Browsing by Subject "Type 1 diabetes"

Sort by: Order: Results:

Now showing items 1-20 of 51
  • Lonnrot, Maria; Lynch, Kristian; Larsson, Helena Elding; Lernmark, Ake; Rewers, Marian; Hagopian, William; She, Jin-Xiong; Simell, Olli; Ziegler, Anette-G; Akolkar, Beena; Krischer, Jeffrey; Hyoty, Heikki; TEDDY Study Grp; Knip, Mikael (2015)
    Background: Early childhood environmental exposures, possibly infections, may be responsible for triggering islet autoimmunity and progression to type 1 diabetes (T1D). The Environmental Determinants of Diabetes in the Young (TEDDY) follows children with increased HLA-related genetic risk for future T1D. TEDDY asks parents to prospectively record the child's infections using a diary book. The present paper shows how these large amounts of partially structured data were reduced into quantitative data-sets and further categorized into system-specific infectious disease episodes. The numbers and frequencies of acute infections and infectious episodes are shown. Methods: Study subjects (n = 3463) included children who had attended study visits every three months from age 3 months to 4 years, without missing two or more consecutive visits during the follow-up. Parents recorded illnesses prospectively in a TEDDY Book at home. The data were entered into the study database during study visits using ICD-10 codes by a research nurse. TEDDY investigators grouped ICD-10 codes and fever reports into infectious disease entities and further arranged them into four main categories of infectious episodes: respiratory, gastrointestinal, other, and unknown febrile episodes. Incidence rate of infections was modeled as function of gender, HLA-DQ genetic risk group and study center using the Poisson regression. Results: A total of 113,884 ICD-10 code reports for infectious diseases recorded in the database were reduced to 71,578 infectious episodes, including 74.0% respiratory, 13.1% gastrointestinal, 5.7% other infectious episodes and 7.2% febrile episodes. Respiratory and gastrointestinal infectious episodes were more frequent during winter. Infectious episode rates peaked at 6 months and began declining after 18 months of age. The overall infectious episode rate was 5.2 episodes per person-year and varied significantly by country of residence, sex and HLA genotype. Conclusions: The data reduction and categorization process developed by TEDDY enables analysis of single infectious agents as well as larger arrays of infectious agents or clinical disease entities. The preliminary descriptive analyses of the incidence of infections among TEDDY participants younger than 4 years fits well with general knowledge of infectious disease epidemiology. This protocol can be used as a template in forthcoming time-dependent TEDDY analyses and in other epidemiological studies.
  • Limonte, Christine P.; Valo, Erkka; Montemayor, Daniel; Afshinnia, Farsad; Ahluwalia, Tarunveer S.; Costacou, Tina; Darshi, Manjula; Forsblom, Carol; Hoofnagle, Andrew N.; Groop, Per-Henrik; Miller, Rachel G.; Orchard, Trevor J.; Pennathur, Subramaniam; Rossing, Peter; Sandholm, Niina; Snell-Bergeon, Janet K.; Ye, Hongping; Zhang, Jing; Natarajan, Loki; de Boer, Ian H.; Sharma, Kumar (2020)
    Background: Individuals with type 1 diabetes (T1D) demonstrate varied trajectories of estimated glomerular filtration rate (eGFR) decline. The molecular pathways underlying rapid eGFR decline in T1D are poorly understood, and individual-level risk of rapid eGFR decline is difficult to predict. Methods: We designed a case-control study with multiple exposure measurements nested within 4 well-characterized T1D cohorts (FinnDiane, Steno, EDC, and CACTI) to identify biomarkers associated with rapid eGFR decline. Here, we report the rationale for and design of these studies as well as results of models testing associations of clinical characteristics with rapid eGFR decline in the study population, upon which "omics" studies will be built. Cases (n = 535) and controls (n = 895) were defined as having an annual eGFR decline of >= 3 and
  • Ahola, A. J.; Forsblom, C.; Groop, Per-Henrik (2018)
    Not much is known about adherence to special diets in type 1 diabetes, characteristics of individuals with special diets, and whether such practices should raise concerns with respect to meeting the dietary recommendations. In this study, we assessed the frequencies of adherence to special diets, in a population of individuals with type 1 diabetes, and investigated the association between special diet adherence and dietary intake, measured as dietary patterns and nutrient intakes. During the Finnish Diabetic Nephropathy Study visit, participants with type 1 diabetes (n = 1429) were instructed to complete a diet questionnaire inquiring about the adherence to special diets. The participants also completed a food record, from which energy and nutrient intakes were calculated. In all, 36.6% participants reported adhering to some special diet. Most commonly reported special diets were lactose-free (17.1%), protein restriction (10.0%), vegetarian (7.0%), and gluten-free (5.6%) diet. Special diet adherents were more frequently women, older, had longer diabetes duration, and more frequently had various diabetes complications. Mean carbohydrate intakes were close to the lower levels of the recommendation in all diet groups, which was reflected in low mean fibre intakes but high frequencies of meeting the sucrose recommendations. The recommendation for saturated fatty acid intake was frequently unmet, with the highest frequencies observed in vegetarians. Of the micronutrients, vitamin D, folate, and iron recommendations were most frequently unmet, with some differences between the diet groups. Special diets are frequently followed by individuals with type 1 diabetes. The adherents are more frequently women, and have longer diabetes duration and more diabetes complications. Achieving the dietary recommendations differed between diets, and depended on the nutrient in question. Overall, intakes of fibre, vitamin D, folate, and iron fell short of the recommendations.
