed to investigate HLA class I expression, enterovirus presence, and the viral immune response proteins signal transducer and activation of transcription 1 (STAT1) and protein kinase R (PKR) in thyroid tissue from GD patients. Methods We collected thyroid tissue from core needle biopsies or surgical specimens from 48 GD patients and 24 controls. Standard immunohistochemistry was used to detect HLA class I and enteroviral capsid protein 1 (VP1) on formalin-fixed and paraffin-embedded tissue. STAT1 and PKR were examined by combined immunofluorescence staining. HLA class I expression score was the main outcome measure. Results The HLA class I expression score, which takes both proportion and intensity of immunostaining into account, was significantly higher in GD patients (3.1 ± 3.3) than in controls (0.5 ± 0.9) (P < .001). Significantly more VP1 positive thyroid cells were found GD samples (50.1 ± 30.5%) than in controls (14.9 ± 10.5%) (P < .001). STAT1 and HLA class I were found within the same thyroid cells and PKR and VP1 were also colocalized within thyroid cells. Conclusion HLA class I is upregulated in GD and enterovirus protein is prevalent in thyroid tissue. The colocalization of HLA class I with STAT1 and VP1 with PKR indicates an antiviral tissue response. These findings support the concept of a link between viral infections and GD.

• Wisting, Line Norøm; Haugvik, Severina; Wennersberg, Anne Louise; Stice, Eric; Hage, Trine Wiig & Olmsted, Marion P. [Show all 11 contributors for this article] (2021). Feasibility of a virtually delivered eating disorder preventionprogram for young females with type 1 diabetes. International Journal of Eating Disorders. ISSN 0276-3478. p. 1–11. doi: 10.1002/eat.23578. Full text in Research Archive Show summary

  Objective This study aimed to develop a virtual diabetes-specific version of the eating disorder (ED) prevention program the Body Project, and to assess feasibility and preliminary efficacy of this program for young females with type 1 diabetes. Method Young females with type 1 diabetes aged 16–35 years were invited to participate in the study. A total of 35 participants were allocated to five Diabetes Body Project groups (six meetings over 6 weeks) and completed pretest assessments; 26 participants completed all sessions and posttest assessments (<7 days after last meeting). Primary measures included ED risk factors and symptoms, and secondary outcomes included diabetes-specific constructs previously found to be associated with ED psychopathology (e.g., diabetes distress and illness perceptions). Results The ease of recruitment, timely conduct of five groups, moderate drop-out rate and appreciation of the intervention by participants indicated that the Diabetes Body Project is feasible. Meaningful reductions occurred on the primary outcomes (i.e., ED psychopathology, body dissatisfaction, and thin ideal internalization) and on internalization of appearance ideals and appearance pressures at posttest (Cohen's d ranging from .63 to .83, which are medium to large effects). Small to medium effect sizes were found for diabetes illness perceptions and distress (.41 and .48, respectively). Discussion The virtual Diabetes Body Project is a promising and much-needed intervention, worthy of more rigorous evaluation. A randomized controlled trial is warranted to determine its effectiveness compared with a control condition.

• Oikarinen, Sami; Krogvold, Lars; Edwin, Bjørn; Buanes, Trond; Korsgren, Olle & Laiho, Jutta E. [Show all 13 contributors for this article] (2021). Characterisation of enterovirus RNA detected in the pancreas and other specimens of live patients with newly diagnosed type 1 diabetes in the DiViD study. Diabetologia. ISSN 0012-186X. 64, p. 2491–2501. doi: 10.1007/s00125-021-05525-0. Full text in Research Archive Show summary

  Abstract 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 EV-negative 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. Graphical abstract

• Poma, Anello Marcello; Hammerstad, Sarah Salehi; Genoni, Angelo; Basolo, Alessio; Dahl-Jorgensen, Knut & Toniolo, Antonio (2021). Immune transcriptome of cells infected with enterovirus strains obtained from cases of autoimmune thyroid disease. Microorganisms. 9(4), p. 1–16. doi: 10.3390/microorganisms9040876. Full text in Research Archive
• Pedersen, Kristina; Haupt-Jorgensen, Martin; Krogvold, Lars; Kaur, Simranjeet; Gerling, Ivan C. & Pociot, Flemming [Show all 8 contributors for this article] (2021). Genetic predisposition in the 2′-5′A pathway in the development of type 1 diabetes: potential contribution to dysregulation of innate antiviral immunity. Diabetologia. ISSN 0012-186X. 64(8), p. 1805–1815. doi: 10.1007/s00125-021-05469-5. Full text in Research Archive
• Rodriguez-Calvo, Teresa; Krogvold, Lars; Amirian, Natalie; Dahl-Jørgensen, Knut & Herrath, Matthias von (2021). One in Ten CD8+ Cells in the Pancreas of Living Individuals With Recent-Onset Type 1 Diabetes Recognizes the Preproinsulin Epitope PPI15-24. Diabetes. ISSN 0012-1797. 70(3), p. 752–758. doi: 10.2337/db20-0908. Full text in Research Archive
• Colli, Maikel L.; Ramos-Rodríguez, Mireia; Nakayasu, Ernesto S.; Alvelos, Maria I.; Lopes, Miguel & Hill, Jessica L.E. [Show all 22 contributors for this article] (2020). An integrated multi-omics approach identifies the landscape of interferon-α-mediated responses of human pancreatic beta cells. Nature Communications. 11:2584, p. 1–17. doi: 10.1038/s41467-020-16327-0. Full text in Research Archive
• Bratset, Vibeke; MARGEIRSDOTTIR, HANNA DIS; Heier, Martin; Solheim, Svein; Arnesen, Harald & Dahl-Jørgensen, Knut [Show all 7 contributors for this article] (2020). Procoagulant activity in children and adolescents on intensive insulin therapy. Pediatric Diabetes. ISSN 1399-543X. 21(3), p. 496–504. doi: 10.1111/pedi.12978. Full text in Research Archive Show summary

  Background Type 1 diabetes is associated with atherothrombosis, but limited data exist on procoagulant activity in the young. We investigated procoagulant activity in children/adolescents with type 1 diabetes using intensified insulin treatment compared with controls in a 5‐year follow‐up study, and further any associations with cardiovascular risk factors. Methods The study included 314 diabetes children/adolescents and 120 healthy controls. Prothrombin fragment 1+2 (F1+2), D‐dimer, tissue‐factor‐procoagulant‐activity (TF‐PCA), and tissue‐factor‐pathway‐inhibitor (TFPI) were analyzed with ELISAs. Results F1+2, D‐dimer, and TF‐PCA did not differ between the groups or correlate to HbA1c in the diabetes group at either time points. TFPI was significantly higher in the diabetes group compared with controls both at inclusion and follow‐up (both P < .001). In the diabetes group, TFPI correlated significantly to HbA1c at both time points (r = 0.221 and 0.304, both P < .001). At follow‐up, females using oral contraceptives had significantly elevated F1+2, D‐dimer, and TF‐PCA and lower TFPI compared to no‐users (all P < .005), and females had lower TFPI (P = .017) and higher F1+2 compared with males (P = .052), also after adjusting for the use of oral contraceptives. Conclusions The current results show similar procoagulant activity in children/adolescents with type 1 diabetes compared with controls over a 5‐year period, indicating that these children using modern intensified insulin treatment are not at high thrombotic risk at younger age. The elevated levels of TFPI in the diabetes group, related to hyperglycaemia, are probably reflecting increased endothelial activation. These findings highlight the significance of optimal blood glucose control in children/adolescents with type 1 diabetes, to maintain a healthy endothelium.

• Nigi, Laura; Brusco, Noemi; Grieco, Giuseppina E.; Licata, Giada; Krogvold, Lars & Marselli, Lorella [Show all 13 contributors for this article] (2020). Pancreatic alpha-cells contribute together with beta-cells to CXCL10 expression in type 1 diabetes. Frontiers in Endocrinology. 11:630, p. 1–13. doi: 10.3389/fendo.2020.00630. Full text in Research Archive Show summary

  C-X-C Motif Chemokine Ligand 10 (CXCL10) is a pro-inflammatory chemokine specifically recognized by the ligand receptor CXCR3 which is mostly expressed in T-lymphocytes. Although CXCL10 expression and secretion have been widely associated to pancreatic islets both in non-obese diabetic (NOD) mice and in human type 1 diabetic (T1D) donors, the specific expression pattern among pancreatic endocrine cell subtypes has not been clarified yet. Therefore, the purpose of this study was to shed light on the pancreatic islet expression of CXCL10 in NOD, in C57Bl/6J and in NOD-SCID mice as well as in human T1D pancreata from new-onset T1D patients (DiViD study) compared to non-diabetic multiorgan donors from the INNODIA European Network for Pancreatic Organ Donors with Diabetes (EUnPOD). CXCL10 was expressed in pancreatic islets of normoglycaemic and new-onset diabetic NOD mice but not in C57Bl/6J and NOD-SCID mice. CXCL10 expression was increased in pancreatic islets of new-onset diabetic NOD mice compared to normoglycaemic NOD mice. In NOD mice, CXCL10 colocalized both with insulin and glucagon. Interestingly, CXCL10-glucagon colocalization rate was significantly increased in diabetic vs. normoglycaemic NOD mouse islets, indicating an increased expression of CXCL10 also in alpha-cells. CXCL10 was expressed in pancreatic islets of T1D patients but not in non-diabetic donors. The analysis of the expression pattern of CXCL10 in human T1D pancreata from DiViD study, revealed an increased colocalization rate with glucagon compared to insulin. Of note, CXCL10 was also expressed in alpha-cells residing in insulin-deficient islets (IDI), suggesting that CXCL10 expression in alpha cells is not driven by residual beta-cells and therefore may represent an independent phenomenon. In conclusion, we show that in T1D CXCL10 is expressed by alpha-cells both in NOD mice and in T1D patients, thus pointing to an additional novel role for alpha-cells in T1D pathogenesis and progression.

