Browsing by Subject "type 1 diabetes"

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  • Niinistö, Sari; Miettinen, Maija E.; Cuthbertson, David; Honkanen, Jarno; Hakola, Leena; Autio, Reija; Erlund, Iris; Arohonka, Petra; Vuorela, Arja; Härkönen, Taina; Hyöty, Heikki; Krischer, Jeffrey P.; Vaarala, Outi; Knip, Mikael; Virtanen, Suvi M. (2022)
    AimsAltered immune functions as well as fatty acid intake and status have been associated with the development of type 1 diabetes. We aimed to study the relationship between fatty acids and immunological markers in young children with increased genetic risk for type 1 diabetes in order to define putative mechanisms related to development of islet autoimmunity. MethodsSerum samples for fatty acid and immunological marker measurements were obtained in the Trial to Reduce IDDM in the Genetically at Risk (TRIGR) ancillary study (Divia) from children born between 2002 and 2007 in 15 countries. Case children (n = 95) were defined as having repeated positivity for at least two out of four diabetes-associated autoantibodies. For each case child, control children were selected matched for country and date of birth (n = 173). Serum fatty acids and immunological markers were measured from cord serum and at the age of 6 and 12 months. Spearman correlation coefficients were calculated between fatty acids and immunological markers. ResultsCorrelations between circulating fatty acids and immunological markers were different in case children who developed islet autoimmunity than in control children already at birth continuing across the first year of life. In case children, saturated fatty acids (SFAs) showed stronger correlations with immunological markers, while in controls, polyunsaturated fatty acids (PUFAs) showed stronger correlations. ConclusionsIn cases, SFAs were associated with several immunological markers (CXCL10, IL-6, IL-9, IL-17, and CM-CSF) previously linked to the type 1 diabetes disease process. Findings indicate that fatty acids could have immunomodulatory potential in the early phase of the disease development, although causality between fatty acids and the immunological pathways remains to be explored. Trial registry numberNCT00179777
  • Pöllänen, Petra M.; Härkönen, Taina; Ilonen, Jorma; Toppari, Jorma; Veijola, Riitta; Siljander, Heli; Knip, Mikael (2022)
    Objective To evaluate the role of autoantibodies to N-terminally truncated glutamic acid decarboxylase GAD(65)(96-585) (t-GADA) as a marker for type 1 diabetes (T1D) and to assess the potential human leukocyte antigen (HLA) associations with such autoantibodies. Design In this cross-sectional study combining data from the Finnish Pediatric Diabetes Register, the Type 1 Diabetes Prediction and Prevention study, the DIABIMMUNE study, and the Early Dietary Intervention and Later Signs of Beta-Cell Autoimmunity study, venous blood samples from 760 individuals (53.7% males) were analyzed for t-GADA, autoantibodies to full-length GAD(65) (f-GADA), and islet cell antibodies. Epitope-specific GAD autoantibodies were analyzed from 189 study participants. Results T1D had been diagnosed in 174 (23%) participants. Altogether 631 (83%) individuals tested positive for f-GADA and 451 (59%) for t-GADA at a median age of 9.0 (range 0.2-61.5) years. t-GADA demonstrated higher specificity (46%) and positive predictive value (30%) for T1D than positivity for f-GADA alone (15% and 21%, respectively). Among participants positive for f-GADA, those who tested positive for t-GADA carried more frequently HLA genotypes conferring increased risk for T1D than those who tested negative for t-GADA (77% vs 53%; P < 0.001). Conclusions Autoantibodies to N-terminally truncated GAD improve the screening for T1D compared to f-GADA and may facilitate the selection of participants for clinical trials. HLA class II-mediated antigen presentation of GAD(96-585)-derived or structurally similar peptides might comprise an important pathomechanism in T1D.