  • Harjutsalo, Valma; Maric-Bilkan, Christine; Forsblom, Carol; Groop, Per-Henrik; FinnDiane Study Grp (2016)
    Aims/hypothesis The aim of this study was to evaluate the relationship among age at onset of diabetes, age at onset of menarche and risk of diabetic nephropathy and laser-treated retinopathy in type 1 diabetes. Methods Data related to age at menarche were collected through questionnaires and were available for 1,304 women who participated in the Finnish Diabetic Nephropathy Study (FinnDiane). A possible association between age at menarche and diabetic nephropathy and retinopathy was investigated. Results There was an inverse relationship between the age at onset of diabetes and age at menarche: the younger the age at onset of diabetes, the higher the age at menarche (p <0.0001). A non-linear relationship between the age of menarche and risk of diabetic microvascular complications was found in patients with diabetes onset before menarche, but there was no such association in patients with diabetes onset after menarche. Women with delayed menarche (> mean age+ 2 years) had a 2.30 (95% CI 1.27, 4.17; p <0.006) times higher risk of nephropathy compared with the women who underwent menarche at the mean age +/- 2 years. Delayed menarche also increased the risk of retinopathy (OR 2.34 [95% CI 1.36, 4.01]). After excluding patients with nephropathy, the OR for retinopathy was 2.11 (95% CI 1.15, 3.90). Earlier menarche (<mean age-2 years) did not have any effect on this risk. Conclusions/interpretation Delayed menarche was associated with an increased risk of diabetic nephropathy and retinopathy, whereas early menarche was not. Delayed menarche may be used as a new tool to identify women at risk of diabetic microvascular complications.
  • Finndiane Study Grp (2018)
    Aims/hypothesis This study aimed to assess the use of ambulatory BP monitoring (ABPM) to identify the presence of masked, nocturnal and white-coat hypertension in individuals with type 1 diabetes, patterns that could not be detected by regular office-based BP monitoring alone. We also analysed associations between BP patterns and arterial stiffness in order to identify individuals at cardiovascular risk. Methods This substudy included 140 individuals with type 1 diabetes from the Helsinki metropolitan area, who attended the Finnish Diabetic Nephropathy Study (FinnDiane) Centre in Helsinki between January 2013 and August 2017. Twenty-four hour ABPM and pulse wave analysis were performed simultaneously using a validated non-invasive brachial oscillometric device (Mobil-O-Graph). Definitions of hypertension were based on the European Society of Hypertension guidelines. Masked hypertension was defined as normal office BP (BP obtained using a standardised automated BP device) but elevated 24 h ABPM, and white-coat hypertension as elevated office BP but normal 24 h ABPM. Results A total of 38% of individuals were normotensive and 33% had sustained hypertension, while 23% had masked and 6% had white-coat hypertension. About half of the cohort had increased absolute levels of night-time BP, half of whom were untreated. In the ambulatory setting, central BP and pulse wave velocity (PWV) were higher in participants with masked hypertension than in those with normotension (p <0.001). In a multivariable linear regression model adjusted for age, sex, BMI, antihypertensive treatment and eGFR, masked hypertension was independently associated with higher 24 h PWV ((3 0.50 [95% CI 0.34, 0.66]), but not with PWV obtained during resting conditions (adjusted 13 0.28 [95% CI -0.53, 1.10]), using normotension as the reference group. Conclusions/interpretation ABPM analysis revealed that one-quarter of the participants with type 1 diabetes had masked hypertension; these individuals would not have been detected by office BP alone. Moreover, arterial stiffness was increased in individuals with masked hypertension. These findings support the use of ABPM to identify individuals at risk of cardiovascular disease.
