Browsing by Subject "BETA-CELL AUTOIMMUNITY"

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  • Syrjälä, Essi; Nevalainen, Jaakko; Peltonen, Jaakko; Takkinen, Hanna-Mari; Hakola, Leena; Åkerlund, Mari; Veijola, Riitta; Ilonen, Jorma; Toppari, Jorma; Knip, Mikael; Virtanen, Suvi M. (2019)
    Several dietary factors have been suspected to play a role in the development of advanced islet autoimmunity (IA) and/or type 1 diabetes (T1D), but the evidence is fragmentary. A prospective population-based cohort of 6081 Finnish newborn infants with HLA-DQB1-conferred susceptibility to T1D was followed up to 15 years of age. Diabetes-associated autoantibodies and diet were assessed at 3-to 12-month intervals. We aimed to study the association between consumption of selected foods and the development of advanced IA longitudinally with Cox regression models (CRM), basic joint models (JM) and joint latent class mixed models (JLCMM). The associations of these foods to T1D risk were also studied to investigate consistency between alternative endpoints. The JM showed a marginal association between meat consumption and advanced IA: the hazard ratio adjusted for selected confounding factors was 1.06 (95% CI: 1.00, 1.12). The JLCMM identified two classes in the consumption trajectories of fish and a marginal protective association for high consumers compared to low consumers: the adjusted hazard ratio was 0.68 (0.44, 1.05). Similar findings were obtained for T1D risk with adjusted hazard ratios of 1.13 (1.02, 1.24) for meat and 0.45 (0.23, 0.86) for fish consumption. Estimates from the CRMs were closer to unity and CIs were narrower compared to the JMs. Findings indicate that intake of meat might be directly and fish inversely associated with the development of advanced IA and T1D, and that disease hazards in longitudinal nutritional epidemiology are more appropriately modeled by joint models than with naive approaches.
  • Lamichhane, Santosh; Ahonen, Linda; Dyrlund, Thomas Sparholt; Siljander, Heli; Hyöty, Heikki; Ilonen, Jorma; Toppari, Jorma; Veijola, Riitta; Hyötyläinen, Tuulia; Knip, Mikael; Oresic, Matej (2018)
    Early prediction and prevention of type 1 diabetes (T1D) are currently unmet medical needs. Previous metabolomics studies suggest that children who develop T1D are characterised by a distinct metabolic profile already detectable during infancy, prior to the onset of islet autoimmunity. However, the specificity of persistent metabolic disturbances in relation T1D development has not yet been established. Here, we report a longitudinal plasma lipidomics dataset from (1) 40 children who progressed to T1D during follow-up, (2) 40 children who developed single islet autoantibody but did not develop T1D and (3) 40 matched controls (6 time points: 3, 6, 12, 18, 24 and 36 months of age). This dataset may help other researchers in studying age-dependent progression of islet autoimmunity and T1D as well as of the age-dependence of lipidomic profiles in general. Alternatively, this dataset could more broadly used for the development of methods for the analysis of longitudinal multivariate data.
  • 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
  • Prasad, Marianne; Takkinen, Hanna-Mari; Uusitalo, Liisa; Tapanainen, Heli; Ovaskainen, Marja-Leena; Alfthan, Georg; Erlund, Iris; Ahonen, Suvi; Åkerlund, Mari; Toppari, Jorma; Ilonen, Jorma; Knip, Mikael; Veijola, Riitta; Virtanen, Suvi M. (2018)
    Fruit and vegetable intake has been associated with a reduced risk of many chronic diseases. These foods are the main dietary source of carotenoids. The aim of the present study was to evaluate the associations between dietary intake and serum concentrations of alpha- and beta-carotene in a sample of young Finnish children from the population-based birth cohort of the Type 1 Diabetes Prediction and Prevention (DIPP) Study. The current analysis comprised 3-day food records and serum samples from 207 children aged 1, 2 and 3 years. Spearman and partial correlations, as well as a cross-classification analyses, were used to assess the relationship between dietary intake and the corresponding biomarkers. Serum concentrations of alpha- and beta-carotene were significantly higher among the 1-year-old compared to the 3-year-old children. Dietary intakes of alpha- and beta-carotene correlated significantly with their respective serum concentrations in all age groups, the association being highest at the age of 1 year (alpha-carotene r = 0.48; p <0.001 and beta-carotene r = 0.47; p <0.001), and lowest at the age of 3 years (alpha-carotene r = 0.44; p <0.001 and beta-carotene r = 0.30; p <0.001). A cross-classification showed that 72-81% of the participants were correctly classified to the same or adjacent quartile, when comparing the reported dietary intakes and the concentrations of the corresponding carotenoid in serum. The 3-day food record seems to be reasonably valid in the assessment of root vegetable consumption among young Finnish children. Root vegetables were the main dietary source of both carotenoids in all age groups. The high consumption of commercial baby foods among the 1-year-old children was reflected in the relatively high dietary intake and serum concentration of both carotenoids.
