Browsing by Subject "ISLET AUTOIMMUNITY"

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  • 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.
  • the DIABIMMUNE Study Group; Mustonen, Neea; Siljander, Heli; Peet, Aleksandr; Tillmann, Vallo; Härkönen, Taina; Ilonen, Jorma; Hyöty, Heikki; Knip, Mikael (2019)
    Aim Infections in early childhood are common reasons to seek medical attention. This study compares the prevalence of infections, and the use of antibiotics and antipyretic-analgesics, in children from Finland, Estonia and Russian Karelia. Methods Children with a genetically increased risk for type 1 diabetes (N = 797) were observed from birth up to 3 years of age. Illnesses and medications were reported by parents continuously. All reported infections, antibiotics and antipyretic-analgesics were compared between Finland and Estonia, and to a lesser extent with Russian Karelia, due to poor study compliance. Results Compared with Estonians, Finns reported more infections during the first and second years of life. During the follow-up, Finnish children had 10 infections while Estonians only had 8 (p <0.001). Finns also used more antibiotics and antipyretic-analgesics in each year during the follow-up. Russian Karelians reported the lowest frequency of infections and the most infrequent use of antibiotics and antipyretic-analgesics in the first two years of life. Conclusion Infections and the use of antibiotics and antipyretic-analgesics in early childhood were most frequent in Finland, where socio-economic conditions are the most developed and microbial encounters are sparse. This may reflect on the hygiene hypothesis, a less effective immune system that allows normally harmless microbes to attack and cause clinical infections.
  • 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.
  • Miettinen, Maija E.; Smart, Melissa C.; Kinnunen, Leena; Harjutsalo, Valma; Reinert-Hartwall, Linnea; Ylivinkka, Irene; Surcel, Helja-Marja; Lamberg-Allardt, Christel; Hitman, Graham A.; Tuomilehto, Jaakko (2017)
    Objective The in utero environment plays an important role in shaping development and later life health of the fetus. It has been shown that maternal genetic factors in the metabolic pathway of vitamin D associate with type 1 diabetes in the child. In this study we analyzed the genetic determinants of serum 25-hydroxyvitamin D (25OHD) concentration during pregnancy in mothers whose children later developed type 1 diabetes and in control mothers. Study design 474 mothers of type 1 diabetic children and 348 mothers of non-diabetic children were included in the study. We previously selected 7 single nucleotide polymorphisms (SNPs) in four genes in the metabolic pathway of vitamin D vitamin based on our previously published data demonstrating an association between genotype and serum 25OHD concentration. In this re-analysis, possible differences in strength in the association between the SNPs and serum 25OHD concentration in mothers of type 1 diabetic and non-diabetic children were investigated. Serum 25OHD concentrations were previously shown to be similar between the mothers of type 1 diabetic and non-diabetic children and vitamin D deficiency prevalent in both groups. Results Associations between serum 25OHD concentration and 2 SNPs, one in the vitamin D receptor (VDR) gene (rs4516035) and one in the group-specific component (GC) gene (rs12512631), were stronger during pregnancy in mothers whose children later developed type 1 diabetes than in mothers whose children did not (p(interaction) = 0.03, 0.02, respectively). Conclusions We show for the first time that there are differences in the strength of genetic determinants of serum 25OHD concentration during pregnancy between the mothers of type 1 diabetic and non-diabetic children. Our results emphasize that the in utero environment including maternal vitamin D metabolism should be important lines of investigation when searching for factors that lead to early programming of type 1 diabetes.
  • Lamichhane, Santosh; Siljander, Heli; Salonen, Marja; Ruohtula, Terhi; Virtanen, Suvi M.; Ilonen, Jorma; Hyötyläinen, Tuulia; Knip, Mikael; Oresic, Matej (2022)
    Background: Current evidence suggests that the composition of infant formula (IF) affects the gut microbiome, intestinal function, and immune responses during infancy. However, the impact of IF on circulating lipid profiles in infants is still poorly understood. The objectives of this study were to (1) investigate how extensively hydrolyzed IF impacts serum lipidome compared to conventional formula and (2) to associate changes in circulatory lipids with gastrointestinal biomarkers including intestinal permeability. Methods: In a randomized, double-blind controlled nutritional intervention study (n = 73), we applied mass spectrometry-based lipidomics to analyze serum lipids in infants who were fed extensively hydrolyzed formula (HF) or conventional, regular formula (RF). Serum samples were collected at 3, 9, and 12 months of age. Child's growth (weight and length) and intestinal functional markers, including lactulose mannitol (LM) ratio, fecal calprotectin, and fecal beta-defensin, were also measured at given time points. At 3 months of age, stool samples were analyzed by shotgun metagenomics. Results: Concentrations of sphingomyelins were higher in the HF group as compared to the RF group. Triacylglycerols (TGs) containing saturated and monounsaturated fatty acyl chains were found in higher levels in the HF group at 3 months, but downregulated at 9 and 12 months of age. LM ratio was lower in the HF group at 9 months of age. In the RF group, the LM ratio was positively associated with ether-linked lipids. Such an association was, however, not observed in the HF group. Conclusion: Our study suggests that HF intervention changes the circulating lipidome, including those lipids previously found to be associated with progression to islet autoimmunity or overt T1D.