  • Lehto, Maili (University of Helsinki, 1996)
  • Eriksson, Marika (Helsingin yliopisto, 2018)
    Målet med studien är att undersöka blodtryckets betydelse vid cerebral småkärlssjukdom hos typ 1-diabetiker. Sambandet har tidigare varit okänt, men i en studie av FinnDiane verkar högre systoliskt blodtryck vara av betydelse. Typ 1-diabetes är associerat med sjukdomar i hjärnans blodkärl, varav cerebral småkärlssjukdom är ett tillstånd där hjärnans små blodkärl skadas. Tecken på skada kan ses genom avbildning med magnetisk resonanstomografi (MRI). För denna studie undersöktes 73 individer med typ 1-diabetes ur FinnDiane-studien. De undersökta genomgick MRI av hjärnan och 24-timmars blodtrycksuppföljning. Systoliskt och diastoliskt blodtryck, medel arteriellt tryck och pulstryck under dygnets olika perioder registrerades och mätresultaten analyserades i relation till MRI-fynd. I denna studie hade systoliska och diastoliska blodtrycket nattetid samt medel arteriellt tryck nattetid ett signifikant samband med cerebral småkärlssjukdom. Hypertoni nattetid höjde oddsen för cerebral småkärlssjukdom fyrfalt. Av de undersökta hade 30 % maskerad hypertoni (normalt mottagningsblodtryck men förhöjt tryck i dygnsuppföljning) och förekomsten var högre bland individer med cerebral småkärlssjukdom. Slutsatsen är att cerebral småkärlssjukdom verkar ha ett samband med högt blodtryck nattetid samt med maskerad hypertoni hos individer med typ 1-diabetes.
  • Yeo, L.; Pujol-Autonell, I.; Baptista, R.; Eichmann, M.; Kronenberg-Versteeg, D.; Heck, S.; Dolton, G.; Sewell, A. K.; Härkönen, T.; Mikk, M. -L.; Toppari, J.; Veijola, R.; Knip, M.; Ilonen, J.; Peakman, M. (2020)
    In type 1 diabetes (T1D), autoreactive cytotoxic CD8(+) T cells are implicated in the destruction of insulin-producing beta cells. The HLA-B*3906 and HLA-A*2402 class I genes confer increased risk and promote early disease onset, suggesting that CD8(+) T cells that recognize peptides presented by these class I molecules on pancreatic beta cells play a pivotal role in the autoimmune response. We examined the frequency and phenotype of circulating preproinsulin (PPI)-specific and insulin B (InsB)-specific CD8(+) T cells in HLA-B*3906(+) children newly diagnosed with T1D and in high-risk HLA-A*2402(+) children before the appearance of disease-specific autoantibodies and before diagnosis of T1D. Antigen-specific CD8(+) T cells were detected using human leucocyte antigen (HLA) class I tetramers and flow cytometry was used to assess memory status. In HLA-B*3906(+) children with T1D, we observed an increase in PPI5-12-specific transitional memory CD8(+) T cells compared to non-diabetic, age- and HLA-matched subjects. Furthermore, PPI5-12-specific CD8(+) T cells in HLA-B*3906(+) children with T1D showed a significantly more antigen-experienced phenotype compared to polyclonal CD8(+) T cells. In longitudinal samples from high-risk HLA-A*2402(+) children, the percentage of terminal effector cells within the InsB(15-24)-specific CD8(+) T cells was increased before diagnosis relative to samples taken before the appearance of autoantibodies. This is the first study, to our knowledge, to report HLA-B*3906-restricted autoreactive CD8(+) T cells in T1D. Collectively, our results provide evidence that beta cell-reactive CD8(+) T cells restricted by disease-associated HLA class I molecules display an antigen-experienced phenotype and acquire enhanced effector function during the period leading to clinical diagnosis, implicating these cells in driving disease.