  • Ahola, Aila J.; Saraheimo, Markku; Freese, Riitta; Forsblom, Carol; Mäkimattila, Sari; Groop, Per-Henrik; FinnDiane Study Grp (2017)
    Aims: Inflammation plays an important role in the pathogenesis of cardiovascular diseases. Diet, as a modifiable risk factor, may in turn impact systemic inflammation. We therefore assessed whether adherence to the dietary recommendations is associated with high-sensitivity C-reactive protein (hs-CRP) concentrations in type 1 diabetes. Methods: Cross-sectional data from 677 FinnDiane study participants (48% men, mean +/- standard deviation age 46 +/- 13 years) were included. Dietary intake was assessed with a self-administered questionnaire. A diet score, with higher values denoting better adherence to the recommendations, was calculated. Serum hs-CRP concentration was measured, and individuals with hs-CRP <1.0 mg/l, and hs-CRP > 3.0 but <10.0 mg/l were compared. Results: Men and women with high hs-CRP had higher BMI, waist circumference, and triglyceride concentration, but lower HDL-cholesterol concentration. Adjusted for BMI, mean diet score was higher in the low hs-CRP group, both in men (10.8 +/- 3.6 vs. 9.9 +/- 3.8, p = 0.023) and women (12.7 +/- 3.4 vs. 11.6 +/- 3.5, p = 0.021). After further adjustments with potential confounding factors, the difference remained significant only in men. Conclusions: A diet that more closely adheres to the dietary recommendations is associated with lower hs-CRP in men. A prudent diet may help reduce systemic inflammation in type 1 diabetes. (C) 2017 Elsevier B.V. All rights reserved.
  • Finndiane Study Grp (2018)
    Background and aims: Increased arterial stiffness contributes to diabetic vascular complications. We identified dietary factors related to arterial stiffness in individuals with type 1 diabetes, a population with high risk of cardiovascular disease. Methods and results: Altogether, 612 participants (40% men, mean +/- standard deviation age 45 +/- 13 years) completed a validated diet questionnaire and underwent measurements of arterial stiffness. Of these, 470 additionally completed a food record. Exploratory factor analysis was applied to identify dietary patterns from the diet questionnaires, and nutrient intakes were calculated from food record entries. Arterial stiffness was measured by applanation tonometry. Of the seven dietary factors formed, the factor scores of "Full-fat cheese and eggs" and "Sweet" patterns were negatively associated with measures of arterial stiffness. In the multivariable macronutrient substitution models, favouring carbohydrates over fats was associated with higher aortic mean arterial pressure and aortic pulse wave velocity. When carbohydrates were consumed in place of proteins, higher aortic pulse pressure, aortic mean arterial pressure, and augmentation index were recorded. Replacing energy from alcohol with proteins, was associated with lower aortic pulse pressure, aortic mean arterial pressure, and augmentation index. Relative distributions of dietary fatty acids were neutral with respect to the measures of arterial stiffness. Conclusion: The macronutrient distribution of the diet is likely to affect the resilience of the arteries. Our observations suggest that reducing energy intake from carbohydrates and alcohol may be beneficial. These observations, especially those dealing with dietary patterns, need to be confirmed in a longitudinal study. (C) 2018 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.
  • TRIGR Investigators; Pacaud, Daniele; Nucci, Anita M.; Cuthbertson, David; Becker, Dorothy J.; Virtanen, Suvi M.; Ludvigsson, Johnny; Ilonen, Jorma; Knip, Mikael (2021)
    Aims/hypothesis The aim of this work was to examine the relationship between family history of type 1 diabetes, birthweight, growth during the first 2 years and development of multiple beta cell autoantibodies in children with a first-degree relative with type 1 diabetes and HLA-conferred disease susceptibility. Methods In a secondary analysis of the Trial to Reduce IDDM in the Genetically at Risk (TRIGR), clinical characteristics and development of beta cell autoantibodies were compared in relation to family history of type 1 diabetes (mother vs father vs sibling) in 2074 children from families with a single affected family member. Results Multiple autoantibodies (>= 2 of 5 measured) developed in 277 (13%) children: 107 (10%), 114 (16%) and 56 (18%) born with a mother, father or sibling with type 1 diabetes, respectively (p <0.001). The HR for time to multiple autoimmunity was 0.54 (95% CI 0.39, 0.75) in offspring of affected mothers (n = 107/1046,p <0.001) and 0.81 (95% CI 0.59, 1.11) (n = 114/722,p = 0.19) in offspring of affected fathers, compared with participants with a sibling with type 1 diabetes (comparator groupn = 56/306). The time to the first autoantibody present (to insulin, GAD, tyrosine phosphatase-related insulinoma-associated 2 molecules, islet cell or zinc transporter 8) was similar in the three groups. Height velocity (zscore/year) in the first 24 months was independently associated with developing multiple antibodies in the total cohort (HR 1.31 [95% CI 1.01, 1.70],p = 0.04). A higher birthweight in children born to an affected mother vs affected father or an affected sibling was not related to the risk of multiple autoimmunity. Conclusions/interpretation The risk of developing multiple autoantibodies was lower in children with maternal type 1 diabetes. For the whole group, this risk of developing multiple autoantibodies was independent of birthweight but was greater in those with increased height velocity during the first 2 years of life. However, the risk associated with paternal type 1 diabetes was not linked to differences in birthweight or early growth.