• Veiby, Nina; Simeunovic, Aida; Heier, Martin; Brunborg, Cathrine; Saddique, Naila & Moe, Morten Carsten [Show all 9 contributors for this article] (2020). Venular oxygen saturation is increased in young patients with type 1 diabetes and mild nonproliferative diabetic retinopathy. Acta Ophthalmologica. ISSN 1755-375X. 98(8), p. 800–807. doi: 10.1111/aos.14462. Full text in Research Archive
• Wisting, Line Norøm; Siegwarth, Cecilie; Skrivarhaug, Torild; Dahl-Jørgensen, Knut & Rø, Øyvind (2020). The impact of psychological aspects, age, and BMI on eating disorder psychopathology among adult males and females with type 1 diabetes. Health Psychology Open (HPO). 7(2). doi: 10.1177/2055102920975969. Full text in Research Archive Show summary

  This study investigated correlates of eating disorder (ED) psychopathology among adults with type 1 diabetes (T1D). A total of 282 males (n = 112) and females (n = 170) with T1D (18–79 years) participated. Overall, psychological aspects (i.e. illness perceptions, coping strategies, insulin beliefs, anxiety, and depression) were associated with ED psychopathology. Associations were generally stronger among females than males. In a regression model, age, BMI, personal control, and anxiety explained 51% of the variance in ED psychopathology among females, whereas BMI, personal control, and anxiety explained 47% of the variance among males. Greater clinical awareness of health psychological aspects may contribute to reduce the risk of developing ED.

• Bratset, Vibeke; MARGEIRSDOTTIR, HANNA DIS; Chiva-Blanch, Gemma; Heier, Martin; Solheim, Svein & Arnesen, Harald [Show all 8 contributors for this article] (2020). Annexin V+ Microvesicles in Children and Adolescents with Type 1 Diabetes: A Prospective Cohort Study. Journal of Diabetes Research. ISSN 2314-6745. 2020, p. 1–8. doi: 10.1155/2020/7216863. Full text in Research Archive Show summary

  Background. Type 1 diabetes is a chronic disease including hyperglycemia and accelerated atherosclerosis, with high risk of micro- andmacrovascular complications. Circulating microvesicles (cMVs) are procoagulant cell fragments shed during activation/apoptosis anddiscussed to be markers of vascular dysfunction and hypercoagulability. Limited knowledge exists on hypercoagulability in youngdiabetics. We aimed to investigate cMVs over afive-year period in children/adolescents with type 1 diabetes compared withcontrols and any associations with glycemic control and cardiovascular risk factors. We hypothesized increased shedding of cMVsin type 1 diabetes in response to vascular activation.Methods. The cohort included type 1 diabetics (n=40) and healthy controls(n=40), mean age 14 years (range 11) at inclusion, randomly selected from the Norwegian Atherosclerosis and ChildhoodDiabetes (ACD) study. Citrated plasma was prepared and stored at -80°C until cMV analysis byflow cytometry.Results.Comparable levels of Annexin V (AV+) cMVs were observed at inclusion. Atfive-year follow-up, total AV+cMVs weresignificantly lower in subjects with type 1 diabetes compared with controls; however, no significant differences were observed afteradjusting for covariates. In the type 1 diabetes group, the total AV+, tissue factor-expressing AV+/CD142+, neutrophil-derivedAV+/CD15+and AV+/CD45+/CD15+, and endothelial-derived AV+/CD309+and CD309+/CD34+cMVs were inversely correlatedwith HbA1c (r=‐0:437,r=‐0:515,r=‐0:575,r=‐0:529,r=‐0:416,andr=‐0:445, respectively; allp≤0:01), however, only atinclusion. No significant correlations with cardiovascular risk factors were observed.Conclusions. Children/adolescents with type1 diabetes show similar levels of AV+cMVs as healthy controls and limited associations with glucose control. This indicatesthat our young diabetics on intensive insulin treatment have preserved vascular homeostasis and absence of procoagulant cMVs.

• Weider, Therese; Richardson, Sarah; Morgan, Noel; Paulsen, Trond; Dahl-Jørgensen, Knut & Hammerstad, Sara Salehi (2020). Upregulation of HLA Class i and Antiviral Tissue Responses in Hashimoto's Thyroiditis. Thyroid. ISSN 1050-7256. 30(3), p. 432–442. doi: 10.1089/thy.2019.0607. Full text in Research Archive Show summary

  Background: Hashimoto's thyroiditis (HT) is a common autoimmune disease of unknown origin. However, viral infections have been implicated as triggers for autoimmunity. Human leukocyte antigen (HLA) class I presents antigens to circulating immune cells and plays a crucial role in the defense against viral infections. This study aimed to investigate the presence of enterovirus and HLA class I expression in one of the largest HT thyroid tissue cohorts to date. In addition, viral receptors and viral immune response proteins were examined. Methods: Thyroid tissue samples from 46 HT patients were obtained using core needle biopsy. Thyroid tissue collected during neck surgery for other reasons than thyroid autoimmunity served as controls. Standard immunohistochemistry on formalin-fixed, paraffin-embedded tissue samples were used to detect HLA class I, enteroviral capsid protein 1 (VP1), and coxsackie and adenovirus receptor (CAR) in thyroid cells. A subset of the samples was examined with combined immunofluorescence staining for signal transducer and activator of transcription 1 (STAT1) and protein kinase R (PKR). Results: Significantly more HLA class I-positive samples were found in the HT group (31 out of 46 [67.4%]) than in the control group (5 out of 24 [20.8%]) (p < 0.001). Moreover, the semiquantitative score assessing the grade of HLA class I expression was significantly higher in the HT group (3.9 ± 3.1) than in the control group (0.5 ± 0.9) (p < 0.001). In addition, STAT1 was colocalized with HLA class I, and PKR and VP1 were also found and were colocalized together. VP1 was detected in both controls and the HT samples, with slightly more VP1+ thyroid cells in the HT samples (20.1% ± 16.4%) than in controls (14.9% ± 10.5%). Finally, the presence of CAR in thyroid cells was confirmed. Conclusion: The current study confirmed that HLA class I hyperexpression is a defining feature of HT. Thyroid cells express CAR, thus making them susceptible to enterovirus infection. The colocalization of HLA class I with STAT1 and VP1 with PKR indicates an intracellular, antiviral host response. These findings support the concept of a firm link between viral infection and autoimmune thyroid diseases.

• Veiby, Nina; Simeunovic, Aida; Heier, Martin; Brunborg, Cathrine; Saddique, Naila & Moe, Morten Carsten [Show all 9 contributors for this article] (2020). Associations between macular OCT angiography and nonproliferative diabetic retinopathy in young patients with type 1 diabetes mellitus. Journal of Diabetes Research. ISSN 2314-6745. 2020, p. 1–12. doi: 10.1155/2020/8849116. Full text in Research Archive Show summary

  Background/Objective. Optical coherence tomography angiography (OCTA) is increasingly used to supplement ophthalmoscopy in the diagnosis and follow-up of diabetic retinopathy. Our objective was to confirm if OCTA parameters can predict the development of nonproliferative diabetic retinopathy (NPDR) and to clarify if any single OCTA parameter is associated with NPDR independently of well-known risk factors in young type 1 diabetes (T1D) patients. Methods. OCTA of both eyes was performed in a cross-sectional study of 14 to 30-year-old individuals with at least 10-year duration of T1D and controls recruited from the Norwegian Atherosclerosis and Childhood Diabetes (ACD) study. Vessel density (VD) and foveal avascular zone (FAZ) area in the superficial and deep capillary plexus (SCP and DCP), total retinal volume (TRV), and central macular thickness (CMT) were calculated using automated software. Univariate and multivariate ordered logistic regression (OLR) models were used accordingly. Results. We included 168 control eyes and 315 T1D eyes. Lower VD in DCP (OR 0.65, 95% CI 0.51–0.83), longer diabetes duration (OR 1.51, 95% CI 1.22–1.87), and higher waist circumference (OR 1.08, 95% CI 1.02–1.14) were significantly associated with progression of NPDR. VD in SCP and DCP were significantly lower in T1D patients without diabetic retinopathy than in controls. Conclusions. Sparser VD in DCP is significantly associated with severity of NPDR, supporting that OCTA might detect the earliest signs of NPDR before it is visible by ophthalmoscopy.

• Anderzén, Johan; Hermann, Julia M.; Samuelsson, Ulf; Charalampopoulos, Dimitrios; Svensson, Jannet & Skrivarhaug, Torild [Show all 27 contributors for this article] (2020). International benchmarking in type 1 diabetes: Large difference in childhood HbA1c between eight high-income countries but similar rise during adolescence—A quality registry study. Pediatric Diabetes. ISSN 1399-543X. 21(4), p. 621–627. doi: 10.1111/pedi.13014. Full text in Research Archive
• Russell, Mark A.; Redick, Sambra; Blodgett, David M.; Richardson, Sarah J.; Leete, Pia & Krogvold, Lars [Show all 20 contributors for this article] (2019). HLA class II antigen processing and presentation pathway components demonstrated by transcriptome and protein analyses of islet ?-cells from donors with type 1 diabetes. Diabetes. ISSN 0012-1797. 68(5), p. 988–1001. doi: 10.2337/db18-0686. Full text in Research Archive
• Wisting, Line Norøm; Rø, Astrid Valborg; Skrivarhaug, Torild; Dahl-Jørgensen, Knut & Rø, Øyvind (2019). Disturbed eating, illness perceptions, and coping among adults with type 1 diabetes on intensified insulin treatment, and their associations with metabolic control. Journal of Health Psychology. ISSN 1359-1053. p. 1–13. doi: 10.1177/1359105319840688. Full text in Research Archive Show summary

  This study investigated associations between psychological aspects and metabolic control among adults with type 1 diabetes (n = 282). Linear regression analyses demonstrated that the illness perception personal control and the coping strategy seeking emotional social support explained 23.2 percent of the variance in hemoglobin A1c among females (β = 0.40, p < 0.001 and β = −0.22, p < 0.01, respectively). Among males, only personal control remained significant, explaining 13.9 percent of the variance in hemoglobin A1c (β = 0.37, p < 0.001). The associations between psychological correlates and hemoglobin A1c indicate that addressing such aspects clinically may facilitate metabolic control, thereby potentially contributing to reduce the risk of complications.