  • Kivelä, Laura; Euren, Anna; Repo, Marleena; Huhtala, Heini; Kaukinen, Katri; Kurppa, Kalle (2022)
    PurposeWe evaluated adherence to a gluten-free diet and associated factors in adult celiac disease patients diagnosed in childhood. MethodsComprehensive medical data on 955 pediatric celiac disease patients was collected and study questionnaires sent to 559 who were now adults. All variables were compared between strictly adherent and non-adherent patients. ResultsAltogether 237 adults (median age 27 years, 69% women) responded to the questionnaires a median of 18 (range 3-51) years after the childhood diagnosis. Altogether 78% were reportedly adherent and 22% non-adherent. The non-adherent patients had more concomitant type 1 diabetes (18% vs. 4%, p = 0.003), whereas the groups did not differ in demographic data or clinical and histological features at diagnosis, or in short-term dietary adherence. In adulthood, non-adherent patients found gluten-free diet more challenging (39% vs. 17%, p < 0.001) and had higher prevalence (39% vs. 19%, p = 0.004) and severity of symptoms. The main motivation factors for dietary adherence were attempts to avoid symptoms and complications, but these were considered less important and price of gluten-free products more important among non-adherent patients. Adherent and non-adherent patients did not differ in socioeconomic or lifestyle factors, comorbidities other than type 1 diabetes, self-reported general health, health concerns, follow-up, or in quality of life. ConclusionMost originally pediatric celiac disease patients reported strict dietary adherence in adulthood. However, particularly those with concomitant type 1 diabetes, persistent symptoms or financial issues may require attention during the transition from pediatric to adult care.
  • Lamichhane, Santosh; Ahonen, Linda; Dyrlund, Thomas Sparholt; Dickens, Alex M.; Siljander, Heli; Hyöty, Heikki; Ilonen, Jorma; Toppari, Jorma; Veijola, Riitta; Hyötyläinen, Tuulia; Knip, Mikael; Oresic, Matej (2019)
    Previous studies suggest that children who progress to type 1 diabetes (T1D) later in life already have an altered serum lipid molecular profile at birth. Here, we compared cord blood lipidome across the three study groups: children who progressed to T1D (PT1D; n = 30), children who developed at least one islet autoantibody but did not progress to T1D during the follow-up (P1Ab; n = 33), and their age-matched controls (CTR; n = 38). We found that phospholipids, specifically sphingomyelins, were lower in T1D progressors when compared to P1Ab and the CTR. Cholesterol esters remained higher in PT1D when compared to other groups. A signature comprising five lipids was predictive of the risk of progression to T1D, with an area under the receiver operating characteristic curve (AUROC) of 0.83. Our findings provide further evidence that the lipidomic profiles of newborn infants who progress to T1D later in life are different from lipidomic profiles in P1Ab and CTR.
  • Rosenback, Susanna (Helsingfors universitet, 2010)
    Syftet med studien var att undersöka sambanden mellan de diabetesassocierade autoantikropparna ICA, IAA, GADA, IA-2A och klinisk manifestation, HLA-genotyp, släktanamnes samt demografiska faktorer såsom ålder och kön hos finländska barn under 15 år med nydiagnostiserad typ 1 diabetes. Analyserna baserades på ett utdrag ur det finländska pediatriska diabetesregistret (2257 barn). Antikroppsfrekvenserna fastställdes utgående från halterna i serum. Alla barn HLA-genotypades och indelades i DR3- och DR4-positiva. Småbarnen (< 5 år) hade ofta 3-4 positiva antikroppar. Äldre barn hade färre autoantikroppar men en allvarligare metabolisk dekompensering vid diagnostillfället. Diabetisk ketoacidos var vanligare hos flickor. I gruppen med endast en positiv autoantikropp var IA-2A-barnen oftare acidotiska, i övrigt påverkade inte antikroppsprofilen den kliniska bilden. Högriskgenotypen DR4/non-DR3 var associerad med IA-2A, som verkar fungera som en markör för betacelldestruktion. Det omfattande patientmaterialet gav stöd åt tidigare rapporter om samband mellan autoantikroppar och ålder, kön samt genotyp. Den allvarligare metaboliska dekompenseringen hos äldre barn tyder på att de inte diagnostiseras lika snabbt som småbarn.