  • Finndiane Study Grp (2018)
    Background and aims: In the general population, habitual coffee consumption is inversely associated with the metabolic syndrome, a syndrome that is rather common also in patients with type 1 diabetes. However, whether coffee intake is beneficially related to the metabolic syndrome also in type 1 diabetes, is not known. We, therefore, studied the potential association between coffee consumption and the metabolic syndrome in a large population of individuals with type 1 diabetes. Furthermore, we investigated whether coffee consumption is associated with insulin resistance (estimated glucose disposal rate, eGDR), kidney function (estimated glomerular filtration rate, eGFR), and low-grade chronic inflammation (high-sensitivity C-reactive protein, hsCRP). Methods and results: Data from 1040 participants in the Finnish Diabetic Nephropathy Study were included in these cross-sectional analyses. Metabolic syndrome was assumed if at least 3 of the following cardiovascular risk factors were present: central obesity, high blood pressure, low HDL-cholesterol concentration, high triglyceride concentration, and hyperglycaemia. Subjects were categorized based on self-reported daily coffee intake: non-consumers (= 1 cups/d <3), moderate (>= 3 cups/d <5), and high coffee consumption (>= 5 cups/d). In multivariable logistic regression analysis, moderate and high coffee consumption was associated with increased odds of the metabolic syndrome. Moreover, any level of coffee consumption was associated with increased risk of the blood pressure-component. An increasing trend was observed in the eGFR with increasing coffee consumption. Conclusions: In type 1 diabetes, high coffee intake is associated with the metabolic syndrome, and especially its blood pressure-component. (C) 2018 Published by Elsevier B.V.
  • Ahola, Aila J.; Radzeviciene, Lina; Zaharenko, Linda; Bulum, Tomislav; Skrebinska, Sabine; Prakapiene, Edita; Blaslov, Kristina; Roso, Vinko; Rovite, Vita; Pirags, Valdis; Duvnjak, Lea; Sokolovska, Jelizaveta; Verkauskiene, Rasa; Forsblom, Carol (2020)
    Aims: To investigate the association between depressive symptomatology and health markers in type 1 diabetes. Methods: Four countries from the InterDiane Consortium had adopted the Finnish Diabetic Nephropathy Study protocol, including the Beck Depression Inventory (BDI). Associations between depression symptomatology, diabetes complications (diabetic nephropathy, proliferative retinopathy, major adverse cardiovascular events [MACE]) and vascular risk factors (metabolic syndrome, body mass index, glycaemic control) were investigated. Results: In a sample of 1046 participants (Croatia n = 99; Finland n = 314; Latvia n = 315; Lithuania n = 318), 13.4% displayed symptoms of depression (BDI score 16) with no statistically significant difference in the prevalence of depression among the cohorts. The highest rates of diabetic nephropathy (37.1%) and proliferative retinopathy (36.3%) were observed in Lithuania. The rates of MACE and metabolic syndrome were highest in Finland. In joint analyses, individuals exhibiting depression symptomatology had higher HbA(1c) (79 vs. 72 mmol/mol, p <0.001) and higher triglyceride concentration (1.67 vs. 1.28 mmol/l, p <0.001), than those without. In the multivariable model, BDI score was positively associated with the presence of diabetic nephropathy, proliferative retinopathy, MACE, and metabolic syndrome and its triglyceride component. Moreover, BDI score was positively associated with the number of metabolic syndrome components, triglyceride concentration, and HbA(1c). Conclusions: Comorbid depression should be considered a relevant factor explaining metabolic problems and vascular outcomes. Causality cannot be inferred from this crosssectional study. (c) 2020 Elsevier B.V. All rights reserved.