• Seiron, Peter; Wiberg, Anna; Kuric, Enida; Krogvold, Lars; Jahnsen, Frode Lars & Dahl-Jørgensen, Knut [Show all 8 contributors for this article] (2019). Characterisation of the endocrine pancreas in type 1 diabetes: islet size is maintained but islet number is markedly reduced. The journal of pathology. Clinical research. 5(4), p. 248–255. doi: 10.1002/cjp2.140. Full text in Research Archive
• Rajendran, Sakthi; Anquetil, Florence; Quesada-Masachs, Estefania; Graef, Madeleine; Gonzalez, Nathaly & McArdle, Sara [Show all 10 contributors for this article] (2019). IL-6 is present in beta and alpha cells in human pancreatic islets: Expression is reduced in subjects with type 1 diabetes. Clinical Immunology. ISSN 1521-6616. 211. doi: 10.1016/j.clim.2019.108320. Full text in Research Archive
• Wisting, Line Norøm; Wonderlich, Joseph; Skrivarhaug, Torild; Dahl-Jørgensen, Knut & Rø, Øyvind (2019). Psychometric properties and factor structure of the diabetes eating problem survey - revised (DEPS-R) among adult males and females with type 1 diabetes. Journal of Eating Disorders. 7:2, p. 1–7. doi: 10.1186/s40337-018-0232-0. Full text in Research Archive Show summary

  Background Although an increasing amount of research has now established good psychometric properties and a three-component factor structure of the Diabetes Eating Problem Survey – Revised (DEPS-R) in pediatric samples with type 1 diabetes (T1D), research using adult samples has been limited and divergent. This study therefore aimed to investigate psychometric properties and test a three-factor model of the DEPS-R among adults with T1D. Methods A total of 282 adults with T1D aged 18–79 years participated in the study. Measures included the DEPS-R, the Eating Disorder Examination Questionnaire (EDE-Q), and clinical data from the Norwegian Quality Improvement of Laboratory Examinations (NOKLUS) system. Results The DEPS-R total mean score (SD) for the total sample, males, and females were 13.8 (9.2), 11.2 (7.8), and 15.6 (9.6) respectively. Good fit indices for the confirmatory factor analysis were found. The Cronbach’s alpha of the DEPS-R was .84, suggesting good internal consistency. The DEPS-R correlated significantly with the EDE-Q among both males (.52, p < .01) and females (.68, p < .001). Also, the DEPS-R correlated significantly with BMI in both genders (.33, p < .001 in females and .35, p < .001 in males). HbA1c correlated significantly with the DEPS-R in females (.27, p < .01), but not in males. Conclusions Good fit for a three-factor structure of the DEPS-R was confirmed. Further, the DEPS-R demonstrated good psychometric properties among adults with T1D, and can be recommended for clinical use for this patient group.

• Dunne, Jessica L.; Richardson, Sarah J.; Atkinson, Mark A.; Craig, Maria E.; Dahl-Jørgensen, Knut & Flodström-Tullberg, Malin [Show all 12 contributors for this article] (2019). Rationale for enteroviral vaccination and antiviral therapies in human type 1 diabetes. Diabetologia. ISSN 0012-186X. 62(5), p. 744–753. doi: 10.1007/s00125-019-4811-7. Full text in Research Archive Show summary

  In type 1 diabetes, pancreatic beta cells are destroyed by chronic autoimmune responses. The disease develops in genetically susceptible individuals, but a role for environmental factors has been postulated. Viral infections have long been considered as candidates for environmental triggers but, given the lack of evidence for an acute, widespread, cytopathic effect in the pancreas in type 1 diabetes or for a closely related temporal association of diabetes onset with such infections, a role for viruses in type 1 diabetes remains unproven. Moreover, viruses have rarely been isolated from the pancreas of individuals with type 1 diabetes, mainly (but not solely) due to the inaccessibility of the organ. Here, we review past and recent literature to evaluate the proposals that chronic, recurrent and, possibly, persistent enteroviral infections occur in pancreatic beta cells in type 1 diabetes. We also explore whether these infections may be sustained by different virus strains over time and whether multiple viral hits can occur during the natural history of type 1 diabetes. We emphasise that only a minority of beta cells appear to be infected at any given time and that enteroviruses may become replication defective, which could explain why they have been isolated from the pancreas only rarely. We argue that enteroviral infection of beta cells largely depends on the host innate and adaptive immune responses, including innate responses mounted by beta cells. Thus, we propose that viruses could play a role in type 1 diabetes on multiple levels, including in the triggering and chronic stimulation of autoimmunity and in the generation of inflammation and the promotion of beta cell dysfunction and stress, each of which might then contribute to autoimmunity, as part of a vicious circle. We conclude that studies into the effects of vaccinations and/or antiviral drugs (some of which are currently on-going) is the only means by which the role of viruses in type 1 diabetes can be finally proven or disproven.

• Reddy, Shiva; Krogvold, Lars; Martin, Charlton; Holland, Rebecca; Choi, Jaimin & Woo, Hannah [Show all 8 contributors for this article] (2018). Distribution of IL-1β immunoreactive cells in pancreatic biopsies from living volunteers with new-onset type 1 diabetes: comparison with donors without diabetes and with longer duration of disease. Diabetologia. ISSN 0012-186X. 61(6), p. 1362–1373. doi: 10.1007/s00125-018-4600-8. Full text in Research Archive Show summary

  Aims/hypothesis Although IL-1β is considered a key mediator of beta cell destruction, its cellular expression in islets during early type 1 diabetes remains unclear. We compared its expression in rare pancreatic biopsies from new-onset living volunteers with its expression in cadaveric pancreas sections from non-diabetic autoantibody-positive and -negative individuals and those with long-standing disease. Methods Pancreatic biopsy sections from six new-onset living volunteers (group 1) and cadaveric sections from 13 non-diabetic autoantibody-negative donors (group 2), four non-diabetic autoantibody-positive donors (group 3) and nine donors with diabetes of longer duration (0.25–12 years of disease; group 4) were triple-immunostained for IL-1β, insulin and glucagon. Intra- and peri-islet IL-1β-positive cells in insulin-positive and -negative islets and in random exocrine fields were enumerated. Results The mean number of IL-1β-positive cells per islet from each donor in peri- and intra-islet regions was <1.25 and <0.5, respectively. In all study groups, the percentage of islets with IL-1β cells in peri- and/or intra-islet regions was highly variable and ranged from 4.48% to 17.59% in group 1, 1.42% to 44.26% in group 2, 7.93% to 17.53% in group 3 and 3.85% to 42.86% in group 4, except in a single case where the value was 75%. In 25/32 donors, a higher percentage of islets showed IL-1β-positive cells in peri-islet than in intra-islet regions. In sections from diabetic donors (groups 1 and 4), a higher mean number of IL-1β-positive cells occurred in insulin-positive islets than in insulin-negative islets. In group 2, 70–90% of islets in 3/13 sections had weak-to-moderate IL-1β staining in alpha cells but staining was virtually absent or substantially reduced in the remaining groups. The mean number of exocrine IL-1β-positive cells in group 1 was lower than in the other groups. Conclusions/interpretation At onset of type 1 diabetes, the low number of islet-associated IL-1β-positive cells may be insufficient to elicit beta cell destruction. The variable expression in alpha cells in groups 2–4 suggests their cellular heterogeneity and probable physiological role. The significance of a higher but variable number of exocrine IL-1β-positive cells seen in non-diabetic individuals and those with long-term type 1 diabetes remains unclear.

• Horwitz, Elad; Krogvold, Lars; Zhitomirsky, Sophia; Swisa, Avital; Fischman, Maya & Lax, Tsuria [Show all 17 contributors for this article] (2018). B-cell DNA damage response promotes islet inflammation in type 1 diabetes. Diabetes. ISSN 0012-1797. 67(11), p. 2305–2318. doi: 10.2337/db17-1006. Full text in Research Archive
• Kuric, Enida; Krogvold, Lars; Hanssen, Kristian Folkvord; Dahl-Jørgensen, Knut; Skog, Oskar & Korsgren, Olle (2018). No evidence for presence of mucosal-associated invariant T cells in the insulitic lesions in patients recently diagnosed with Type 1 diabetes. American Journal of Pathology. ISSN 0002-9440. 188(8), p. 1744–1748. doi: 10.1016/j.ajpath.2018.04.009. Full text in Research Archive
• Holm, Laurits J.; Krogvold, Lars; Hasselby, Jane P.; Kaur, Simranjeet; Claessens, Laura A. & Russell, Mark A. [Show all 15 contributors for this article] (2018). Abnormal islet sphingolipid metabolism in type 1 diabetes. Diabetologia. ISSN 0012-186X. 61(7), p. 1650–1661. doi: 10.1007/s00125-018-4614-2. Full text in Research Archive Show summary

  Aims/hypothesis Sphingolipids play important roles in beta cell physiology, by regulating proinsulin folding and insulin secretion and in controlling apoptosis, as studied in animal models and cell cultures. Here we investigate whether sphingolipid metabolism may contribute to the pathogenesis of human type 1 diabetes and whether increasing the levels of the sphingolipid sulfatide would prevent models of diabetes in NOD mice. Methods We examined the amount and distribution of sulfatide in human pancreatic islets by immunohistochemistry, immunofluorescence and electron microscopy. Transcriptional analysis was used to evaluate expression of sphingolipid-related genes in isolated human islets. Genome-wide association studies (GWAS) and a T cell proliferation assay were used to identify type 1 diabetes related polymorphisms and test how these affect cellular islet autoimmunity. Finally, we treated NOD mice with fenofibrate, a known activator of sulfatide biosynthesis, to evaluate the effect on experimental autoimmune diabetes development. Results We found reduced amounts of sulfatide, 23% of the levels in control participants, in pancreatic islets of individuals with newly diagnosed type 1 diabetes, which were associated with reduced expression of enzymes involved in sphingolipid metabolism. Next, we discovered eight gene polymorphisms (ORMDL3, SPHK2, B4GALNT1, SLC1A5, GALC, PPARD, PPARG and B4GALT1) involved in sphingolipid metabolism that contribute to the genetic predisposition to type 1 diabetes. These gene polymorphisms correlated with the degree of cellular islet autoimmunity in a cohort of individuals with type 1 diabetes. Finally, using fenofibrate, which activates sulfatide biosynthesis, we completely prevented diabetes in NOD mice and even reversed the disease in half of otherwise diabetic animals. Conclusions/interpretation These results indicate that islet sphingolipid metabolism is abnormal in type 1 diabetes and suggest that modulation may represent a novel therapeutic approach.