  • the TRIGR Invest; Virtanen, Suvi M.; Cuthbertson, David; Nucci, Anita M.; Hyytinen, Mila; Salonen, Marja; Savilahti, Erkki; Knip, Mikael (2021)
    The international Trial to Reduce IDDM in the Genetically at Risk (TRIGR) tested the hypothesis whether extensively hydrolyzed casein-based versus regular cow's milk-based infant formula reduces the risk of type 1 diabetes. We describe dietary compliance in the trial in terms of study formula intake, feeding of nonrecommended foods, and serum cow's milk antibody concentration reflecting intake of cow's milk protein among 2,159 eligible newborn infants with a biological first-degree relative affected by type 1 diabetes and with HLA-conferred susceptibility to type 1 diabetes. The participating infants were introduced to the study formula feeding at the median age of 15 days with a median duration of study formula use of 63 days. During the intervention, 80% of the infants received study formula. Of these, 57% received study formula for at least 2 months. On average, 45.5 l of study formula were used per infant. Only 13% of the population had received a nonrecommended food by the age of 6 months. The dietary compliance was similar in the intervention and control arm. The reported cow's milk consumption by the families matched very well with measured serum casein IgA and IgG antibody concentration. To conclude, good compliance was observed in this randomized infant feeding trial. Compliance varied between the regions and those infants who were breastfed for a longer period of time had a shorter exposure to the study formula. High dietary compliance in infant feeding trial is necessary to allow accurate interpretation of study results.
  • Ahola, Aila J.; Forsblom, Carol; Harjutsalo, Valma; Groop, Per-Henrik (2019)
    Aim Diet plays an important role in the kidney health of individuals with type 1 diabetes. However, not much is known about dietary practices at different stages of diabetic nephropathy. We aimed at investigating food intake, dietary patterns, and nutrient intakes in individuals with type 1 diabetes differing in renal status. Methods Data were available from 1874 individuals with type 1 diabetes (45% men, age 48 ± 13 years). Diet was assessed at the levels of food items and diet patterns (diet questionnaire), and energy and nutrient intakes (food record). Six groups were formed based on the eGFR or dialysis and transplantation status. Results Reductions in liquid-milk product and salt consumption, and increase in special diet adherence were observed at the early stages of eGFR decline. Reduced coffee consumption was observed after eGFR was
  • Pöllänen, Petra M.; Ryhänen, Samppa J.; Toppari, Jorma; Ilonen, Jorma; Vähäsalo, Paula; Veijola, Riitta; Siljander, Heli; Knip, Mikael (2020)
    Context: We set out to characterize the dynamics of islet autoantibodies over the first 15 years of life in children carrying genetic susceptibility to type 1 diabetes (T1D). We also assessed systematically the role of zinc transporter 8 autoantibodies (ZnT8A) in this context. Design: HLA-predisposed children (N = 1006, 53.0% boys) recruited from the general population during 1994 to 1997 were observed from birth over a median time of 14.9 years (range, 1.9-15.5 years) for ZnT8A, islet cell (ICA), insulin (IAA), glutamate decarboxylase (GADA), and islet antigen-2 (IA-2A) antibodies, and for T1D. Results: By age 15.5 years, 35 (3.5%) children had progressed to T1D. Islet autoimmunity developed in 275 (27.3%) children at a median age of 7.4 years (range, 0.3-15.1 years). The ICA seroconversion rate increased toward puberty, but the biochemically defined autoantibodies peaked at a young age. Before age 2 years, ZnT8A and IAA appeared commonly as the first autoantibody, but in the preschool years IA-2A- and especially GADA-initiated autoimmunity increased. Thereafter, GADA-positive seroconversions continued to appear steadily until ages 10 to 15 years. Inverse IAA seroconversions occurred frequently (49.3% turned negative) and marked a prolonged delay from seroconversion to diagnosis compared to persistent IAA (8.2 vs 3.4 years; P = .01). Conclusions: In HLA-predisposed children, the primary autoantibody is characteristic of age and might reflect the events driving the disease process toward clinical T1D. Autoantibody persistence affects the risk of T1D. These findings provide a framework for identifying disease subpopulations and for personalizing the efforts to predict and prevent T1D.