  • Kurkela, Olli; Forma, Leena; Ilanne-Parikka, Pirjo; Nevalainen, Jaakko; Rissanen, Pekka (2021)
    Aims/hypothesis Diabetes and diabetes complications are a cause of substantial morbidity, resulting in early exits from the labour force and lost productivity. The aim of this study was to examine differences in early exits between people with type 1 and 2 diabetes and to assess the role of chronic diabetes complications on early exit. We also estimated the economic burden of lost productivity due to early exits. Methods People of working age (age 17-64) with diabetes in 1998-2011 in Finland were detected using national registers (N-type 1 = 45,756, N-type 2 = 299,931). For the open cohort, data on pensions and deaths, healthcare usage, medications and basic demographics were collected from the registers. The outcome of the study was early exit from the labour force defined as pension other than old age pension beginning before age 65, or death before age 65. We analysed the early exit outcome and its risk factors using the Kaplan-Meier method and extended Cox regression models. We fitted linear regression models to investigate the risk factors of lost working years and productivity costs among people with early exit. Results The difference in median age at early exit from the labour force between type 1 (54.0) and type 2 (58.3) diabetes groups was 4.3 years. The risk of early exit among people with type 1 diabetes increased faster after age 40 compared with people with type 2 diabetes. Each of the diabetes complications was associated with an increase in the hazard of early exit regardless of diabetes type compared with people without the complication, with eye-related complications as an exception. Diabetes complications partly but not completely explained the difference between diabetes types. The mean lost working years was 6.0 years greater in the type 1 diabetes group than in the type 2 diabetes group among people with early exit. Mean productivity costs of people with type 1 diabetes and early exit were found to be 1.4-fold greater compared with people with type 2 diabetes. The total productivity costs of incidences of early exits in the type 2 diabetes group were notably higher compared with the type 1 group during the time period (euro14,400 million, euro2800 million). Conclusions/interpretation We found a marked difference in the patterns of risk of early exit between people with type 1 and type 2 diabetes. The difference was largest close to statutory retirement age. On average, exits in the type 1 diabetes group occurred at an earlier age and resulted in higher mean lost working years and mean productivity costs. The potential of prevention, timely diagnosis and management of diabetes is substantial in terms of avoiding reductions in individual well-being and productivity.
  • Krischer, Jeffrey P.; Cuthbertson, David; Couluris, Marisa; Knip, Mikael; Virtanen, Suvi M. (2020)
    Aims/hypothesis This paper presents the relationship between islet autoantibodies, precursors of type 1 diabetes, and the development of persistent asthma, allergic rhinitis and atopic eczema. Methods A total of 2159 newborns who had a first-degree relative with type 1 diabetes and selected HLA genotypes were followed until the youngest participant reached 10 years of age. Islet cell antibodies (ICA) were detected using indirect immunofluorescence. Autoantibodies to insulin (IAA), GAD (GADA), the tyrosine phosphatase-related insulinoma-associated 2 molecule (IA-2A) and zinc transporter 8 (ZnT8A) were quantified with the use of specific radiobinding assays. As an ancillary study, the incidence of asthma, allergic rhinitis and eczema was assessed in 1106 of these children using the International Study of Asthma and Allergies in Childhood (ISAAC) core questionnaire when the children were 9-11 years old. HRs with 95% CIs were calculated to depict the incidence of these diseases following seroconversion to autoantibody positivity. Results The cumulative incidence of atopic eczema, allergic rhinitis and persistent asthma were 22%, 9% and 7.5%, respectively, by 9-11 years of age. The occurrence of diabetes-related autoantibodies showed a protective association with subsequently reported incidence of asthma and eczema. The incidence of rhinitis was not significantly related to the occurrence of IAA or GADA (statistical power was limited), but demonstrated the same inverse relationship as did the other diseases with ICA or when multiple autoantibodies first appeared together. Conclusions/interpretation The findings add evidence to the relationships between these atopic diseases and diabetes-related autoimmunity and also suggest that, for eczema, the interaction depends upon which autoantibody appeared first.
  • Pollanen, Petra M.; Lempainen, Johanna; Laine, Antti-Pekka; Toppari, Jorma; Veijola, Riitta; Vahasalo, Paula; Ilonen, Jorma; Siljander, Heli; Knip, Mikael (2017)
    Aims/hypothesis In this study, we aimed to characterise rapid progressors to type 1 diabetes among children recruited from the general population, on the basis of HLA-conferred disease susceptibility. Methods We monitored 7410 HLA-predisposed children participating in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study for the development of beta cell autoimmunity and type 1 diabetes from birth over a median follow-up time of 16.2 years (range 0.9-21.1 years). Islet cell antibodies (ICA) and autoantibodies to insulin (IAA), GAD (GADA) and islet antigen 2 (IA-2A) were assessed as markers of beta cell autoimmunity. Rapid progression was defined as progression to clinical type 1 diabetes within 1.5 years of autoantibody seroconversion. We analysed the association between rapid progression and demographic and autoantibody characteristics as well as genetic markers, including 25 non-HLA SNPs predisposing to type 1 diabetes. Results Altogether, 1550 children (21%) tested positive for at least one diabetes-associated autoantibody in at least two samples, and 248 (16%) of seroconverters progressed to type 1 diabetes by the end of 2015. The median time from seroconversion to diagnosis was 0.51 years in rapid progressors (n = 42, 17%) and 5.4 years in slower progressors. Rapid progression was observed both among young (<5 years) and early pubertal children (> 7 years), resulting in a double-peak distribution of seroconversion age. Compared with slower progressors, rapid progressors had a higher frequency of positivity for multiple (>= 2) autoantibodies and had higher titres of ICA, IAA and IA-2A at seroconversion, and there was a higher prevalence of the secretor genotype in the FUT2 gene among those carrying the high-risk HLA genotype. Compared with autoantibody-positive non-progressors, rapid progressors were younger, were more likely to carry the high-risk HLA genotype and a predisposing SNP in the PTPN22 gene, had higher frequency of ICA, IAA, GADA and IA-2A positivity and multipositivity, and had higher titres of all four autoantibodies at seroconversion. Conclusions/interpretation At seroconversion, individuals with rapid progression to type 1 diabetes were characterised by a younger age, higher autoantibody titres, positivity for multiple autoantibodies and higher prevalence of a FUT2 SNP. The double-peak profile for seroconversion age among the rapid progressors demonstrates for the first time that rapid progression may take place not only in young children but also in children in early puberty. Rapid progressors might benefit from careful clinical follow-up and early preventive measures.