• Charalampopoulos, Dimitrios; Hermann, Julia M.; Svensson, Jannet; Skrivarhaug, Torild; Maahs, David M. & Åkesson, Karin [Show all 24 contributors for this article] (2018). Exploring variation in glycemic control across and within eight high-income countries: A cross sectional analysis of 64,666 children and adolescents with type 1 diabetes. Diabetes Care. ISSN 0149-5992. 41(6), p. 1180–1187. doi: 10.2337/dc17-2271. Full text in Research Archive
• Anquetil, Florence; Mondanelli, Giada; Gonzalez, Nathaly; Calvo, Teresa Rodriguez; Gonzalo, Jose Zapardiel & Krogvold, Lars [Show all 11 contributors for this article] (2018). Loss of IDO1 expression from human pancreatic β-cells precedes their destruction during the development of Type 1 diabetes. Diabetes. ISSN 0012-1797. 67(9), p. 1858–1866. doi: 10.2337/db17-1281. Full text in Research Archive
• Colli, Maikel L.; Hill, Jessica L.E.; Marroqui, Laura; Chaffey, Jessica; Santos, Reinaldo S. Dos & Leete, Pia [Show all 17 contributors for this article] (2018). PDL1 is expressed in the islets of people with type 1 diabetes and is up-regulated by interferons-α and-γ via IRF1 induction. EBioMedicine. 36, p. 367–375. doi: 10.1016/j.ebiom.2018.09.040. Full text in Research Archive
• Heier, Martin; Stensæth, Knut Haakon; Brunborg, Cathrine; Seljeflot, Ingebjørg; Margeirsdottir, Hanna Dis & Hanssen, Kristian Folkvord [Show all 7 contributors for this article] (2018). Increased arterial stiffness in childhood onset diabetes: A cardiovascular magnetic resonance study. European Heart Journal-Cardiovascular Imaging. ISSN 2047-2404. 19(6), p. 694–700. doi: 10.1093/ehjci/jex178. Full text in Research Archive
• Wisting, Line Norøm; Skrivarhaug, Torild; Dahl-Jørgensen, Knut & Rø, Øyvind (2018). Prevalence of disturbed eating behavior and associated symptoms of anxiety and depression among adult males and females with type 1 diabetes. Journal of Eating Disorders. 6(28), p. 1–10. doi: 10.1186/s40337-018-0209-z. Full text in Research Archive Show summary

  Background The increased prevalence of disturbed eating behaviors (DEB), depression, and anxiety in type 1 diabetes (T1D) is generally well established; however the majority of existing research to date has focused on female adolescents and young adults. Data on males and older females is scarce. The aim of this study was to assess prevalence of DEB and symptoms of depression and anxiety among adult males and females with type 1 diabetes, to investigate differences between individuals scoring below and above the cut-off on psychopathology, and to examine patterns of eating disorder psychopathology by age and weight. Methods A total of 282 adults with type 1 diabetes aged 18–79 years participated in the study. Measures included the Diabetes Eating Problem Survey – Revised (DEPS-R), the Hospital Anxiety and Depression Scale (HADS), and clinical data from the Norwegian Quality Improvement of Laboratory Examinations (NOKLUS) system. Results A total of 20.3% of the whole sample (13.3% among males and 24.8% among females) scored above the DEPS-R cut-off score for DEB. As for depression and anxiety, the prevalence in the whole sample was 6.2% and 19.0%, respectively. The prevalence was generally higher in females than males across all psychopathology measures. HbA1c was significantly associated with the DEPS-R total score (p < .01) among females, but not with depression and anxiety. Mean DEPS-R score decreased with increasing age, and when our previous reported data from children and adolescents are included, a peak prevalence in DEB in adolescence and young adult age is demonstrated. Conclusions The results of this study point to the need for increased awareness of psychological comorbidity among adults with type 1 diabetes, in particular young adult females. Screening is recommended to secure early detection and subsequent intervention for these individuals.

• Vecchio, Federica; Buono, Nicola Lo; Stabilini, Angela; Nigi, Laura; Dufort, Matthew J. & Geyer, Susan [Show all 23 contributors for this article] (2018). Abnormal neutrophil signature in the blood and pancreas of presymptomatic and symptomatic type 1 diabetes. JCI Insight. 3(18), p. 1–17. doi: 10.1172/jci.insight.122146. Full text in Research Archive
• Heier, Martin; Nygaard, Cathrine Skorpen; Brunborg, Cathrine; Seljeflot, Ingebjørg; MARGEIRSDOTTIR, HANNA DIS & Hanssen, Kristian Folkvord [Show all 8 contributors for this article] (2018). Preserved endothelial function in young adults with type 1 diabetes. PLOS ONE. 13:e0206523(10), p. 1–8. doi: 10.1371/journal.pone.0206523. Full text in Research Archive Show summary

  Background and aim Endothelial dysfunction is involved in the pathogenesis of atherosclerosis and is typically present in older adults with type 1 diabetes (T1D). In young adults, we aimed to assess the impact of T1D on endothelial function as detected by digital peripheral arterial tonometry (PAT) and its relationship with cardiovascular risk factors and long term glycemic control. Materials and methods Reactive hyperemia index (RHI) as a measure of endothelial function was assessed by PAT in 46 T1D patients and 32 healthy controls. All were participants in the "Atherosclerosis and Childhood Diabetes" study, with baseline values registered five years previously. Annual measurements of HbA1c for assessment of glycemic burden were provided by the Norwegian Childhood Diabetes Registry. Results The diabetes patients had a mean age of 20.8 years, a median duration of diabetes of 10.0 years and a mean HbA1c of 8.7%. RHI was not significantly decreased in the diabetes group, mean 2.00 (SD = 0.59) vs. 2.21 (SD = 0.56), p = .116. There was no gender difference or any associations with traditional risk factors. Furthermore, there was no significant association between RHI and either HbA1c or long term glycemic burden. Conclusions RHI as a measure of endothelial function was preserved in young adults with T1D compared with healthy controls.

• Lundberg, Marcus; Lindqvist, Andreas; Wierup, Nils; Krogvold, Lars; Dahl-Jørgensen, Knut & Skog, Oskar (2017). The density of parasympathetic axons is reduced in the exocrine pancreas of individuals recently diagnosed with type 1 diabetes. PLOS ONE. 12(6). doi: 10.1371/journal.pone.0179911. Full text in Research Archive
• Rodriguez-Calvo, Teresa; Zapardiel-Gonzalo, Jose; Amirian, Natalie; Castillo, Ericka; Lajevardi, Yasaman & Krogvold, Lars [Show all 8 contributors for this article] (2017). Increase in pancreatic proinsulin and preservation of β-cell mass in autoantibody-positive donors prior to type 1 diabetes onset. Diabetes. ISSN 0012-1797. 66(5), p. 1334–1345. doi: 10.2337/db16-1343. Full text in Research Archive Show summary

  Type 1 diabetes is characterized by the loss of insulin production caused by β-cell dysfunction and/or destruction. The hypothesis that β-cell loss occurs early during the prediabetic phase has recently been challenged. Here we show, for the first time in situ, that in pancreas sections from autoantibody-positive (Ab+) donors, insulin area and β-cell mass are maintained before disease onset and that production of proinsulin increases. This suggests that β-cell destruction occurs more precipitously than previously assumed. Indeed, the pancreatic proinsulin-to-insulin area ratio was also increased in these donors with prediabetes. Using high-resolution confocal microscopy, we found a high accumulation of vesicles containing proinsulin in β-cells from Ab+ donors, suggesting a defect in proinsulin conversion or an accumulation of immature vesicles caused by an increase in insulin demand and/or a dysfunction in vesicular trafficking. In addition, islets from Ab+ donors were larger and contained a higher number of β-cells per islet. Our data indicate that β-cell mass (and function) is maintained until shortly before diagnosis and declines rapidly at the time of clinical onset of disease. This suggests that secondary prevention before onset, when β-cell mass is still intact, could be a successful therapeutic strategy. © 2017 American Diabetes Association

• Wisting, Line Norøm; Reas, Deborah; Bang, Lasse; Skrivarhaug, Torild; Dahl-Jørgensen, Knut & Rø, Øyvind (2017). Eating patterns in adolescents with type 1 diabetes: Associations with metabolic control, insulin omission, and eating disorder pathology. Appetite. ISSN 0195-6663. 114, p. 226–231. doi: 10.1016/j.appet.2017.03.035. Full text in Research Archive Show summary