  • Pöllänen, Petra M.; Lempainen, Johanna; Laine, Antti-Pekka; Toppari, Jorma; Veijola, Riitta; Ilonen, Jorma; Siljander, Heli; Knip, Mikael (2019)
    Context: Characterization of slow progression to type 1 diabetes (T1D) may reveal novel means for prevention of T1D. Slow progressors might carry natural immunomodulators that delay beta-cell destruction and mediate preservation of beta-cell function. Objective: To identify demographic, genetic, and immunological characteristics of slow progression from seroconversion to clinical T1D. Design: H LA-susceptible children (n = 7410) were observed from birth for islet cell antibody (ICA), insulin autoantibody (IAA), glutamic acid decarboxylase (GADA), and islet antigen-2 autoantibodies (IA-2A), and for clinical T1D. Disease progression that lasted >= 7.26 years (slowest) quartile from initial seroconversion to diagnosis was considered slow. Autoantibody and genetic characteristics including 45 non-HLA single nucleotide polymorphisms (SNPs) predisposing to T1D were analyzed. Results: By the end of 2015, 1528 children (21 %) had tested autoantibody positive and 247 (16%) had progressed to T1D. The median delay from seroconversion to diagnosis was 8.7 years in slow (n = 62, 25%) and 3.0 years in other progressors. Compared with other progressors, slow progressors were less often multipositive, had lower ICA and IAA titers, and lower frequency of IA-2A at seroconversion. Slow progressors were born more frequently in the fall, whereas other progressors were born more often in the spring. Compared with multipositive nonprogressors, slow progressors were younger, had higher ICA titers, and higher frequency of IAA and multiple autoantibodies at seroconversion. We found no differences in the distributions of non-HLA SNPs between progressors. Conclusions: We observed differences in autoantibody characteristics and the season of birth among progressors, but no characteristics present at seroconversion that were specifically predictive for slow progression.
  • Koskinen, Maarit K.; Lempainen, Johanna; Löyttyniemi, Eliisa; Helminen, Olli; Hekkala, Anne; Härkönen, Taina; Kiviniemi, Minna; Simell, Olli; Knip, Mikael; Ilonen, Jorma; Toppari, Jorma; Veijola, Riitta (2018)
    Context: A declining first-phase insulin response (FPIR) is characteristic of the disease process leading to clinical type 1 diabetes. It is not known whether reduced FPIR depends on class II human leukocyte antigen (HLA) genotype, islet autoimmunity, or both. Objective: To dissect the role of class II HLA DR-DQ genotypes and biochemical islet autoantibodies in the compromised FPIR. Design, Setting, Participants: A total of 438 children with defined HLA DR-DQ genotype in the prospective Finnish Type 1 Diabetes Prediction and Prevention Study were analyzed for FPIR in a total of 1149 intravenous glucose tolerance tests and were categorized by their HLA DR-DQ genotype and the number of biochemical islet autoantibodies at the time of the first FPIR. Age-adjusted hierarchical linear mixed models were used to analyze repeated measurements of FPIR. Main Outcome Measure: The associations between class II HLA DR-DQ genotype, islet autoantibody status, and FPIR. Results: A strong association between the degree of risk conferred by HLA DR-DQ genotype and positivity for islet autoantibodies existed (P <0.0001). FPIR was inversely associated with the number of biochemical autoantibodies (P <0.0001) irrespective of HLA DR-DQ risk group. FPIR decreased over time in children with multiple autoantibodies and increased in children with no biochemical autoantibodies (P <0.0001 and P = 0.0013, respectively). Conclusions: The class II HLA DR-DQ genotype association with FPIR was secondary to the association between HLA and islet autoimmunity. Declining FPIR was associated with positivity for multiple islet autoantibodies irrespective of class II HLA DR-DQ genotype.
