Maternal dietary supplement use and development of islet autoimmunity in the offspring: TEDDY study.

OBJECTIVE: We investigated the association between maternal use of vitamin D and omega-3 fatty acids (n-3 FAs) supplements during pregnancy and risk of islet autoimmunity (IA) in the offspring. METHODS: The Environmental Determinants of Diabetes in the Young (TEDDY) Study is prospectively following 8676 children with increased genetic risk for type 1 diabetes in Finland, Germany, Sweden, and the United States. Blood samples were collected every 3 months between 3 and 48 months of age then every 6 months thereafter to determine persistent IA. Duration, frequency, and supplement dose during pregnancy were recalled by mothers at 3 to 4 months postpartum. Cumulative intakes of supplemental vitamin D and n-3 FAs were analyzed as continuous or binary variables. We applied time-to-event analysis to study the association between maternal supplement use and IA, adjusting for country, human leukocyte antigen-DR-DQ genotype, family history of type 1 diabetes and sex. Secondary outcomes included insulin autoantibodies (IAA) or glutamic acid decarboxylase (GADA) as the first appearing autoantibody. RESULTS: As of February 2018, there were 747 (9.0%) children with IA. Vitamin D supplement intake during pregnancy (any vs none) was not associated with risk for IA (hazard ratio [HR] 1.11; 95% confidence interval [CI] 0.94, 1.31); neither was cumulative vitamin D supplement intake. Supplemental n-3 FA intake was similarly not associated with IA risk (HR: 1.19, 95% CI 0.98, 1.45). Similar lack of association was observed for either IAA or GADA as the first appearing autoantibody. CONCLUSIONS: The TEDDY cohort showed no evidence of benefit regarding IA risk for vitamin D or n-3 FA supplementation during pregnancy.

Maternal dietary folate, folic acid and vitamin D intakes during pregnancy and lactation and the risk of cows' milk allergy in the offspring.

Maternal nutrient intake during pregnancy and lactation potentially influences the development of allergic diseases. Cows' milk allergy (CMA) is often the first manifestation of atopic diseases, but the impact of early nutritional influences on CMA has not been explored. The associations between maternal intakes of folate, folic acid and vitamin D during pregnancy and lactation were addressed in a prospective, population-based birth cohort within the Finnish Type 1 Diabetes Prediction and Prevention Study. Mothers of 4921 children during pregnancy and 2940 children during lactation provided information on maternal dietary intake during the 8th month of pregnancy and the 3rd month of lactation using a detailed, validated FFQ. Information on diagnosed CMA in the offspring was obtained from a medical registry as well as queried from the parents. The Finnish food composition database was used to calculate nutrient intake. Logistic regression was applied for statistical analyses. Folate intake and folic acid and vitamin D supplement use were associated with an increased risk of CMA in the offspring, whereas vitamin D intake from foods during pregnancy was associated with a decreased risk of CMA. Thus, maternal nutrient intake during pregnancy and lactation may affect the development of CMA in offspring. Supplementation with folic acid may not be beneficial in terms of CMA development, especially in children of allergic mothers. The association between dietary supplement use and CMA risk can at least partly be explained by increased health-seeking behaviour among more educated mothers who also use more dietary supplements.

Association of Early Exposure of Probiotics and Islet Autoimmunity in the TEDDY Study.

IMPORTANCE: Probiotics have been hypothesized to affect immunologic responses to environmental exposures by supporting healthy gut microbiota and could therefore theoretically be used to prevent the development of type 1 diabetes mellitus (T1DM)-associated islet autoimmunity. OBJECTIVE: To examine the association between supplemental probiotic use during the first year of life and islet autoimmunity among children at increased genetic risk of T1DM. DESIGN, SETTING, AND PARTICIPANTS: In this ongoing prospective cohort study that started September 1, 2004, children from 6 clinical centers, 3 in the United States (Colorado, Georgia/Florida, and Washington) and 3 in Europe (Finland, Germany, and Sweden), were followed up for T1DM-related autoantibodies. Blood samples were collected every 3 months between 3 and 48 months of age and every 6 months thereafter to determine persistent islet autoimmunity. Details of infant feeding, including probiotic supplementation and infant formula use, were monitored from birth using questionnaires and diaries. We applied time-to-event analysis to study the association between probiotic use and islet autoimmunity, stratifying by country and adjusting for family history of type 1 diabetes, HLA-DR-DQ genotypes, sex, birth order, mode of delivery, exclusive breastfeeding, birth year, child's antibiotic use, and diarrheal history, as well as maternal age, probiotic use, and smoking. Altogether 8676 infants with an eligible genotype were enrolled in the follow-up study before the age of 4 months. The final sample consisted of 7473 children with the age range of 4 to 10 years (as of October 31, 2014). EXPOSURES: Early intake of probiotics. MAIN OUTCOMES AND MEASURES: Islet autoimmunity revealed by specific islet autoantibodies. RESULTS: Early probiotic supplementation (at the age of 0-27 days) was associated with a decreased risk of islet autoimmunity when compared with probiotic supplementation after 27 days or no probiotic supplementation (hazard ratio [HR], 0.66; 95% CI, 0.46-0.94). The association was accounted for by children with the DR3/4 genotype (HR, 0.40; 95% CI, 0.21-0.74) and was absent among other genotypes (HR, 0.97; 95% CI, 0.62-1.54). CONCLUSIONS AND RELEVANCE: Early probiotic supplementation may reduce the risk of islet autoimmunity in children at the highest genetic risk of T1DM. The result needs to be confirmed in further studies before any recommendation of probiotics use is made.