  Objective: The purpose of this study was to investigate eating patterns among male and female adolescents with type 1 diabetes (T1D), and the associations with age, zBMI, eating disorder (ED) pathology, intentional insulin omission, and metabolic control. Method: The sample consisted of 104 adolescents (58.6% females) with child-onset T1D, mean age of 15.7 years (SD 1.8) and mean zBMI of 0.4 (SD 0.8). The Child Eating Disorder Examination (ChEDE) assessed meal/snack frequency and ED pathology. T1D clinical data was obtained from the Norwegian Childhood Diabetes Registry. Results: A significantly lower proportion of females than males (73.8% vs 97.7%) consumed breakfast on a daily basis. Approximately 50% of both genders ate lunch and 90% ate dinner daily. Among females, skipping breakfast was significantly associated with higher global ED psychopathology, shape concerns, self-induced vomiting, binge eating, insulin omission due to shape/weight concerns, and poorer metabolic control. Less frequent lunch consumption was significantly associated with poorer metabolic control. Skipping dinner was significantly associated with older age, higher dietary restraint, eating concerns, self-induced vomiting, and insulin omission. Among males, less frequent consumption of lunch and evening snacks was associated with attitudinal features of ED, including shape/weight concerns and dietary restraint. Discussion: Among adolescents with T1D, irregular or infrequent meal consumption appears to signal potential ED pathology, as well as being associated with poorer metabolic control. These findings suggest the importance of routinely assessing eating patterns in adolescents with T1D to improve detection of ED pathology and to facilitate improved metabolic control and the associated risk of somatic complications.

• Martin, Charlton; Krogvold, Lars; Farik, Shebani; Amirapu, Satya; Wu, Fiona & Reddy, Shiva [Show all 7 contributors for this article] (2017). An immunohistochemical study of nitrotyrosine expression in pancreatic islets of cases with increasing duration of type 1 diabetes and without diabetes. Histochemistry and Cell Biology. ISSN 0948-6143. 147(5), p. 605–623. doi: 10.1007/s00418-016-1533-5. Full text in Research Archive
• Kuric, Enida; Seiron, Peter; Krogvold, Lars; Edwin, Bjørn; Buanes, Trond & Hanssen, Kristian Folkvord [Show all 9 contributors for this article] (2017). Demonstration of tissue resident memory CD8 T cells in insulitic lesions in adult patients with recent-onset type 1 diabetes. American Journal of Pathology. ISSN 0002-9440. 187(3), p. 581–588. doi: 10.1016/j.ajpath.2016.11.002. Full text in Research Archive
• Heier, Martin; Borja, Mark S.; Brunborg, Cathrine; Seljeflot, Ingebjørg; MARGEIRSDOTTIR, HANNA DIS & Hanssen, Kristian Folkvord [Show all 8 contributors for this article] (2017). Reduced HDL function in children and young adults with type 1 diabetes. Cardiovascular Diabetology. 16:85, p. 1–8. doi: 10.1186/s12933-017-0570-2. Full text in Research Archive Show summary

  Background Patients with type 1 diabetes (T1D) are at increased risk of cardiovascular disease (CVD). Measures of high-density lipoprotein (HDL) function provide a better risk estimate for future CVD events than serum levels of HDL cholesterol. The objective of this study was to evaluate HDL function in T1D patients shortly after disease onset compared with healthy control subjects. Methods Participants in the atherosclerosis and childhood diabetes study were examined at baseline and after 5 years. At baseline, the cohort included 293 T1D patients with a mean age of 13.7 years and mean HbA1c of 8.4%, along with 111 healthy control subjects. Their HDL function, quantified by HDL-apoA-I exchange (HAE), was assessed at both time points. HAE is a measure of HDL’s dynamic property, specifically its ability to release lipid-poor apolipoprotein A-I (apoA-I), an essential step in reverse cholesterol transport. Results The HAE-apoA-I ratio, reflecting the HDL function per concentration unit apoA-I, was significantly lower in the diabetes group both at baseline, 0.33 (SD = 0.06) versus 0.36 (SD = 0.06) %HAE/mg/dL, p < 0.001 and at follow-up, 0.34 (SD = 0.06) versus 0.36 (SD = 0.06)  %HAE/mg/dL, p = 0.003. HAE-apoA-I ratio was significantly and inversely correlated with HbA1c in the diabetes group. Over the 5 years of the study, the mean HAE-apoA-I ratio remained consistent in both groups. Individual changes were less than 15% for half of the study participants. Conclusions This study shows reduced HDL function, quantified as HAE-apoA-I ratio, in children and young adults with T1D compared with healthy control subjects. The differences in HDL function appeared shortly after disease onset and persisted over time.

• Viken, Marte K; Flåm, Siri Tennebø; Skrivarhaug, Torild; Amundsen, Silja Svanstrøm; Sollid, Ludvig Magne & Drivvoll, Ann Kristin [Show all 9 contributors for this article] (2017). HLA class II alleles in Norwegian patients with coexisting type 1 diabetes and celiac disease. HLA. ISSN 2059-2302. 89(5), p. 278–284. doi: 10.1111/tan.12986. Full text in Research Archive
• Brunvand, Leif; Heier, Martin; Brunborg, Cathrine; Hanssen, Kristian Folkvord; Fugelseth, Drude & STENSÆTH, KNUT HAAKON [Show all 8 contributors for this article] (2017). Advanced glycation end products in children with type 1 diabetes and early reduced diastolic heart function. BMC Cardiovascular Disorders. 17(133). doi: 10.1186/s12872-017-0551-0. Full text in Research Archive Show summary

  Background Reduced diastolic function is an early sign of diabetes cardiomyopathy in adults and is associated with elevated levels of HbA1c and advanced glycation end products (AGEs). Objective To assess the associations between early reduced diastolic function and elevated levels of HbA1c and AGEs in children and adolescents with type 1 diabetes (T1D). Methods One hundred fourty six T1D patients (age 8–18 years) without known diabetic complications were examined with tissue Doppler imaging and stratified into two groups according to diastolic function. A clinical examination and ultrasound of the common carotid arteries were performed. Methylglyoxal-derived hydroimidazolone-1 (MG-H1) was measured by immunoassay. Results At inclusion, 36 (25%) participants were stratified into a low diastolic function group (E’/A’-ratio < 2.0). Compared to the rest of the T1D children, these participants had higher body mass index (BMI), 22.8 (SD = 4.0) vs. 20.1 (SD = 3.4) kg/m2, p < 0.001, higher systolic blood pressure 104.2 (SD = 8.7) vs. 99.7 (SD = 9.3) mmHg, p = 0.010, and higher diastolic blood pressure, 63.6 (SD = 8.3) vs. 59.9 (SD = 7.9) mmHg, p = 0.016. The distensibility coefficient was lower, 0.035 (SD = 0.010) vs. 0.042 (SD = 0.02) kPa−1, p = 0.013, Young’s modulus higher, 429 (SD = 106) vs. 365 (SD = 143), p = 0.009, and MG-H1 higher, 163.9 (SD = 39.2) vs. 150.3 (SD = 33.4) U/ml, p = 0.046. There was no difference in carotid intima-media thickness between the groups. There were no associations between reduced diastolic function and years from diagnosis, HBA1c, mean HBA1c, CRP or calculated glycemic burden. Logistic regression analysis showed that BMI was an independent risk factor for E’/A’-ratio as well as a non-significant, but relatively large effect size for MG-H1, indicating a possible role for AGEs. Conclusions Early signs of reduced diastolic function in children and adolescents with T1D had higher BMI, but not higher HbA1c. They also had elevated serum levels of the advanced glycation end product MG-H1, higher blood pressure and increased stiffness of the common carotid artery, but these associations did not reach statistical significance when tested in a logistic regression model.

• Wisting, Line Norøm; Bang, Lasse; Skrivarhaug, Torild; Dahl-Jørgensen, Knut & Rø, Øyvind (2016). Psychological barriers to optimal insulin therapy: More concerns in adolescent females than males. BMJ Open Diabetes Research & Care. 4(1). doi: 10.1136/bmjdrc-2016-000203. Full text in Research Archive
• Leete, Pia; Willcox, Abby; Krogvold, Lars; Dahl-Jørgensen, Knut; Foulis, Alan K. & Richardson, Sarah J. [Show all 7 contributors for this article] (2016). Differential insulitic profiles determine the extent of β-cell destruction and the age at onset of type 1 diabetes. Diabetes. ISSN 0012-1797. 65(5), p. 1362–1369. doi: 10.2337/db15-1615. Full text in Research Archive Show summary

  Type 1 diabetes (T1D) results from a T cell–mediated destruction of pancreatic β-cells following the infiltration of leukocytes (including CD8+, CD4+, and CD20+ cells) into and around pancreatic islets (insulitis). Recently, we reported that two distinct patterns of insulitis occur in patients with recent-onset T1D from the U.K. and that these differ principally in the proportion of infiltrating CD20+ B cells (designated CD20Hi and CD20Lo, respectively). We have now extended this analysis to include patients from the Network for Pancreatic Organ Donors with Diabetes (U.S.) and Diabetes Virus Detection (DiViD) study (Norway) cohorts and confirm that the two profiles of insulitis occur more widely. Moreover, we show that patients can be directly stratified according to their insulitic profile and that those receiving a diagnosis before the age of 7 years always display the CD20Hi profile. By contrast, individuals who received a diagnosis beyond the age of 13 years are uniformly defined as CD20Lo. This implies that the two forms of insulitis are differentially aggressive and that patients with a CD20Hi profile lose their β-cells at a more rapid rate. In support of this, we also find that the proportion of residual insulin-containing islets (ICIs) increases in parallel with age at the onset of T1D. Importantly, those receiving a diagnosis in, or beyond, their teenage years retain ∼40% ICIs at diagnosis, implying that a functional deficit rather than an absolute β-cell loss may be causal for disease onset in these patients. We conclude that appropriate patient stratification will be critical for correct interpretation of the outcomes of intervention therapies targeted to islet-infiltrating immune cells in T1D.