  • Lofvenborg, Josefin E.; Ahlqvist, Emma; Alfredsson, Lars; Andersson, Tomas; Groop, Leif; Tuomi, Tiinamaija; Wolk, Alicja; Carlsson, Sofia (2021)
    Purpose Red meat consumption is positively associated with type 1 (T1D) and type 2 (T2D) diabetes. We investigated if red meat consumption increases the risk of latent autoimmune diabetes in adults (LADA) and T2D, and potential interaction with family history of diabetes (FHD), HLA and TCF7L2 genotypes. Methods Analyses were based on Swedish case-control data comprising incident cases of LADA (n = 465) and T2D (n = 1528) with matched, population-based controls (n = 1789; n = 1553 in genetic analyses). Multivariable-adjusted ORs in relation to self-reported processed and unprocessed red meat intake were estimated by conditional logistic regression models. Attributable proportion (AP) due to interaction was used to assess departure from additivity of effects. Results Consumption of processed red meat was associated with increased risk of LADA (per one servings/day OR 1.27, 95% CI 1.07-1.52), whereas no association was observed for unprocessed red meat. For T2D, there was no association with red meat intake once BMI was taken into account. The combination of high (> 0.3 servings/day vs. less) processed red meat intake and high-risk HLA-DQB1 and -DRB1 genotypes yielded OR 8.05 (95% CI 4.86-13.34) for LADA, with indications of significant interaction (AP 0.53, 95% CI 0.32-0.73). Results were similar for the combination of FHD-T1D and processed red meat. No interaction between processed red meat intake and FHD-T2D or risk variants of TCF7L2 was seen in relation to LADA or T2D. Conclusion Consumption of processed but not unprocessed red meat may increase the risk of LADA, especially in individuals with FHD-T1D or high-risk HLA genotypes.
  • Sioofy-Khojine, Amir-Babak; Lehtonen, Jussi; Nurminen, Noora; Laitinen, Olli H.; Oikarinen, Sami; Huhtala, Heini; Pakkanen, Outi; Ruokoranta, Tanja; Hankaniemi, Minna M.; Toppari, Jorma; Vähä-Mäkilä, Mari; Ilonen, Jorma; Veijola, Riitta; Knip, Mikael; Hyöty, Heikki (2018)
    Aims/hypothesis Islet autoimmunity usually starts with the appearance of autoantibodies against either insulin (IAA) or GAD65 (GADA). This categorises children with preclinical type 1 diabetes into two immune phenotypes, which differ in their genetic background and may have different aetiology. The aim was to study whether Coxsackievirus group B (CVB) infections, which have been linked to the initiation of islet autoimmunity, are associated with either of these two phenotypes in children with HLA-conferred susceptibility to type 1 diabetes. Methods All samples were from children in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study. Individuals are recruited to the DIPP study from the general population of new-born infants who carry defined HLA genotypes associated with susceptibility to type 1 diabetes. Our study cohort included 91 children who developed IAA and 78 children who developed GADA as their first appearing single autoantibody and remained persistently seropositive for islet autoantibodies, along with 181 and 151 individually matched autoantibody negative control children, respectively. Seroconversion to positivity for neutralising antibodies was detected as the surrogate marker of CVB infections in serial follow-up serum samples collected before and at the appearance of islet autoantibodies in each individual. Results CVB1 infections were associated with the appearance of IAA as the first autoantibody (OR 2.4 [95% CI 1.4, 4.2], corrected p = 0.018). CVB5 infection also tended to be associated with the appearance of IAA, however, this did not reach statistical significance (OR 2.3, [0.7, 7.5], p = 0.163); no other CVB types were associated with increased risk of IAA. Children who had signs of a CVB1 infection either alone or prior to infections by other CVBs were at the highest risk for developing IAA (OR 5.3 [95% CI 2.4, 11.7], p <0.001). None of the CVBs were associated with the appearance of GADA. Conclusions/interpretation CVB1 infections may contribute to the initiation of islet autoimmunity being particularly important in the insulin-driven autoimmune process.