Food consumption and risk of childhood asthma.

BACKGROUND: The consumption of foods rich in n-3 polyunsaturated fatty acids has been proposed to protect against childhood asthma. This study explores the association of food consumption (including cow's milk (CM)-free diet) in early life and the risk of atopic and non-atopic asthma. METHODS: Food intake of 182 children with asthma and 728 matched controls was measured using 3-day food records, within the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Nutrition Study cohort. The diagnoses of food allergies came both from the written questionnaire and from the registers of the Social Insurance Institution. Conditional logistic regression with generalized estimating equations framework was used in the analyses. RESULTS: The diagnosis of cow's milk allergy (CMA) led to multiple dietary restrictions still evident at 4 yr of age. Even after adjusting for CMA, higher consumption of CM products was inversely associated with the risk of atopic asthma and higher consumption of breast milk and oats inversely with the risk of non-atopic asthma. Early consumption of fish was associated with a decreased risk of all asthma. CONCLUSIONS: Dietary intake in early life combined with atopy history has a clear impact on the risk of developing asthma. Our results indicate that CM restriction due to CMA significantly increases and mediates the association between food consumption and childhood asthma risk.

Interactions between genetic variants and dietary lipid composition: effects on circulating LDL cholesterol in children.

BACKGROUND: Elevated serum low-density lipoprotein (LDL) cholesterol is a predictor of cardiovascular disease events, and the quality of dietary fat is known to influence serum concentrations of LDL cholesterol in children. Interindividual differences in response to diet exist, but the underlying genetic factors remain largely unknown. OBJECTIVE: We aimed to identify genetic variants that modify the variation in serum lipid response to dietary fat quality. DESIGN: We used data from 2 longitudinal Finnish cohorts designed to study risk factors for cardiovascular diseases. Large-scale genotyping was performed with Metabochip in a long-term randomized controlled dietary intervention trial, the Special Turku Coronary Risk Factor Intervention Project (STRIP), for discovery of genetic polymorphisms. The observational Cardiovascular Risk in Young Finns Study (YFS) with genome-wide genetic data was used as a replication sample for the initial findings. Dietary records were used to calculate the ratio of unsaturated to saturated fats. Interaction models and multiple follow-ups were used in the analysis. RESULTS: In the STRIP cohort, a variant within the PARK2 locus, rs9364628, showed moderate interaction with dietary fat quality and a consistent direction of effect in both scans on serum LDL-cholesterol concentration in children aged 5 and 7 y (P < 0.0084 and P < 0.0057, respectively). In the YFS cohort, we were unable to replicate the initial discovery signal, but rs12207186 within the PARK2 locus and dietary lipid quality had a stronger interaction effect on serum LDL-cholesterol concentration (P < 9.44 × 10(-5)) than did rs9364628 in children aged 6 y. CONCLUSION: This genotyping study involving 2 cohorts of healthy Finnish children indicates a possible interaction between PARK2 variants and dietary fat quality on serum LDL-cholesterol concentration. This trial was registered at clinicaltrials.gov as NCT00223600.

An increase in serum 25-hydroxyvitamin D concentrations preceded a plateau in type 1 diabetes incidence in Finnish children.

