Browsing by Subject "type 1 diabetes"

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  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Honkimaa, Anni; Kimura, Bryn; Sioofy-Khojine, Amir-Babak; Lin, Jake; Laiho, Jutta; Oikarinen, Sami; Hyöty, Heikki (2020)
    Coxsackie B (CVB) viruses have been associated with type 1 diabetes. We have recently observed that CVB1 was linked to the initiation of the autoimmune process leading to type 1 diabetes in Finnish children. Viral persistency in the pancreas is currently considered as one possible mechanism. In the current study persistent infection was established in pancreatic ductal and beta cell lines (PANC-1 and 1.1B4) using four different CVB1 strains, including the prototype strain and three clinical isolates. We sequenced 5 ' untranslated region (UTR) and regions coding for structural and non-structural proteins and the second single open reading frame (ORF) protein of all persisting CVB1 strains using next generation sequencing to identify mutations that are common for all of these strains. One mutation, K257R in VP1, was found from all persisting CVB1 strains. The mutations were mainly accumulated in viral structural proteins, especially at BC, DE, EF loops and C-terminus of viral capsid protein 1 (VP1), the puff region of VP2, the knob region of VP3 and infection-enhancing epitope of VP4. This showed that the capsid region of the viruses sustains various changes during persistency some of which could be hallmark(s) of persistency.
  • Finnish Pediat Diabet Register; Mikk, Mari-Liis; Pfeiffer, Sophie; Kiviniemi, Minna; Laine, Antti-Pekka; Lempainen, Johanna; Härkönen, Taina; Toppari, Jorma; Veijola, Riitta; Knip, Mikael; Ilonen, Jorma (2020)
    Objective We aimed to clarify the association of various HLA risk alleles with different types of autoantibodies initiating islet specific autoimmunity. Methods Follow-up cohorts from the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study and children diagnosed with type 1 diabetes (T1D) from the Finnish Pediatric Diabetes Register (FPDR) were analyzed for the presence of autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA), IA-2 antigen (IA-2A), and zinc transporter 8 (ZnT8A); and genotyped for HLA DR/DQ alleles. In the DIPP study, autoantibodies were regularly analyzed from birth up to 15 years of age. Results In the DIPP cohort, 621 children developed one single persistent autoantibody, GADA in 284, IAA in 268, and IA-2A in 40 cases. Highly significant differences in the specificity of the first autoantibody were observed between HLA genotypes. Homozygotes for the DR3-DQ2 haplotype had almost exclusively GADA as the first autoantibody, whereas a more even distribution between GADA and IAA was found in DR3-DQ2/DR4-DQ8 as well as DR3-DQ/x and DR4-DQ8/x genotypes (x referring to neutral haplotypes). In DR4-DQ8 positive genotypes with the DRB1*04:01 allele IAA was more often the first autoantibody than in DRB1*04:04 positive genotypes. Various neutral haplotypes also significantly affected the relative proportions of different initial autoantibodies. These findings were confirmed and expanded in a series of 1591 T1D children under the age of 10 years from FPDR. Conclusions These results emphasize the importance of HLA class II polymorphisms in the recognition of autoantigen epitopes in the initiation of various pathways of the autoimmune response.
  • Diabimmune Study Grp; Ruohtula, Terhi; Kondrashova, Anita; Lehtonen, Jussi; Oikarinen, Sami; Hämäläinen, Anu-Maaria; Niemelä, Onni; Peet, Aleksandr; Tillmann, Vallo; Nieminen, Janne K.; Ilonen, Jorma; Knip, Mikael; Vaarala, Outi; Hyöty, Heikki (2021)
    Early childhood infections have been implicated in the development of immune-mediated diseases, such as allergies, asthma, and type 1 diabetes. We set out to investigate the immunomodulatory effects of early viral infections experienced before the age of one year on the peripheral regulatory T cell population (Treg) and circulating cytokines in a birth-cohort study of Estonian and Finnish infants. We show here a temporal association of virus infection with the expression of FOXP3 in regulatory T cells. Infants with rhinovirus infection during the preceding 30 days had a higher FOXP3 expression in Treg cells and decreased levels of several cytokines related to Th1 and Th2 responses in comparison to the children without infections. In contrast, FOXP3 expression was significantly decreased in highly activated (CD4+CD127-/loCD25+FOXP3high) regulatory T cells (TregFOXP3high) in the infants who had enterovirus infection during the preceding 30 or 60 days. After enterovirus infections, the cytokine profile showed an upregulation of Th1- and Th17-related cytokines and a decreased activation of CCL22, which is a chemokine derived from dendritic cells and associated with Th2 deviation. Our results reveal that immunoregulatory mechanisms are up-regulated after rhinovirus infections, while enterovirus infections are associated with activation of proinflammatory pathways and decreased immune regulation.
  • Kristensen, Peter L.; Pedersen-Bjergaard, Ulrik; Due-Andersen, Rikke; Hoi-Hansen, Thomas; Grimmeshave, Lise; Lyssenko, Valeriya; Groop, Leif; Holst, Jens J.; Vaag, Allan A.; Thorsteinsson, Birger (2016)
    Introduction: In healthy carriers of the T allele of the transcription factor 7-like 2 (TCF7L2), fasting plasma glucagon concentrations are lower compared with those with the C allele. We hypothesised that presence of the T allele is associated with a diminished glucagon response during hypoglycaemia and a higher frequency of severe hypoglycaemia (SH) in type 1 diabetes (T1DM). Material and methods: This is a post hoc study of an earlier prospective observational study of SH and four mechanistic studies of physiological responses to hypoglycaemia. 269 patients with T1DM were followed in a one-year observational study. A log-linear negative binomial model was applied with events of SH as dependent variable and TCF7L2 alleles as explanatory variable. In four experimental studies including 65 people, TCF7L2 genotyping was done and plasma glucagon concentration during experimental hypoglycaemia was determined. Results: Incidences of SH were TT 0.54, TC 0.98 and CC 1.01 episodes per patient-year with no significant difference between groups. During experimental hypoglycaemia, the TCF7L2 polymorphism did not influence glucagon secretion. Discussion: Patients with T1DM carrying the T allele of the TCF7L2 polymorphism do not exhibit diminished glucagon response during hypoglycaemia and are not at increased risk of severe hypoglycaemia compared with carriers of the C allele.