  • 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.
  • DIABIMMUNE Study Grp; Schmidt, Felicitas; Hose, Alexander J.; Siljander, Heli; Knip, Mikael; Ege, Markus J. (2019)
    Background: The prevalence of atopy is associated with a Western lifestyle, as shown by studies comparing neighboring regions with different socioeconomic backgrounds. Atopy might reflect various conditions differing in their susceptibility to environmental factors. Objective: We sought to define phenotypes of atopic sensitization in early childhood and examine their association with allergic diseases and hereditary background in Finland and Estonia. Methods: The analysis included 1603 Finnish and 1657 Estonian children from the DIABIMMUNE multicenter young children cohort. Specific IgE levels were measured at age 3, 4, and 5 years, respectively, and categorized into 3 CAP classes. Latent class analysis was performed with the statistical software package poLCA in R software. Results: Both populations differed in terms of socioeconomic status and environmental determinants, such as pet ownership, farm-related exposure, time spent playing outdoors, and prevalence of allergic diseases (all P Conclusion: Despite profound differences in environmental exposures, there might exist genuine patterns of atopic sensitization. The distribution of these patterns might determine the contribution of atopic sensitization to disease onset.
  • 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.
  • 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.
  • Knip, Mikael; Luopajarvi, Kristiina; Harkonen, Taina (2017)
    Type 1 diabetes (T1D) is perceived as a chronic immune-mediated disease with a subclinical prodromal period characterized by selective loss of insulin-producing beta cells in the pancreatic islets in genetically susceptible subjects. The incidence of T1D has increased manifold in most developed countries after World War II in parallel with a series of other immune-mediated diseases. T1D results from gene-environmental interactions. The appearance of disease-associated autoantibodies into the peripheral circulation is the first detectable sign of the initiation of the disease process leading to clinical T1D. The first autoantibodies may appear already before the age of 6 months and the seroconversion rate peaks during the second year of life. This implies that exogenous factors involved in the pathogenesis of T1D must be operative in early life, some of them most likely already during pregnancy. Here, we discuss putative endogenous factors that may contribute to the development of T1D during fetal and early postnatal life. Many environmental factors operative in early life have been implicated in the pathogenesis of T1D, but relatively few have been firmly confirmed.
  • Siljander, Heli; Jason, Eeva; Ruohtula, Terhi; Selvenius, Jenni; Koivusaari, Katariina; Salonen, Marja; Ahonen, Suvi; Honkanen, Jarno; Ilonen, Jorma; Vaarala, Outi; Virtanen, Suvi M.; Lähdeaho, Marja-Leena; Knip, Mikael (2021)
    Objectives To assess whether weaning to an extensively hydrolyzed formula (EHF) decreases gut permeability and/or markers of intestinal inflammation in infants with HLA-conferred diabetes susceptibility, when compared with conventional formula. Study design By analyzing 1468 expecting biological parent pairs for HLA-conferred susceptibility for type 1 diabetes, 465 couples (32 %) potentially eligible for the study were identified. After further parental consent, 332 babies to be born were randomized at 35th gestational week. HLA genotyping was performed at birth in 309 infants. Out of 87 eligible children, 73 infants participated in the intervention study: 33 in the EHF group and 40 in the control group. Clinical visits took place at 3, 6, 9, and 12 months of age. The infants were provided either EHF or conventional formula whenever breastfeeding was not available or additional feeding was required over the first 9 months of life. The main outcome was the lactulose to mannitol ratio (L/M ratio) at 9months. The secondary outcomes were L/M ratio at 3, 6, and 12 months of age, and fecal calprotectin and human beta-defensin 2 (HBD-2) levels at each visit. Results Compared with controls, the median L/M ratio was lower in the EHF group at 9 months (.006 vs.028; P = .005). Otherwise, the levels of intestinal permeability, fecal calprotectin, and HBD-2 were comparable between the two groups, although slight differences in the age-related dynamics of these markers were observed. Conclusions It is possible to decrease intestinal permeability in infancy through weaning to an extensively hydrolyzed formula. This may reduce the early exposure to dietary antigens.