CONTEXT: In Finland the world-record for the highest incidence of type 1 diabetes has risen steeply over the past decades. However, after 2006 the incidence rate has plateaued. We showed earlier, that despite the strong genetic disease component, environmental factors are driving the increasing disease incidence. OBJECTIVE: Since vitamin D intake has increased considerably in the country since 2003, we analyzed how serum 25-hydroxyvitamin D (25[OH]D) concentration changed over time in healthy children, and the timely relation of these changes to disease incidence. DESIGN, SETTING AND PARTICIPANTS: The birth cohort of the Finnish Type 1 Diabetes Prediction and Prevention project was used to explore longitudinal changes in serum 25-hydroxyvitamin concentrations. The sampling period was limited to children born from 1994 to 2004, with serum samples collected during 1998-2006 in the Turku area, Southwest Finland (60 °N). MAIN OUTCOME MEASURE: 25(OH)D concentrations were measured every 3-6 months from birth, ages ranging from 0.3 to 12.2 years (387 subjects, 5334 measurements). RESULTS: Serum 25(OH)D concentrations were markedly lower before 2003 than after (69.3 ± 1.0 nmol/L vs 84.9 ± 1.3 nmol/L, respectively, P < .001) in both genders. The mean difference between the periods was 15.7 ± 1.3 nmol/L (P < .001). Importantly, the frequency of children with low serum 25(OH)D levels (< 50 nmol/L) was reduced to almost half from 2003 (37.3% vs 69.9 %; P < .001). Similarly, severe vitamin D deficiency (<25 nmol/L) also decreased (2.7% vs 7.7%; P = .005). In addition, we detected higher 25(OH)D concentrations in young children (< 2 years) as compared to older children, which is explained by higher vitamin D intake in this group. CONCLUSIONS: We provide evidence that an increase in circulating concentrations of 25(OH)D shows a delayed temporal association with leveling off of type 1 diabetes incidence in Finland after 2006.

Nutrient intake variability and number of days needed to assess intake in preschool children.

The duration of the period of time during which diet should be recorded for sufficiently accurate results on the usual intake of an individual is an especially challenging issue in prospective studies among children. We set out to describe nutrient intake variability in preschoolers and to determine the number of record days required (D) to estimate intake of energy and thirty-two nutrients. The diet and the use of dietary supplements were assessed with three consecutive daily food records including one weekend day in 1639 children participating in the population-based birth cohort of the Type 1 Diabetes Prediction and Prevention Project (DIPP) in Finland. Variance ratios and D stratified by sex and age groups were calculated for 455 (1-year-old), 471 (3-year-old) and 713 (6-year-old) children (born between 1998 and 2003). Within:between variance ratios and D increase with increasing age, and are slightly higher for girls. Vitamin A, cholesterol, n-3 and n-6 fatty acids, ß-carotene and folate intakes require the most replicates. Including supplemental intake has an impact on the variance estimates according to the proportion of supplement users. In the DIPP Nutrition Study with 3 d food records, the correlation coefficients between observed and true intakes of energy and thirty-two nutrients averaged 0·91 in 1-year-old children, 0·79 in 3-year-old children and 0·74 in 6-year-old children. For providing accurate nutrient intake estimates, three replicates of food records are reasonable in 1-year-old children but must be questioned for several nutrients in 3- and 6-year-old children. The accuracy of ranking boys is greater than that for girls.

Intake of antioxidant vitamins and trace elements during pregnancy and risk of advanced beta cell autoimmunity in the child.

BACKGROUND: Type 1 diabetes may have its origins in the fetal period of life. Free radicals were implicated in the cause of type 1 diabetes. It was hypothesized that antioxidant nutrients could protect against type 1 diabetes. OBJECTIVE: We assessed whether high maternal intake of selected dietary antioxidants during pregnancy is associated with a reduced risk of advanced beta cell autoimmunity in the child, defined as repeated positivity for islet cell antibodies plus >/=1 other antibody, overt type 1 diabetes, or both. DESIGN: The study was carried out as part of the population-based birth cohort of the Type 1 Diabetes Prediction and Prevention Project. The data comprised 4297 children with increased genetic susceptibility to type 1 diabetes, born at the University Hospital of Oulu or Tampere, Finland, between October 1997 and December 2002. The children were monitored for diabetes-associated autoantibodies from samples obtained at 3-12-mo intervals. Maternal antioxidant intake during pregnancy was assessed postnatally with a self-administered food-frequency questionnaire, which contained a question about consumption of dietary supplements. RESULTS: Maternal intake of none of the studied antioxidant nutrients showed association with the risk of advanced beta cell autoimmunity in the child. The hazard ratios, indicating the change in risk per a 2-fold increase in the intake of each antioxidant, were nonsignificant and close to 1. CONCLUSION: High maternal intake of retinol, beta-carotene, vitamin C, vitamin E, selenium, zinc, or manganese does not protect the child from development of advanced beta cell autoimmunity in early childhood.

Carnitine deficiency and L-carnitine supplementation in lysinuric protein intolerance.

The aim of the study was to investigate the prevalence and mechanisms of development of carnitine deficiency in patients with lysinuric protein intolerance (LPI). In our cohort of 37 Finnish patients with LPI, 8 (8-52 years of age) have been diagnosed with hypocarnitinemia. Their free and total serum carnitine levels, acyl carnitine profiles, renal function, diet, and medication were compared with the data from 8 age- and sex-matched patients with LPI not treated with carnitine supplementation. In patients with LPI, hypocarnitinemia was strongly associated with female sex, renal insufficiency, and the use of ammonia-scavenging drugs. Of the 8 hypocarnitinemic patients, 3 complained of muscle weakness, and their symptoms disappeared during carnitine supplementation. Oral lysine supplementation did not correct hypocarnitinemia in our patients. The patients with LPI are at considerable risk for carnitine deficiency. Supplementation of hypocarnitinemic LPI patients with oral L-carnitine improved serum total carnitine values, but the ratio of free and total carnitine remained subnormal in all supplemented patients except one. Furthermore, decreased ratio of free and total serum carnitine was common even in LPI patients with normal total serum carnitine concentration.