  • Ekman, Ilse; Vuorinen, Tytti; Knip, Mikael; Veijola, Riitta; Toppari, Jorma; Hyöty, Heikki; Kinnunen, Tuure; Ilonen, Jorma; Lempainen, Johanna (2019)
    Aims/Hypothesis Evidence of the role of cytomegalovirus (CMV) infection in the pathogenesis of type 1 diabetes (T1D) has remained inconclusive. Our aim was to elucidate the possible role of CMV infection in the initiation of islet autoimmunity and in the progression to clinical T1D among children with human leukocyte antigen (HLA)-conferred T1D risk. Methods A total of 1402 children from the prospective Type 1 Diabetes Prediction and Prevention (DIPP) study were analyzed for CMV-specific IgG antibodies during early childhood. All the children carried HLA-DQ genotypes associated with increased risk for T1D. The effect of CMV infection on the appearance of T1D-associated autoantibodies (insulin autoantibodies [IAA], glutamic acid decarboxylase [GADA], and insulinoma antigen-2 [IA-2A], n = 356) and on the progression rate to clinical T1D (n = 233) were analyzed with Kaplan-Meier survival analysis and Log-rank test. Results Early childhood CMV infection was inversely associated with the development of T1D during childhood. Cumulative progression to T1D was decreased in subjects with an early CMV infection (P = 0.035). In further analyses, the effect of early CMV infection on the initiation of islet autoimmunity and progression to clinical T1D were examined separately. Interestingly, early CMV infection did not affect the appearance of T1D-associated autoantibodies but a decelerating effect was observed on the progression rate from islet autoimmunity to clinical T1D (P = 0.015). Conclusion Our results suggest that an early childhood CMV infection may decelerate the progression from islet autoimmunity to clinical T1D among at-risk children and may thus protect these children from progressing to T1D during childhood.
  • Tougaard, Ninna H.; Frimodt-Moller, Marie; Salmenkari, Hanne; Stougaard, Elisabeth B.; Zawadzki, Andressa D.; Mattila, Ismo M.; Hansen, Tine W.; Legido-Quigley, Cristina; Horkko, Sohvi; Forsblom, Carol; Groop, Per-Henrik; Lehto, Markku; Rossing, Peter (2022)
    Type 1 diabetes is associated with increased intestinal inflammation and decreased abundance of butyrate-producing bacteria. We investigated the effect of butyrate on inflammation, kidney parameters, HbA1c, serum metabolites and gastrointestinal symptoms in persons with type 1 diabetes, albuminuria and intestinal inflammation. We conducted a randomized placebo-controlled, double-blind, parallel clinical study involving 53 participants randomized to 3.6 g sodium butyrate daily or placebo for 12 weeks. The primary endpoint was the change in fecal calprotectin. Additional endpoints were the change in fecal short chain fatty acids, intestinal alkaline phosphatase activity and immunoglobulins, serum lipopolysaccharide, CRP, albuminuria, kidney function, HbA1c, metabolites and gastrointestinal symptoms. The mean age was 54 +/- 13 years, and the median [Q1:Q3] urinary albumin excretion was 46 [14:121] mg/g. The median fecal calprotectin in the butyrate group was 48 [26:100] mu g/g at baseline, and the change was -1.0 [-20:10] mu g/g; the median in the placebo group was 61 [25:139] mu g/g at baseline, and the change was -12 [-95:1] mu g/g. The difference between the groups was not significant (p = 0.24); neither did we find an effect of butyrate compared to placebo on the other inflammatory markers, kidney parameters, HbA1c, metabolites nor gastrointestinal symptoms. Twelve weeks of butyrate supplementation did not reduce intestinal inflammation in persons with type 1 diabetes, albuminuria and intestinal inflammation.