• Brunvand, Leif; Fugelseth, Drude; STENSÆTH, KNUT-HAAKON; Dahl-Jørgensen, Knut & MARGEIRSDOTTIR, HANNA DIS (2016). Early reduced myocardial diastolic function in children and adolescents with type 1 diabetes mellitus a population-based study. BMC Cardiovascular Disorders. 16(103). doi: 10.1186/s12872-016-0288-1. Full text in Research Archive Show summary

  Background Reduced diastolic myocardial function is an early sign of diabetic cardiomyopathy. The aim of this study was to test the hypothesis that children and adolescents with type 1 diabetes mellitus (T1D), but without other known complications, have early reduced diastolic myocardial function diagnosed with echocardiographic color tissue Doppler imaging (cTDI). Methods cTDI examination was carried out in 173 T1D patients and 62 age-matched controls. The T1D-patients were 8–18 years old with (mean (SD)) diabetes duration of 5.6 (3.4) years and HbA1c of 8.4 (1.3). All were treated with either insulin pumps or 4–6 daily insulin injections. cTDI early (E’) and late (A’) peak diastolic velocities and systolic peak velocity were measured from the lateral, septal, anterior and posterior mitral annulus and from the lateral tricuspidal annulus. Results Myocardial diastolic function was reduced in the T1D-patients with higher peak A’-velocity and lower E’/A’-ratio in all registrations. Overall mean (SD) mitral E’/A’-ratio was 2.3 (0.5) in T1D and 2.7 (0.6) in the controls (p < 0001). The overall mitral E’/A’-ratio was negative associated with blood pressure (BP) and body mass index (BMI). Stratifying all participants into three groups according to BMI (<25, 25–75, >75 centile, respectively), the T1D had lower E’/A’-values in all stratified groups, except for in the highest BMI-group where both T1D and controls had the lowest E’/A’-ratio. Systolic function did not differ in any of the measurements. There were no associations with sex, diabetes duration, carotid artery intima-media-thickness, vessel elasticity or HbA1c. Conclusion Diabetic children and adolescents using modern intensive insulin treatment had echocardiographic signs of reduced diastolic myocardial function despite short duration of disease. The reduced function was associated with higher BP and higher BMI.

• Lundberg, Marcus; Krogvold, Lars; Kuric, Enida; Dahl-Jørgensen, Knut & Skog, Oskar (2016). Expression of interferon-stimulated genes in insulitic pancreatic islets of patients recently diagnosed with type 1 diabetes. Diabetes. ISSN 0012-1797. 65(10), p. 3104–3110. doi: 10.2337/db16-0616. Full text in Research Archive Show summary

  A primary insult to the pancreatic islets of Langerhans, leading to the activation of innate immunity, has been suggested as an important step in the inflammatory process in type 1 diabetes (T1D). The aim of this study was to examine whether interferon (IFN)-stimulated genes (ISGs) are overexpressed in human T1D islets affected with insulitis. By using laser capture microdissection and a quantitative PCR array, 23 of 84 examined ISGs were found to be overexpressed by at least fivefold in insulitic islets from living patients with recent-onset T1D, participating in the Diabetes Virus Detection (DiViD) study, compared with islets from organ donors without diabetes. Most of the overexpressed ISGs, including GBP1, TLR3, OAS1, EIF2AK2, HLA-E, IFI6, and STAT1, showed higher expression in the islet core compared with the peri-islet area containing the surrounding immune cells. In contrast, the T-cell attractant chemokine CXCL10 showed an almost 10-fold higher expression in the peri-islet area than in the islet, possibly partly explaining the localization of T cells mainly to this region. In conclusion, insulitic islets from recent-onset T1D subjects show overexpression of ISGs, with an expression pattern similar to that seen in islets infected with virus or exposed to IFN-γ/interleukin-1β or IFN-α.

• Richardson, Sarah J.; Rodriguez-Calvo, Teresa; Gerling, Ivan C.; Mathews, Clayton E.; Kaddis, John S. & Russell, Mark A. [Show all 14 contributors for this article] (2016). Islet cell hyperexpression of HLA class I antigens: a defining feature in type 1 diabetes. Diabetologia. ISSN 0012-186X. 59(11), p. 2448–2458. doi: 10.1007/s00125-016-4067-4. Full text in Research Archive Show summary

  Aims/hypothesis Human pancreatic beta cells may be complicit in their own demise in type 1 diabetes, but how this occurs remains unclear. One potentially contributing factor is hyperexpression of HLA class I antigens. This was first described approximately 30 years ago, but has never been fully characterised and was recently challenged as artefactual. Therefore, we investigated HLA class I expression at the protein and RNA levels in pancreases from three cohorts of patients with type 1 diabetes. The principal aims were to consider whether HLA class I hyperexpression is artefactual and, if not, to determine the factors driving it. Methods Pancreas samples from type 1 diabetes patients with residual insulin-containing islets (n = 26) from the Network for Pancreatic Organ donors with Diabetes (nPOD), Diabetes Virus Detection study (DiViD) and UK recent-onset type 1 diabetes collections were immunostained for HLA class I isoforms, signal transducer and activator of transcription 1 (STAT1), NLR family CARD domain containing 5 (NLRC5) and islet hormones. RNA was extracted from islets isolated by laser-capture microdissection from nPOD and DiViD samples and analysed using gene-expression arrays. Results Hyperexpression of HLA class I was observed in the insulin-containing islets of type 1 diabetes patients from all three tissue collections, and was confirmed at both the RNA and protein levels. The expression of β2-microglobulin (a second component required for the generation of functional HLA class I complexes) was also elevated. Both ‘classical’ HLA class I isoforms (i.e. HLA-ABC) as well as a ‘non-classical’ HLA molecule, HLA-F, were hyperexpressed in insulin-containing islets. This hyperexpression did not correlate with detectable upregulation of the transcriptional regulator NLRC5. However, it was strongly associated with increased STAT1 expression in all three cohorts. Islet hyperexpression of HLA class I molecules occurred in the insulin-containing islets of patients with recent-onset type 1 diabetes and was also detectable in many patients with disease duration of up to 11 years, declining thereafter. Conclusions/interpretation Islet cell HLA class I hyperexpression is not an artefact, but is a hallmark in the immunopathogenesis of type 1 diabetes. The response is closely associated with elevated expression of STAT1 and, together, these occur uniquely in patients with type 1 diabetes, thereby contributing to their selective susceptibility to autoimmune-mediated destruction.

• Wisting, Line Norøm; Bang, Lasse; Natvig, Henrik; Skrivarhaug, Torild; Dahl-Jørgensen, Knut & Lask, Bryan [Show all 7 contributors for this article] (2016). Metabolic Control and Illness Perceptions in Adolescents with Type 1 Diabetes. Journal of Diabetes Research. ISSN 2314-6745. 2016. doi: 10.1155/2016/3486094. Full text in Research Archive
• Hodik, Monika; Anagandula, Mahesh; Fuxe, Jonas; Krogvold, Lars; Dahl-Jørgensen, Knut & Hyöty, Heikki [Show all 8 contributors for this article] (2016). Coxsackie-adenovirus receptor expression is enhanced in pancreas from patients with type 1 diabetes. BMJ Open Diabetes Research & Care. 4:219(1). doi: 10.1136/bmjdrc-2016-000219. Full text in Research Archive
• Wisting, Line Norøm; Bang, Lasse; Skrivarhaug, Torild; Dahl-Jørgensen, Knut & Rø, Øyvind (2015). Adolescents with type 1 diabetes - The impact of gender, age, and health-related functioning on eating disorder psychopathology. PLOS ONE. 10(11). doi: 10.1371/journal.pone.0141386. Full text in Research Archive
• Heier, Martin; MARGEIRSDOTTIR, HANNA DIS; Torjesen, Peter A; Seljeflot, Ingebjørg; STENSÆTH, KNUT-HAAKON & Gaarder, Mario [Show all 9 contributors for this article] (2015). The advanced glycation end product methylglyoxal-derived hydroimidazolone-1 and early signs of atherosclerosis in childhood diabetes. Diabetes & vascular disease research. ISSN 1479-1641. 12(2), p. 139–145. doi: 10.1177/1479164114560910. Full text in Research Archive
• Heier, Martin; MARGEIRSDOTTIR, HANNA DIS; Brunborg, Cathrine; Hanssen, Kristian Folkvord; Dahl-Jørgensen, Knut & Seljeflot, Ingebjørg (2015). Inflammation in childhood type-1 diabetes; influence of glycemic control. Atherosclerosis. ISSN 0021-9150. 238, p. 33–37. doi: 10.1016/j.atherosclerosis.2014.11.018. Full text in Research Archive
• Heier, Martin; MARGEIRSDOTTIR, HANNA DIS; Gaarder, Mario; STENSÆTH, KNUT-HAAKON; Brunborg, Cathrine & Torjesen, Peter A [Show all 9 contributors for this article] (2015). Soluble RAGE and atherosclerosis in youth with type 1 diabetes: A 5-year follow-up study. Cardiovascular Diabetology. 14(126). doi: 10.1186/s12933-015-0292-2. Full text in Research Archive Show summary