  • Siljander, Heli; Honkanen, Jarno; Knip, Mikael (2019)
    The steep increase in the incidence of type 1 diabetes (T1D), in the Western world after World War II, cannot be explained solely by genetic factors but implies that this rise must be due to crucial interactions between predisposing genes and environmental changes. Three parallel phenomena in early childhood – the dynamic development of the immune system, maturation of the gut microbiome, and the appearance of the first T1D-associated autoantibodies – raise the question whether these phenomena might reflect causative relationships. Plenty of novel data on the role of the microbiome in the development of T1D has been published over recent years and this review summarizes recent findings regarding the associations between islet autoimmunity, T1D, and the intestinal microbiota.
  • 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.
  • Sen, Partho; Carlsson, Cecilia; Virtanen, Suvi M.; Simell, Satu; Hyöty, Heikki; Ilonen, Jorma; Toppari, Jorma; Veijola, Riitta; Hyötyläinen, Tuulia; Knip, Mikael; Oresic, Matej (2019)
    OBJECTIVES: Celiac disease (CD) is a chronic enteropathy characterized by an autoimmune reaction in the small intestine of genetically susceptible individuals. The underlying causes of autoimmune reaction and its effect on host metabolism remain largely unknown. Herein, we apply lipidomics to elucidate the early events preceding clinical CD in a cohort of Finnish children, followed up in the Type 1 Diabetes Prediction and Prevention study. METHODS: Mass spectrometry-based lipidomics profiling was applied to a longitudinal/prospective series of 233 plasma samples obtained from CD progressors (n = 23) and healthy controls (n = 23), matched for human leukocyte antigen (HLA) risk, sex, and age. The children were followed from birth until diagnosis of clinical CD and subsequent introduction of a gluten-free diet. RESULTS: Twenty-three children progressed to CD at a mean age of 4.8 years. They showed increased amounts of triacylglycerols (TGs) of low carbon number and double bond count and a decreased level of phosphatidylcholines by age 3 months as compared to controls. These differences were exacerbated with age but were not observed at birth (cord blood). No significant differences were observed in the essential TGs. DISCUSSION: Our preliminary findings suggest that abnormal lipid metabolism associates with the development of clinical CD and occurs already before the first introduction of gluten to the diet. Moreover, our data suggest that the specific TGs found elevated in CD progressors may be due to a host response to compromised intake of essential lipids in the small intestine, requiring de novo lipogenesis.
  • McGlinchey, Aidan; Sinioja, Tim; Lamichhane, Santosh; Sen, Partho; Bodin, Johanna; Siljander, Heli; Dickens, Alex M.; Geng, Dawei; Carlsson, Cecilia; Duberg, Daniel; Ilonen, Jorma; Virtanen, Suvi M.; Dirven, Hubert; Berntsen, Hanne Friis; Zimmer, Karin; Nygaard, Unni C.; Oresic, Matej; Knip, Mikael; Hyötyläinen, Tuulia (2020)
    In the last decade, increasing incidence of type 1 diabetes (T1D) stabilized in Finland, a phenomenon that coincides with tighter regulation of perfluoroalkyl substances (PFAS). Here, we quantified PFAS to examine their effects, during pregnancy, on lipid and immune-related markers of T1D risk in children. In a mother-infant cohort (264 dyads), high PFAS exposure during pregnancy associated with decreased cord serum phospholipids and progression to T1D-associated islet autoantibodies in the offspring. This PFAS-lipid association appears exacerbated by increased human leukocyte antigen-conferred risk of T1D in infants. Exposure to a single PFAS compound or a mixture of organic pollutants in non-obese diabetic mice resulted in a lipid profile characterized by a similar decrease in phospholipids, a marked increase of lithocholic acid, and accelerated insulitis. Our findings suggest that PFAS exposure during pregnancy contributes to risk and pathogenesis of T1D in offspring.