  • 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.
  • Niinisto, Sari; Takkinen, Hanna-Mari; Erlund, Iris; Ahonen, Suvi; Toppari, Jorma; Ilonen, Jorma; Veijola, Riitta; Knip, Mikael; Vaarala, Outi; Virtanen, Suvi M. (2017)
    Aims/hypothesis We investigated the association of early serum fatty acid composition with the risk of type 1 diabetes-associated autoimmunity. Our hypothesis was that fatty acid status during infancy is related to type 1 diabetes-associated autoimmunity and that long-chain n-3 fatty acids, in particular, are associated with decreased risk. Methods We performed a nested case-control analysis within the Finnish Type 1 Diabetes Prediction and Prevention Study birth cohort, carrying HLA-conferred susceptibility to type 1 diabetes (n = 7782). Serum total fatty acid composition was analysed by gas chromatography in 240 infants with islet autoimmunity and 480 control infants at the age of 3 and 6 months. Islet autoimmunity was defined as repeated positivity for islet cell autoantibodies in combination with at least one of three selected autoantibodies. In addition, a subset of 43 infants with primary insulin autoimmunity (i.e. those with insulin autoantibodies as the first autoantibody with no concomitant other autoantibodies) and a control group (n = 86) were analysed. A third endpoint was primary GAD autoimmunity defined as GAD autoantibody appearing as the first antibody without other concomitant autoantibodies (22 infants with GAD autoimmunity; 42 infants in control group). Conditional logistic regression was applied, considering multiple comparisons by false discovery rate <0.05. Results Serum fatty acid composition differed between breastfed and non-breastfed infants, reflecting differences in the fatty acid composition of the milk. Fatty acids were associated with islet autoimmunity (higher serum pentadecanoic, palmitic, palmitoleic and docosahexaenoic acids decreased risk; higher arachidonic: docosahexaenoic and n-6: n-3 acid ratios increased risk). Furthermore, fatty acids were associated with primary insulin autoimmunity, these associations being stronger (higher palmitoleic acid, cis-vaccenic, arachidonic, docosapentaenoic and docosahexaenoic acids decreased risk; higher a-linoleic acid and arachidonic: docosahexaenoic and n-6: n-3 acid ratios increased risk). Moreover, the quantity of breast milk consumed per day was inversely associated with primary insulin autoimmunity, while the quantity of cow's milk consumed per day was directly associated. Conclusions/interpretation Fatty acid status may play a role in the development of type 1 diabetes-associated autoimmunity. Fish-derived fatty acids may be protective, particularly during infancy. Furthermore, fatty acids consumed during breastfeeding may provide protection against type 1 diabetes-associated autoimmunity. Further studies are warranted to clarify the independent role of fatty acids in the development of type 1 diabetes.
  • Knip, Mikael; Honkanen, Jarno (2017)
    Purpose of Review The purpose of this review is to summarize potential modulations of the intestinal microbiome aimed at preventing or delaying progression to overt type 1 diabetes in the light of recently identified perturbations of the gut microbiota associated with the development of type 1 diabetes. Recent Findings Accumulated data suggest that the gut microbiota is involved at two different steps in the evolution of type 1 diabetes. At the first step, the intestinal tract is colonized by a microbial community unable to provide an adequate education of the immune system. As a consequence, the infant acquires susceptibility to immune-mediated diseases, type 1 diabetes included. At the other step, the young child seroconverts to positivity for diabetes-associated autoantibodies. This is preceded or accompanied by a decrease in the diversity of the intestinal microbiota and an increased abundance of Bacteroides species. These changes will affect the disease process promoting progression toward overt type 1 diabetes. Summary By providing specific probiotics, one can affect the colonization of the intestinal tract in the newborn infant or strengthen the immune education in early life. Human milk oligosaccharides function as nutrients for "healthy" bacteria. Dietary interventions applying modified starches can influence the numbers and activities of both autoreactive and regulatory T cells and provide protection against autoimmune diabetes in non-obese diabetic mice. Modulation of the intestinal microbiome holds the promise of effective protection against human type 1 diabetes.