  • Pöllänen, Petra (Helsingfors universitet, 2016)
    Aims/hypothesis To characterise rapid progressors to type 1 diabetes among children recruited from the general population based on HLA-conferred disease susceptibility. Methods We observed 7410 HLA-predisposed children participating in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Study from birth for development of beta cell autoimmunity and type 1 diabetes over a median follow-up time of 16.2 (range 0.9-21.1) years. Islet cell antibodies, and autoantibodies to insulin (IAA), GAD (GADA), and islet antigen 2 (IA-2A) were analysed as markers of beta cell autoimmunity. Rapid progression was defined as progression to clinical type 1 diabetes within 1.5 years after autoantibody seroconversion. We analysed the association between rapid progression and demographic and autoantibody characteristics as well as genetic markers including 25 non-HLA single nucleotide polymorphisms (SNPs) predisposing to type 1 diabetes. Results Altogether 1645 children (22%) tested positive for at least one diabetes-associated autoantibody, and 248 (15%) of the seroconverters progressed to type 1 diabetes by the end of 2015. The median time from seroconversion to diagnosis was 0.51 years in rapid progressors (n=42, 17%), and 5.4 years in slower progressors. Rapid progression was observed both among young and early pubertal children. Compared to slower progressors, rapid progressors had higher frequency of multipositivity, higher titres of ICA, IAA, and IA-2A at seroconversion, and higher prevalence of the secretor genotype in the FUT2 gene. Compared to autoantibody-positive non-progressors, rapid progressors were younger, carried more often the high-risk HLA genotype, the FUT2 secretor genotype, and a predisposing SNP in the PTPN22 gene, had higher frequency of ICA, IAA, GADA, IA-2A, and multipositivity, and higher titres of all four autoantibodies at seroconversion. Conclusions At seroconversion, individuals with rapid progression to type 1 diabetes are characterised by young age, higher autoantibody titres, positivity for multiple autoantibodies, and higher prevalence of a FUT2 SNP. The double-peak profile of seroconversion age among the rapid progressors demonstrates for the first time that rapid progression may take place not only in young children, but also in children in early puberty. Rapid progressors might benefit from careful clinical follow-up and early preventive measures.
  • Finnish Pediat Diabet Register; Turtinen, Maaret; Härkönen, Taina; Parkkola, Anna; Ilonen, Jorma; Knip, Mikael (2019)
    Aims/hypothesis In previous studies, the risk of developing familial type 1 diabetes has been reported to be more than two times higher in the offspring of affected fathers than in those of affected mothers. We tested the hypothesis that index children with an affected father may have a more aggressive disease process at diagnosis than those with other affected first-degree relatives. Methods A cross-sectional, observational study was performed using the Finnish Pediatric Diabetes Register. Clinical and metabolic characteristics, beta cell autoantibodies and HLA class II genetics were analysed from index children in Finland diagnosed before the age of 15 years between January 2003 and December 2016. Information on the presence of type 1 diabetes in first-degree relatives was collected at diagnosis using a structured questionnaire. Results Out of 4993 newly diagnosed index children, 519 (10.4%) had familial type 1 diabetes. More than 5% (n = 253, 5.1%) had an affected father, 2.8% (n = 141) had an affected mother, 1.9% (n = 95) had an affected sibling and 0.6% (n = 30) had two or more affected family members. All clinical and metabolic variables were markedly poorer in children with sporadic vs familial diabetes. The index children with an affected father or mother were younger than those with an affected sibling (median age 7.59 vs 6.74 vs 10.73 years, respectively; p <0.001). After age- and sex-adjusted analyses, index children with an affected father presented more often with ketoacidosis (9.7% vs 3.6%; p = 0.033) and had greater weight loss before diagnosis (3.2% vs 0%; p = 0.006) than those with an affected mother. Children with familial disease tested negative for all autoantibodies more often (3.5% vs 2.1%; p = 0.041) and had insulin autoantibodies more frequently (49.8% vs 42.2%; p = 0.004) than those with sporadic disease. Both major HLA risk haplotypes (DR3-DQ2 and DR4-DQ8) were more often lacking among children with sporadic vs familial disease (15.9% vs 11.2%; p = 0.006). The DR4-DQ8 haplotype was more frequent in the familial vs the sporadic group (75.7% vs 68.5%; p = 0.001) and especially among children with an affected father when compared with children with sporadic disease (77.5% vs 68.5%; p <0.05). When comparing index children with affected parents diagnosed before or after the birth of the index child, a clear male preponderance was seen among the affected parents diagnosed before the birth of the index child (fathers 66.2% vs mothers 33.8%; p = 0.006), whereas the proportion of fathers and mothers was similar if type 1 diabetes was diagnosed after the birth of the index child. Conclusions/interpretation The more severe metabolic derangement at diagnosis in children with sporadic type 1 diabetes compared with those with familial type 1 diabetes was confirmed. The higher frequency of diabetic ketoacidosis and increased weight loss at diagnosis in index children with an affected father compared with an affected mother support the hypothesis that paternal type 1 diabetes is associated with more severe disease in the offspring than maternal diabetes. The sex difference seen between affected parents diagnosed before and after the birth of the index child supports the hypothesis that maternal insulin treatment protects against type 1 diabetes.