  • Sane, Famara; Bertin, Antoine; Sioofy-Khojine, Amir-Babak; Oikarinen, Sami; Alidjinou, Enagnon K.; Veijola, Riitta; Toppari, Jorma; Ilonen, Jorma; Knip, Mikael; Engelmann, Ilka; Hyöty, Heikki; Hober, Didier (2020)
    Abstract Studies in prospective cohorts have suggested that enterovirus infections are associated with the appearance of islet autoantibodies that precede later appearance of type 1 diabetes (T1D). It was shown that in addition to an antibody-mediated anti-coxsackievirus (CV)-B neutralizing activity of serum from patients with T1D, there was also enhancing anti-CV-B activity in vitro. In this study the patterns of enhancing and neutralizing anti-CV activities were analyzed from consecutive serum samples collected from children who were followed from birth until they developed T1D in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study and compared to those in non-diabetic control children. The titers of serum neutralizing activity were analyzed against those CVs which were detected in the stools in these children (CV-B3, CV-B5 or CV-A4) using plaque assay. The enhancing activity of these serum samples was analysed by measuring interferon-alpha (INF-α) production in cultures of peripheral blood mononuclear cells (PBMC) inoculated with a mixture of these viruses and diluted serum. A sustained anti-CV enhancing activity was observed in consecutive serum samples in patients with T1D. The pattern of responses differed between children who developed T1D and control children. In patients, the anti-CV enhancing activity was predominant or even exclusive over the neutralizing activity, whereas in controls the enhancing and neutralizing activities were more balanced or the neutralizing activity was largely predominant. In conclusion, evaluating the anti-enterovirus neutralizing and enhancing activity of serum samples can be useful to investigate further the relationship between enteroviruses and the development of T1D. This article is protected by copyright. All rights reserved.
  • Bompada, Pradeep; Goncalves, Isabel; Wu, Chuanyan; Gao, Rui; Sun, Jiangming; Mir, Bilal Ahmad; Luan, Cheng; Renstroem, Erik; Groop, Leif; Weng, Jianping; Hansson, Ola; Edsfeldt, Andreas; De Marinis, Yang (2021)
    There is emerging evidence of an association between epigenetic modifications, glycemic control and atherosclerosis risk. In this study, we mapped genome-wide epigenetic changes in patients with type 2 diabetes (T2D) and advanced atherosclerotic disease. We performed chromatin immunoprecipitation sequencing (ChIP-seq) using a histone 3 lysine 9 acetylation (H3K9ac) mark in peripheral blood mononuclear cells from patients with atherosclerosis with T2D (n = 8) or without T2D (ND, n = 10). We mapped epigenome changes and identified 23,394 and 13,133 peaks in ND and T2D individuals, respectively. Out of all the peaks, 753 domains near the transcription start site (TSS) were unique to T2D. We found that T2D in atherosclerosis leads to an H3K9ac increase in 118, and loss in 63 genomic regions. Furthermore, we discovered an association between the genomic locations of significant H3K9ac changes with genetic variants identified in previous T2D GWAS. The transcription factor 7-like 2 (TCF7L2) rs7903146, together with several human leukocyte antigen (HLA) variants, were among the domains with the most dramatic changes of H3K9ac enrichments. Pathway analysis revealed multiple activated pathways involved in immunity, including type 1 diabetes. Our results present novel evidence on the interaction between genetics and epigenetics, as well as epigenetic changes related to immunity in patients with T2D and advanced atherosclerotic disease.