  Background: Advanced glycation end products (AGEs) play a role in the development of late complications and ath‑ erosclerosis in diabetes by engaging the receptor for advanced glycation end products, RAGE. Receptor binding leads to activation of the vascular endothelium and increased inflammation in the vessel wall. The soluble variants of the receptor, endogenous secretory RAGE (esRAGE) and the cleaved cell ‑ surface part of RAGE, which together comprise soluble RAGE (sRAGE), are suggested to have a protective effect acting as decoys for RAGE. We aimed to test whether high levels of soluble variants of RAGE could be protective against atherosclerosis development. Methods: Participants in the prospective atherosclerosis and childhood diabetes study were examined at baseline (aged 8–18) and at follow ‑ up after 5 years. Both sRAGE and esRAGE were measured by immunoassay in 299 patients with type 1 diabetes and 112 healthy controls at baseline and 241 patients and 128 controls at follow ‑ up. The AGEs methylglyoxal ‑ derived hydroimidazolone ‑ 1 (MG ‑ H1) and carboxymethyllysine (CML) were measured by immunoas‑ say. The surrogate markers of atherosclerosis assessed were carotid intima ‑ media thickness (cIMT ), C ‑ reactive protein (CRP) and Young’s modulus, measures of arterial wall thickness, inflammation and arterial stiffness, respectively. Results: Levels of sRAGE and esRAGE correlated strongly both at baseline and at follow ‑ up in both diabetes patients and controls. With increasing age, mean values of both variants declined, independent of gender, diabetes or pubertal stage. In the diabetes group, multiple regression analysis showed a positive association between both variants of solu ‑ ble RAGE and cIMT. There was no significant relationship with Young’s modulus, but a negative association between sRAGE at baseline and CRP at follow ‑ up. The ratios between the AGEs and the variants of soluble RAGE were increased in diabetes patients compared to controls. Conclusions: The results show a possible protective effect of high levels of sRAGE at baseline against inflammation 5 years later, but not on arterial stiffness or wall thickness, in this cohort of adolescents and young adults with T1D. Keywords: Advanced glycation end products, Receptor for advanced glycation end products, sRAGE, esRAGE, Atherosclerosis, Type 1 diabetes, CRP.

• Krogvold, Lars; Skog, Oskar; Sundström, Görel; Edwin, Bjørn; Buanes, Trond & Hanssen, Kristian Folkvord [Show all 10 contributors for this article] (2015). Function of isolated pancreatic islets from patients at onset of type 1 diabetes: Insulin secretion can be restored after some days in a nondiabetogenic environment in vitro results from the divid study. Diabetes. ISSN 0012-1797. 64(7), p. 2506–2512. doi: 10.2337/db14-1911. Full text in Research Archive
• Sveen, Kari Anne; Dahl-Jørgensen, Knut; STENSÆTH, KNUT-HAAKON; Angel, Kristin; Seljeflot, Ingebjørg & Sell, David R [Show all 8 contributors for this article] (2015). Glucosepane and oxidative markers in skin collagen correlate with intima media thickness and arterial stiffness in long-term type 1 diabetes. Journal of Diabetes and its Complications (JDC). ISSN 1056-8727. 29(3), p. 407–412. doi: 10.1016/j.jdiacomp.2014.12.011. Full text in Research Archive
• Krogvold, Lars; Wiberg, Anna; Edwin, Bjørn; Buanes, Trond; Jahnsen, Frode Lars & Hanssen, Kristian Folkvord [Show all 10 contributors for this article] (2015). Insulitis and characterisation of infiltrating T cells in surgical pancreatic tail resections from patients at onset of type 1 diabetes. Diabetologia. ISSN 0012-186X. 59(3), p. 492–501. doi: 10.1007/s00125-015-3820-4. Full text in Research Archive Show summary

  Aims/hypothesis It is thought that T cells play a major role in the immune-mediated destruction of beta cells in type 1 diabetes, causing inflammation of the islets of Langerhans (insulitis). The significance of insulitis at the onset of type 1 diabetes is debated, and the role of the T cells poorly understood. Methods In the Diabetes Virus Detection (DiViD) study, pancreatic tissue from six living patients with recent-onset type 1 diabetes was collected. The insulitis was characterised quantitatively by counting CD3+ T cells, and qualitatively by transcriptome analysis targeting 84 T and B lymphocyte genes of laser-captured microdissected islets. The findings were compared with gene expression in T cells collected from kidney biopsies from allografts with ongoing cellular rejection. Cytokine and chemokine release from isolated islets was characterised and compared with that from islets from nondiabetic organ donors. Results All six patients fulfilled the criteria for insulitis (5–58% of the insulin-containing islets in the six patients had ≥15 T cells/islet). Of all the islets, 36% contained insulin, with several resembling completely normal islets. The majority (61– 83%) of T cells were found as peri-insulitis rather than within the islet parenchyma. The expression pattern of T cell genes was found to be markedly different in islets compared with the rejected kidneys. The islet-infiltrating T cells showed only background levels of cytokine/chemokine release in vitro. Conclusions/interpretation Insulitis and a significant reserve reservoir for insulin production were present in all six cases of recent-onset type 1 diabetes. Furthermore, the expression patterns and levels of cytokines argue for a different role of the T cells in type 1 diabetes when compared with allograft rejection.

• Krogvold, Lars; Edwin, Bjørn; Buanes, Trond; Frisk, Gun; Skog, Oskar & Anagandula, Mahesh [Show all 19 contributors for this article] (2015). Detection of a low-grade enteroviral infection in the islets of langerhans of living patients newly diagnosed with type 1 diabetes. Diabetes. ISSN 0012-1797. 64(5), p. 1682–1687. doi: 10.2337/db14-1370. Full text in Research Archive Show summary

  The Diabetes Virus Detection study (DiViD) is the first to examine fresh pancreatic tissue at the diagnosis of type 1 diabetes for the presence of viruses. Minimal pancreatic tail resection was performed 3-9 weeks after onset of type 1 diabetes in six adult patients (age 24-35 years). The presence of enteroviral capsid protein 1 (VP1) and the expression of class I HLA were investigated by immunohistochemistry. Enterovirus RNA was analyzed from isolated pancreatic islets and from fresh-frozen whole pancreatic tissue using PCR and sequencing. Nondiabetic organ donors served as controls. VP1 was detected in the islets of all type 1 diabetic patients (two of nine controls). Hyperexpression of class I HLA molecules was found in the islets of all patients (one of nine controls). Enterovirus-specific RNA sequences were detected in four of six patients (zero of six controls). The results were confirmed in various laboratories. Only 1.7% of the islets contained VP1(+) cells, and the amount of enterovirus RNA was low. The results provide evidence for the presence of enterovirus in pancreatic islets of type 1 diabetic patients, which is consistent with the possibility that a low-grade enteroviral infection in the pancreatic islets contributes to disease progression in humans.

• Krogvold, Lars; Edwin, Bjørn; Buanes, Trond; Ludvigsson, Johnny; Korsgren, Olle & Hyöty, Heikki [Show all 9 contributors for this article] (2014). Pancreatic biopsy by minimal tail resection in live adult patients at the onset of type 1 diabetes: experiences from the DiViD study. Diabetologia. ISSN 0012-186X. 57(4), p. 841–843. doi: 10.1007/s00125-013-3155-y. Full text in Research Archive
• Hammerstad, Sara Salehi; Jahnsen, Frode Lars; Tauriainen, Sisko; Hyöty, Heikki; Paulsen, Trond Harder & Nordheim, Ingrid [Show all 7 contributors for this article] (2014). Immunological changes and increased expression of myxovirus resistance protein A in thyroid tissue of patients with recent onset and untreated graves' disease. Thyroid. ISSN 1050-7256. 24(3), p. 537–544. doi: 10.1089/thy.2013.0287. Full text in Research Archive
• Sveen, Kari Anne; Nerdrum, Tone; Hanssen, Kristian Folkvord; Brekke, Magne; Torjesen, Peter A & Strauch, Christopher M [Show all 10 contributors for this article] (2014). Impaired left ventricular function and myocardial blood flow reserve in patients with long-term type 1 diabetes and no significant coronary artery disease: Associations with protein glycation. Diabetes & vascular disease research. ISSN 1479-1641. 11(2), p. 84–91. doi: 10.1177/1479164113518805. Full text in Research Archive
• Skog, Oskar; Korsgren, Stella; Wiberg, Anna; Danielsson, Angelika; Edwin, Bjørn & Buanes, Trond [Show all 9 contributors for this article] (2014). Expression of human leukocyte antigen class i in endocrine and exocrine pancreatic tissue at onset of type 1 diabetes. American Journal of Pathology. ISSN 0002-9440. 185(1), p. 129–138. doi: 10.1016/j.ajpath.2014.09.004. Full text in Research Archive
• Negahdar, Maria; Aukrust, Ingvild; Molnes, Janne; Solheim, Marie Holm; Johansson, Bente Berg & Sagen, Jørn V. [Show all 12 contributors for this article] (2014). GCK-MODY diabetes as a protein misfolding disease: The mutation R275C promotes protein misfolding, self-association and cellular degradation. Molecular and Cellular Endocrinology. ISSN 0303-7207. 382(1), p. 55–65. doi: 10.1016/j.mce.2013.08.020. Full text in Research Archive
• Frøisland, Dag Helge; Graue, Marit; Markestad, Trond; Skrivarhaug, Torild; Wentzel-Larsen, Tore & Dahl-Jørgensen, Knut (2013). Health-related quality of life among Norwegian children and adolescents with type 1 diabetes on intensive insulin treatment: a population-based study. Acta Paediatrica. ISSN 0803-5253. 102(9), p. 889–895. doi: 10.1111/apa.12312. Full text in Research Archive
• Wisting, Line Norøm; Frøisland, Dag Helge; Skrivarhaug, Torild; Dahl-Jørgensen, Knut & Rø, Øyvind (2013). Disturbed Eating Behavior and Omission of Insulin in Adolescents Receiving Intensified Insulin Treatment A nationwide population-based study. Diabetes Care. ISSN 0149-5992. 36(11), p. 3382–3387. doi: 10.2337/dc13-0431. Full text in Research Archive
• Hammerstad, Sara Salehi; Tauriainen, S; Hyöty, Heikki; Paulsen, Trond Harder; Nordheim, Ingrid & Dahl-Jørgensen, Knut (2013). Detection of enterovirus in the thyroid tissue of patients with graves' disease. Journal of Medical Virology. ISSN 0146-6615. 85(3), p. 512–518. doi: 10.1002/jmv.23476. Full text in Research Archive
• Hammerstad, Sara Salehi; Jahnsen, Frode Lars; Tauriainen, Sisko; Hyöty, Heikki; Paulsen, Trond & Nordheim, Ingrid [Show all 7 contributors for this article] (2013). Inflammation and Increased Myxovirus Resistance Protein A Expression in Thyroid Tissue in the Early Stages of Hashimoto's Thyroiditis. Thyroid. ISSN 1050-7256. 23(3), p. 334–341. doi: 10.1089/thy.2012.0264. Full text in Research Archive
• Sveen, Kari Anne; Karimé, Bassam; Jørum, Ellen; Mellgren, Svein Ivar; Fagerland, Morten & Monnier, Vincent [Show all 8 contributors for this article] (2013). Small- and large-fiber neuropathy after 40 years of type 1 diabetes associations with glycemic control and advanced protein glycation: the Oslo Study. Diabetes Care. ISSN 0149-5992. 36(11), p. 3712–3717. doi: 10.2337/dc13-0788. Full text in Research Archive Show summary