  • Ekman, Ilse; Ihantola, Emmi-Leena; Viisanen, Tyyne; Rao, Deepak A.; Näntö-Salonen, Kirsti; Knip, Mikael; Veijola, Riitta; Toppari, Jorma; Ilonen, Jorma; Kinnunen, Tuure (2019)
    Aims/hypothesis Type 1 diabetes is preceded by a period of asymptomatic autoimmunity characterised by positivity for islet autoantibodies. Therefore, T helper cell responses that induce B cell activation are likely to play a critical role in the disease process. Here, we aimed to evaluate the role of a recently described subset, C-X-C motif chemokine receptor type 5-negative, programmed cell death protein 1-positive (CXCR5(-)PD-1(hi)) peripheral T helper (Tph) cells, in human type 1 diabetes. Methods The phenotype of blood CXCR5(-)PD-1(hi) CD4(+) T cells was analysed by multicolour flow cytometry. The frequencies of circulating CXCR5(-)PD-1(hi) T cells were analysed in a cohort of 44 children with newly diagnosed type 1 diabetes, 40 autoantibody-positive (AAb(+)) at-risk children and 84 autoantibody-negative healthy control children, and the findings were replicated in a separate cohort of 15 children with newly diagnosed type 1 diabetes and 15 healthy control children. Results Circulating CXCR5(-)PD-1(hi) Tph cells share several features associated with B cell helper function with circulating CXCR5(+)PD-1(hi) follicular T helper (Tfh) cells. Moreover, the frequency of circulating Tph cells was increased in children with newly diagnosed type 1 diabetes, especially in those who are positive for multiple autoantibodies. Importantly, circulating Tph cells were also increased in autoantibody-positive at-risk children who later progressed to type 1 diabetes. Conclusions/interpretation Our results demonstrate that circulating CXCR5(-)PD-1(hi) Tph cells are associated with progression to clinical type 1 diabetes. Consequently, Tph cells could have potential both as a biomarker of disease progression and as a target for immunotherapy in type 1 diabetes.
  • Lamichhane, Santosh; Kemppainen, Esko; Trost, Kajetan; Siljander, Heli; Hyöty, Heikki; Ilonen, Jorma; Toppari, Jorma; Veijola, Riitta; Hyötyläinen, Tuulia; Knip, Mikael; Oresic, Matej (2019)
    Aims/hypothesis Metabolic dysregulation may precede the onset of type 1 diabetes. However, these metabolic disturbances and their specific role in disease initiation remain poorly understood. In this study, we examined whether children who progress to type 1 diabetes have a circulatory polar metabolite profile distinct from that of children who later progress to islet autoimmunity but not type 1 diabetes and a matched control group. Methods We analysed polar metabolites from 415 longitudinal plasma samples in a prospective cohort of children in three study groups: those who progressed to type 1 diabetes; those who seroconverted to one islet autoantibody but not to type 1 diabetes; and an antibody-negative control group. Metabolites were measured using two-dimensional GC high-speed time of flight MS. Results In early infancy, progression to type 1 diabetes was associated with downregulated amino acids, sugar derivatives and fatty acids, including catabolites of microbial origin, compared with the control group. Methionine remained persistently upregulated in those progressing to type 1 diabetes compared with the control group and those who seroconverted to one islet autoantibody. The appearance of islet autoantibodies was associated with decreased glutamic and aspartic acids. Conclusions/interpretation Our findings suggest that children who progress to type 1 diabetes have a unique metabolic profile, which is, however, altered with the appearance of islet autoantibodies. Our findings may assist with early prediction of the disease.