  • Kuusela, Salla; Keskinen, Päivi; Pokka, Tytti; Knip, Mikael; Ilonen, Jorma; Vähäsalo, Paula; Veijola, Riitta (2020)
    Objective The aim of this study was to explore the extended family history of type 1 diabetes in children at genetic risk and define the impact of a positive family history on the development of islet autoimmunity and type 1 diabetes. Methods The subjects were participants in The Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study and carried increased HLA-conferred risk for type 1 diabetes. The case children (N = 343) were positive for at least one islet autoantibody, and the control children (N = 343) matched by age, gender and class II HLA genotype were negative for islet autoantibodies at the time of data collection. Extended family history of type 1 diabetes was obtained by using a structured questionnaire. Results Among children who were autoantibody positive and progressed to type 1 diabetes 62.2% (28/45) had at least one relative with type 1 diabetes. Interestingly, 57.8% of these children (26/45) had such a relative outside the nuclear family compared to 30.7% of children with no autoantibodies (P= .001), 35.2% of those with only classical islet cell antibodies (P= .006), and 35.2% of non-progressors with biochemical autoantibodies (P= 0.011). A positive history of type 1 diabetes in the paternal extended family was more common in children with multiple biochemical autoantibodies compared to those with only one biochemical autoantibody (P= .010). No association between the specificity of the first appearing autoantibody and family history of the disease was found. Conclusions Type 1 diabetes in relatives outside the nuclear family is a significant risk factor for islet autoimmunity and progression to clinical disease in HLA susceptible children.
  • Varimo, Tero; Pulkkinen, Mari-Anne; Hakonen, Elina; Hero, Matti; Miettinen, Päivi J; Tuomaala, Anna-Kaisa (2021)
    Objective The hybrid close-loop system (HCL) is a rapidly emerging treatment method for type 1 diabetes (T1D), but the long-term effectiveness of the system remains unclear. This study investigates the influence of the HCL on glycemic control in children and adolescents with T1D in a real-life setting during the first year on HCL. Research design and methods This retrospective study included all the patients (n = 111) aged 3 to 16 years with T1D who initiated the HCL system between 1st of December 2018 and 1st of December 2019 in the Helsinki University Hospital. Time in range (TIR), HbA1c, mean sensor glucose (SG) value, time below range (TBR), and SG coefficient of variance (CV) were measured at 0, 1, 3, 6, and 12 month. The changes over time were analyzed with a repeated mixed model adjusted with baseline glycemic control. Results After the initiation of HCL, all measures of glycemic control, except HbA1c, improved and the effect lasted throughout the study period. Between 0 and 12 month, TIR increased (beta = -2.5 [95%CI: -3.6 - (-1.3)], p < 0.001), whereas mean SG values (beta = -0.7 [95%CI: -0.9 - (-0.4)]), TBR (beta = -2.5 [95%CI: -3.6 - (-1.3)]), and SG CV (beta = -4.5 [95%CI: -6.3 - [-2.8]) decreased significantly (p < 0.001). Importantly, the changes occurred regardless of the age of the patient. Conclusions Measurements of glycemic control, except HbA1c, improved significantly after the initiation of the HCL system and the favorable effect lasted throughout the follow-up. These results support the view that HCL is an efficacious treatment modality for children and adolescents with T1D of all ages.
  • Viisanen, Tyyne; Gazali, Ahmad M.; Ihantola, Emmi-Leena; Ekman, Ilse; Näntö-Salonen, Kirsti; Veijola, Riitta; Toppari, Jorma; Knip, Mikael; Ilonen, Jorma; Kinnunen, Tuure (2019)
    The dysfunction of FOXP3-positive regulatory T cells (Tregs) plays a key role in the pathogenesis of autoimmune diseases, including type 1 diabetes (T1D). However, previous studies analyzing the peripheral blood Treg compartment in patients with T1D have yielded partially conflicting results. Moreover, the phenotypic complexity of peripheral blood Tregs during the development of human T1D has not been comprehensively analyzed. Here, we used multi-color flow cytometry to analyze the frequency of distinct Treg subsets in blood samples from a large cohort comprising of 74 children with newly diagnosed T1D, 76 autoantibody-positive children at-risk for T1D and 180 age- and HLA-matched control children. The frequency of CD4+CD25+CD127lowFOXP3+ Tregs was higher in children with T1D compared to control children, and this change was attributable to a higher proportion of naive Tregs in these subjects. Further longitudinal analyses demonstrated that the increase in Treg frequency correlated with disease onset. The frequencies of the minor subsets of CD25+FOXP3low memory Tregs as well as CD25lowCD127lowFOXP3+ Tregs were also increased in children with T1D. Moreover, the ratio of CCR6-CXCR3+ and CCR6+CXCR3- memory Tregs was altered and the frequency of proliferating Ki67-positive and IFN-gamma producing memory Tregs was decreased in children with T1D. The frequency of CXCR5+FOXP3+ circulating follicular T regulatory cells was not altered in children with T1D. Importantly, none of the alterations observed in children with T1D were observed in autoantibody-positive at-risk children. In conclusion, our study reveals multiple alterations in the peripheral blood Treg compartment at the diagnosis of T1D that appear not to be features of early islet autoimmunity.