  OBJECTIVE To study large- and small-nerve fiber function in type 1 diabetes of long duration and associations with HbA_1c and the advanced glycation end products (AGEs) N-&#949-(carboxymethyl)lysine (CML) and methylglyoxal-derived hydroimidazolone.<p> <p>RESEARCH DESIGN AND METHODS In a long-term follow-up study, 27 persons with type 1 diabetes of 40 &#177 3 years duration underwent large-nerve fiber examinations, with nerve conduction studies at baseline and years 8, 17, and 27. Small-fiber functions were assessed by quantitative sensory thresholds (QST) and intraepidermal nerve fiber density (IENFD) at year 27. HbA_1cwas measured prospectively through 27 years. Serum CML was measured at year 17 by immunoassay. Serum hydroimidazolone was measured at year 27 with liquid chromatography– mass spectrometry. <p>RESULTS Sixteen patients (59%) had large-fiber neuropathy. Twenty-two (81%) had smallfiber dysfunction by QST. Heat pain thresholds in the foot were associated with hydroimidazolone and HbA_1c. IENFD was abnormal in 19 (70%) and significantly lower in diabetic patients than in age-matched control subjects (4.3 &#177 2.3 vs. 11.2 &#177 3.5 mm, P , 0.001). IENFD correlated negatively with HbA_1c over 27 years (r = 20.4, P = 0.04) and CML (r = 20.5, P = 0.01). After adjustment for age, height, and BMI in a multiple linear regression model, CML was still independently associated with IENFD. <p>CONCLUSIONS Small-fiber sensory neuropathy is a major manifestation in type 1 diabetes of 40 years duration and more prevalent than large-fiber neuropathy. HbA1c and the AGEs CML and hydroimidazolone are important risk factors in the development of large- and small-fiber dysfunction in long-term type 1 diabetes.

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• Dunne, Jessica L.; Richardson, Sarah J.; Atkinson, Mark A.; Craig, Maria E.; Dahl-Jørgensen, Knut & Flodström-Tullberg, Malin [Show all 10 contributors for this article] (2019). Large enteroviral vaccination studies to prevent type 1 diabetes should be well founded and rely on scientific evidence. Reply to Skog O, Klingel K, Roivainen M et al [letter]. Diabetologia. ISSN 0012-186X. 62(6), p. 1100–1103. doi: 10.1007/s00125-019-4873-6. Full text in Research Archive
• Birkebaek, Niels Holtum; Hermann, Julia M.; Hanberger, Lena; Charalampopoulos, Dimitrios; Holl, Reinhard W. & Skrivarhaug, Torild [Show all 24 contributors for this article] (2019). Center size and glycemic control: An international study with 504 centers from seven countries. Diabetes Care. ISSN 0149-5992. 42(3), p. E37–E39. doi: 10.2337/dc18-1253. Full text in Research Archive
• Frøisland, Dag Helge; Graue, Marit; Markestad, Trond; Wentzel-Larsen, Tore; Skrivarhaug, Torild & Dahl-Jørgensen, Knut (2017). Norwegian adolescents with Type 1 diabetes undergoing intensive insulin treatment generally report levels of diabetes-related emotional distress. Furthermore, the short version of the Problem Areas in diabetes (PAID5)questionnaire functions as a valid and practical instrument for routine clinical avaluations. Full text in Research Archive Show summary

  https://diabetesjournals.org/diabetes/issue/66/Supplement_1 Norwegian Adolescents score low on diabetes-related distress measured with PAID. A small group have a high score on PAID associated with low score on WHO-5. We suggest PAID-5 as a useful short screening tool among adolescents with type 1 diabetes in order to reveal those with elevated diabetes-related emotional distress.

• Westermark, Gunilla T.; Krogvold, Lars; Dahl-Jørgensen, Knut & Ludvigsson, Johnny (2017). Islet amyloid in recent-onset type 1 diabetes?the DiViD study. Uppsala Journal of Medical Sciences. ISSN 0300-9734. 122(3), p. 201–203. doi: 10.1080/03009734.2017.1359219. Full text in Research Archive
• Borkamo, Hildegunn Styve; Drivvoll, Ann Kristin; Kummernes, Siv Janne; Dahl-Jørgensen, Knut & Skrivarhaug, Torild (2015). Reduced incidence of severe hypoglycemia and changing trends in treatment of Type 1 diabetes (T1D) in children the last 12 years in Norway - a Nationwide study. Full text in Research Archive
• Wisting, Line Norøm; Frøisland, Dag Helge; Skrivarhaug, Torild; Dahl-Jørgensen, Knut; Bang, Lasse & Natvig, Henrik [Show all 8 contributors for this article] (2015). Type 1 diabetes and Disturbed Eating Behaviors - Comorbidity, Prevalence, Psychological Correlates and Metabolic Control. Full text in Research Archive
• Wisting, Line Norøm; Frøisland, Dag Helge; Skrivarhaug, Torild; Dahl-Jørgensen, Knut; Bang, Lasse & Natvig, Henrik [Show all 8 contributors for this article] (2015). Comorbid type 1 diabetes and disturbed eating behaviors - assessment, prevalence, psychological correlates and metabolic Control. Full text in Research Archive
• Haugvik, Severina; Wisting, Line; Skrivarhaug, Torild & Dahl-Jørgensen, Knut (2026). Diabetes Body Project. Contributing to the Development of an Evidence-Based Clinical Toolkit for Eating Disorder Prevention Among Young Women with Type 1 Diabetes. Universitetet i Oslo. ISSN 9788234808715. Full text in Research Archive Show summary

  This doctoral thesis is situated at the intersection of diabetes care, eating disorder research, and preventive health. Young women with type 1 diabetes face an increased risk of disordered eating behaviors and eating disorders, which are associated with diabetes-related complications and higher mortality. Yet effective prevention strategies remain limited. This doctoral thesis, including three papers, addresses this important clinical gap through research focusing on identification and targeted prevention, drawing on both quantitative and qualitative methods. Paper I focused on identification through a cross-sectional validation study of the widely recommended screening questionnaire, the Diabetes Eating Problem Survey – Revised (DEPS-R). The questionnaire demonstrated good discriminative ability for identifying individuals with and without eating disorders, and the current cut-off showed high sensitivity, supporting its use as a screening tool in clinical practice. Papers II and III focused on the Diabetes Body Project, a virtual, diabetes-specific adaptation of an evidence-based eating disorder prevention program for young women with type 1 diabetes. The intervention was evaluated in a multinational randomized controlled trial and complemented by a qualitative analysis of written feedback from participants and facilitators. Compared with the control condition, participants showed significantly larger short-term improvements in eating disorder risk factors, symptoms, and psychological correlates, while qualitative findings indicated high user satisfaction and highlighted the value of peer support within a type 1 diabetes-specific community. Collectively, findings in this doctoral thesis may contribute to the development of an evidence-based clinical toolkit for eating disorder prevention, ultimately supporting improved long-term health outcomes in young women with type 1 diabetes.

• Mynarek, Ida Maria; Krogvold, Lars & Dahl-Jørgensen, Knut (2026). Exploring the role of enteroviruses in type 1 diabetes. The Diabetes Virus Detection and Intervention studies. Universitetet i Oslo. ISSN 9788234808555. Full text in Research Archive Show summary

  Type 1 diabetes is an autoimmune disease in which genetic susceptibility and environmental factors contribute to immune-mediated destruction of insulin-producing β-cells. Increasing evidence suggests that enteroviruses may contribute to disease development. This thesis investigated the role of viral infections in type I diabetes through analyses of pancreatic tissue and a randomized controlled trial. Pancreatic biopsies from living adults newly diagnosed with type 1 diabetes showed signs of persistent viral activity and cellular stress. RNA analyses and immunohistochemistry demonstrated upregulation of pathways associated with viral replication, ongoing infection and cellular stress, and increased expression of antiviral markers, indicating an ongoing antiviral response in the pancreas. A randomized, double-blind clinical trial including 96 children and adolescents newly diagnosed with type 1 diabetes was conducted. They were treated with pleconaril and ribavirin or placebo for six months. Antiviral treatment slowed the decline in endogenous insulin production during the first year after diagnosis, although the effect was not sustained long term. Overall, the findings support the hypothesis that persistent low-grade viral infections contribute to type 1 diabetes pathogenesis. They also provide a foundation for further research into antiviral treatment strategies, both for type 1 diabetes but also for other autoimmune diseases.

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