  • Finndiane Study Grp; Härma, Mari-Anne; Dahlström, Emma H.; Sandholm, Niina; Forsblom, Carol; Groop, Per-Henrik; Lehto, Markku (2020)
    Aims/hypothesis Plasma kallikrein is the central mediator of the plasma kallikrein-kinin system, which is involved both in vascular control and thrombin formation cascades. The plasma kallikrein-kinin system has also been considered protective in pathological conditions, but the impact of plasma kallikreins on diabetic nephropathy remains unknown. The objective of this cross-sectional study was to explore the association of plasma kallikrein with diabetic nephropathy. Methods We measured plasma kallikrein activity in 295 individuals with type 1 diabetes at various stages of diabetic nephropathy, and we tested the genetic association between the plasma kallikrein-kinin system and kidney function in 4400 individuals with type 1 diabetes. Results Plasma kallikrein activity was associated with diabetes duration (p <0.001) and eGFR (p <0.001), and plasma kallikrein activity was lower with more advanced diabetic nephropathy, being lowest in individuals on dialysis. The minor alleles of theKNG1rs5030062 and rs710446 variants, which have previously been associated with increased plasma pre-kallikrein and/or factor XI (FXI) protein levels, were associated with higher eGFR (rs5030062 beta = 0.03,p = 0.01; rs710446 beta = 0.03,p = 0.005) in the FinnDiane cohort of 4400 individuals with type 1 diabetes. Conclusions/interpretation Plasma kallikrein activity and genetic variants known to increase the plasma kallikrein level are associated with higher eGFR in individuals with type 1 diabetes, suggesting that plasma kallikrein might have a protective effect in diabetic nephropathy.
  • Honkanen, Hanna; Oikarinen, Sami; Nurminen, Noora; Laitinen, Olli; Huhtala, Heini; Lehtonen, Jussi; Ruokoranta, Tanja Marjaana; Hankaniemi, Minna M.; Lecouturier, Valerie; Almond, Jeffrey; Tauriainen, Sisko; Simell, Olli; Ilonen, Jorma; Veijola, R; Viskari, Hanna; Knip, Jan Mikael; Hyöty, Heikki (2017)
    Aims/hypothesis This case-control study was nested in a prospective birth cohort to evaluate whether the presence of enteroviruses in stools was associated with the appearance of islet autoimmunity in the Type 1 Diabetes Prediction and Prevention study in Finland. Methods Altogether, 1673 longitudinal stool samples from 129 case children who turned positive for multiple islet autoantibodies and 3108 stool samples from 282 matched control children were screened for the presence of enterovirus RNA using RT-PCR. Viral genotype was detected by sequencing. Results Case children had more enterovirus infections than control children (0.8 vs 0.6 infections per child). Time-dependent analysis indicated that this excess of infections occurred more than 1 year before the first detection of islet autoantibodies (6.3 vs 2.1 infections per 10 follow-up years). No such difference was seen in infections occurring less than 1 year before islet autoantibody seroconversion or after seroconversion. The most frequent enterovirus types included coxsackievirus A4 (28% of genotyped viruses), coxsackievirus A2 (14%) and coxsackievirus A16 (11%). Conculusion/hypothesis The results suggest that enterovirus infections diagnosed by detecting viral RNA in stools are associated with the development of islet autoimmunity with a time lag of several months.
  • The FinnDiane Study Group; Ahola, Aila J.; Forsblom, Carol; Harjutsalo, Valma; Groop, Per-Henrik (2019)
    Aims Low-carbohydrate diet (LCD) has gained interest among individuals with diabetes as a means to manage glycaemia. We investigated the adherence to LCD in the Finnish Diabetic Nephropathy Study and whether carbohydrate restriction is associated with cardio-metabolic risk factors. Methods Cross-sectional data were available from 902 individuals with type 1 diabetes (44% men, age 47±13 years). Dietary data were collected twice with a 3-day diet record. Mean of the measurements was used. Carbohydrate intake 253 g/day or >48 E%). In the whole population, carbohydrate-to-fat ratio was calculated and its association with health variables was investigated. Results Higher carbohydrate-to-fat ratio was associated with higher blood glucose variability, higher blood pressure, lower HDL cholesterol concentration, and in men with lower waist-to-hip ratio. LCD adherence (n=69) was associated with lower BMI (25.6 vs. 27.8 kg/m2, p=0.030), lower variability of blood glucose measurements (0.38 vs. 0.45 mmol/l, p=0.030), and lower diastolic blood pressure (74 vs. 79 mmHg, p=0.048). Men reporting LCD had higher total (5.1 vs. 4.0 mmol/l, p=0.007) and non-HDL cholesterol (3.4 vs. 2.7 mmol/l, p=0.021). Women with LCD had higher HDL-cholesterol concentration (1.9 vs. 1.5 mmol/l, p=0.014). Conclusions Reduced blood glucose variability, related to LCD, could have clinical relevance to individuals with type 1 diabetes.