  • Lehtonen, Kaisa (Helsingfors universitet, 2013)
    For patients with type 1 diabetes maintaining normal blood glucose concentration and avoiding hypoglycemia during physical activity can be difficult. Diabetes may also affect other physiological responses related to exercise, e.g. local muscle oxygenation. Right preparation for exercise and carbohydrate consumption during exercise could help type 1 diabetics to perform physical activity as recommended. The objective of this exploratory study was to compare the effects of water, sports drink and blackcurrant juice on blood glucose concentration, oxidative stress and muscle oxygenation in type 1 diabetic and healthy men during moderate intensity aerobic exercise. Five type 1 diabetic and six age-matched healthy men (age18–45 y) participated in the study. The volunteers performed three 1 h exercise tests on cycle ergometer at their previously measured aerobic threshold intensity. During the tests, the subjects drank in randomized order a total of 0.13 dl/kg of water, sports drink or blackcurrant juice. The sports drink and juice contained carbohydrates 5.8 g / 100 g. Capillary blood glucose, whole blood reduced and oxidized glutathione (a marker of oxidative stress), plasma nitrate and nitrite (a marker of nitric oxide) and local active and inactive muscle oxygenation (by near infrared spectroscopy) were measured. In addition, alveolar gas exchange and cardiac output were measured. Exercise sessions of type 1 diabetics were stopped if capillary blood glucose declined below 5.0 mmol/l. Statistical analysis were performed using general estimation equations. Results were considered significant if p<0.05. Capillary blood glucose concentration in type 1 diabetics declined with each drink (p<0.05). The concentrations before and after cycle ergometer exercise [mean (standard deviation)] were: water 9.44 (2.27) and 5.76 (3.05) mmol/l, sports drink 7.58 (1.46) and 5.74 (1.43) mmol/l and juice 7.96 (1.15) and 5.62 (0.82) mmol/l. One or more of the tests of three diabetics had to be stopped (all the trials, the water and sports drink trial and only water trial). Blood glucose declined more during water trial compared to carbohydrate drink trials (p<0.05). In healthy men, blood glucose concentration did not change during exercise tests. In healthy men and in type 1 diabetics, active muscle oxygenation index indicated that oxygenation was maintained better when juice was drank compared to sports drink (p<0.05). Also oxy- and/or deoxyhemoglobin concentration changes differed in the same way as oxygenation index between juice and sports drink in diabetics (p<0.05) and between juice and water in healthy men (p<0.05), but in pairwise comparisons these results were significant only in some single time points. None of the muscle oxygenation responses differed between healthy and diabetic subjects. Plasma nitrate and nitrite did not differ between the drinks or study groups. The glutathione results could not be interpreted as some of the blood samples had to be rejected. During moderate intensity exercise, it is challenging for type 1 diabetics to maintain blood glucose concentration within safety limits. Nevertheless, blood glucose concentration will decline less if a drink containing carbohydrates is consumed instead of water. Further studies considering type 1 diabetes, nutrition and exercise have to be carried out and this trial may offer some valuable assistance for planning such work.
  • Hekkala, Anne M.; Ilonen, Jorma; Toppari, Jorma; Knip, Mikael; Veijola, Riitta (2018)
    We studied the frequency of diabetic ketoacidosis (DKA) in children at diagnosis of type 1 diabetes (T1D) in a region where newborn infants have since 1995 been recruited for genetic screening for human leukocyte antigen (HLA)-conferred disease susceptibility and prospective follow up. The aim was to study whether participation in newborn screening and follow up affected the frequency of DKA, and to follow the time trends in DKA frequency. We first included children born in Oulu University Hospital since 1995 when the prospective studies have been ongoing and diagnosed with T1D
  • Mattila, Markus; Hakola, Leena; Niinisto, Sari; Tapanainen, Heli; Takkinen, Hanna-Mari; Ahonen, Suvi; Ilonen, Jorma; Toppari, Jorma; Veijola, Riitta; Knip, Mikael; Virtanen, Suvi M. (2021)
    Our aim was to study the associations between maternal vitamin C and iron intake during pregnancy and the offspring's risk of developing islet autoimmunity and type 1 diabetes. The study was a part of the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) prospective birth cohort including children genetically at risk of type 1 diabetes born between 1997-2004. The diets of 4879 mothers in late pregnancy were assessed with a validated food frequency questionnaire. The outcomes were islet autoimmunity and type 1 diabetes. Cox proportional hazards regression analysis adjusted for energy, family history of diabetes, human leukocyte antigen (HLA) genotype and sex was used for statistical analyses. Total intake of vitamin C or iron from food and supplements was not associated with the risk of islet autoimmunity (vitamin C: HR 0.91: 95% CI (0.80, 1.03), iron: 0.98 (0.87, 1.10)) or type 1 diabetes (vitamin C: 1.01 (0.87, 1.17), iron: 0.92 (0.78, 1.08)), neither was the use of vitamin C or iron supplements associated with the outcomes. In conclusion, no association was found between maternal vitamin C or iron intake during pregnancy and the risk of islet autoimmunity or type 1 diabetes in the offspring.