  • Nevalainen, Jaakko; Datta, Somnath; Toppari, Jorma; Ilonen, Jorma; Hyöty, Heikki; Veijola, Riitta; Knip, Mikael; Virtanen, Suvi M. (2021)
    In studies following selective sampling protocols for secondary outcomes, conventional analyses regarding their appearance could provide misguided information. In the large type 1 diabetes prevention and prediction (DIPP) cohort study monitoring type 1 diabetes-associated autoantibodies, we propose to model their appearance via a multivariate frailty model, which incorporates a correlation component that is important for unbiased estimation of the baseline hazards under the selective sampling mechanism. As further advantages, the frailty model allows for systematic evaluation of the association and the differences in regression parameters among the autoantibodies. We demonstrate the properties of the model by a simulation study and the analysis of the autoantibodies and their association with background factors in the DIPP study, in which we found that high genetic risk is associated with the appearance of all the autoantibodies, whereas the association with sex and urban municipality was evident for IA-2A and IAA autoantibodies.
  • Honkanen, Jarno; Vuorela, Arja; Muthas, Daniel; Orivuori, Laura; Luopajärvi, Kristiina; Tejesvi, Mysore Vishakante Gowda; Lavrinienko, Anton; Pirttilä, Anna Maria; Fogarty, Christopher L.; Härkönen, Taina; Ilonen, Jorma; Ruohtula, Terhi; Knip, Mikael; Koskimäki, Janne J.; Vaarala, Outi (2020)
    Although gut bacterial dysbiosis is recognized as a regulator of beta-cell autoimmunity, no data is available on fungal dysbiosis in the children at the risk of type 1 diabetes (T1D). We hypothesized that the co-occurrence of fungal and bacterial dysbiosis contributes to the intestinal inflammation and autoimmune destruction of insulin-producing beta-cells in T1D. Fecal and blood samples were collected from 26 children tested positive for at least one diabetes-associated autoantibody (IAA, GADA, IA-2A or ICA) and matched autoantibody-negative children with HLA-conferred susceptibility to T1D (matched for HLA-DQB1 haplotype, age, gender and early childhood nutrition). Bacterial 16S and fungal ITS2 sequencing, and analyses of the markers of intestinal inflammation, namely fecal human beta-defensin-2 (HBD2), calprotectin and secretory total IgA, were performed. Anti-Saccharomyces cerevisiae antibodies (ASCA) and circulating cytokines, IFNG, IL-17 and IL-22, were studied. After these analyses, the children were followed for development of clinical T1D (median 8 years and 8 months). Nine autoantibody positive children were diagnosed with T1D, whereas none of the autoantibody negative children developed T1D during the follow-up. Fungal dysbiosis, characterized by high abundance of fecal Saccharomyces and Candida, was found in the progressors, i.e., children with beta-cell autoimmunity who during the follow-up progressed to clinical T1D. These children showed also bacterial dysbiosis, i.e., increased Bacteroidales and Clostridiales ratio, which was, however, found also in the non-progressors, and is thus a common nominator in the children with beta-cell autoimmunity. Furthermore, the progressors showed markers of intestinal inflammation detected as increased levels of fecal HBD2 and ASCA IgG to fungal antigens. We conclude that the fungal and bacterial dysbiosis, and intestinal inflammation are associated with the development of T1D in children with beta-cell autoimmunity.