Nephropathy advancing to end-stage renal disease: a novel complication of lysinuric protein intolerance.

OBJECTIVE: To analyze systemically the prevalence of renal involvement in a cohort of Finnish patients with lysinuric protein intolerance (LPI) and to describe the course and outcome of end-stage renal disease in 4 patients. STUDY DESIGN: The clinical information in a cohort of 39 Finnish patients with LPI was analyzed retrospectively. RESULTS: Proteinuria was observed in 74% of the patients and hematuria was observed in 38% of the patients during follow-up. Elevated blood pressure was diagnosed in 36% of the patients. Mean serum creatinine concentration increased in 38% of the patients, and cystatin C concentration increased in 59% of the patients. Four patients required dialysis, and severe anemia with poor response to erythropoietin and iron supplementation also developed in these patients. CONCLUSIONS: Our findings suggest that renal function of patients with LPI needs to be carefully monitored, and hypertension and hyperlipidemia should be treated effectively. Special attention also should be paid to the prevention of osteoporosis and carnitine deficiency in the patients with end-stage renal disease associated with LPI. The primary disease does not prohibit treatment by dialysis and renal transplantation.

Long-term oral lysine supplementation in lysinuric protein intolerance.

In lysinuric protein intolerance (LPI), defective transport of cationic amino acids at the basolateral membrane of the polar epithelial cells in the intestine and renal tubules leads to decreased intestinal absorption and excessive renal loss of lysine, arginine, and ornithine. Citrulline supplementation partially restores the function of the urea cycle that is impaired by deficiency of arginine and ornithine, but does not correct the chronic lysine deficiency. Previous attempts to supplement lysine orally have been hindered by profuse diarrhea, probably caused by excess lysine remaining unabsorbed in the gut. However, individually adjusted minute doses of L-lysine hydrochloride at mealtimes are tolerated well, but the long-term benefits of this therapy remain unknown. The aim of the study was to investigate the long-term benefits and possible adverse effects of oral lysine supplementation in patients with LPI. Supplementation of meals with low doses of oral lysine improved fasting plasma lysine concentrations in 27 Finnish patients with LPI without causing hyperammonemia or other recognizable side effects during 12 months of follow-up. In conclusion, low-dose oral lysine supplementation is potentially beneficial to patients with LPI and can be started safely at an early age.

Enteral virus infections in early childhood and an enhanced type 1 diabetes-associated antibody response to dietary insulin.

Enteral virus infections may trigger the development of beta-cell-specific autoimmunity by interacting with the gut-associated lymphoid system. We analyzed the effect of three different virus infections on immunization to dietary insulin in children carrying increased genetic risk for type 1 diabetes. Forty-six of 238 children developed multiple diabetes-associated autoantibodies and 31 clinical diabetes (median follow-up time 75 months). Insulin-binding antibodies were measured with EIA method (median follow-up time 24 months). Antibodies to enteroviruses, rotavirus and adenovirus were measured with EIA in samples drawn at birth and the ages of 3 and 6 months. Nineteen enterovirus, 14 rotavirus and 8 adenovirus infections were diagnosed. At the ages of 6, 12, and 18 months, the concentrations of insulin-binding antibodies were higher in children with postnatal entero-, rota- and/or adenovirus infections than in children without these infections. Children who subsequently developed ICA or IA-2 antibodies or clinical type 1 diabetes had higher concentrations of insulin-binding antibodies than children who remained autoantibody negative. Our data suggest that enteral virus infections can enhance immune response to insulin, induced primarily by bovine insulin in cow's milk. An enhanced antibody response to dietary insulin preceded the development of beta-cell specific autoimmunity and type 1 diabetes.

Vitamin D receptor polymorphisms: no association with type 1 diabetes in the Finnish population.

OBJECTIVE: The effect of polymorphisms of the vitamin D receptor (VDR) gene on susceptibility to type 1 diabetes has recently been investigated extensively. Several findings on positive disease associations have been observed and, in addition, a protective effect of vitamin D supplementation has been reported. DESIGN: We studied the effect of three vitamin D receptor gene polymorphisms (VDRA, VDRB, VDRF) on susceptibility to type 1 diabetes in a large case-control series (more than 2000 controls and about 1000 patients) from the Finnish population. METHODS: A combination of case-control and affected-family based approaches was used. Subjects were genotyped for VDRA (ApaI), VDRB (BsmI) and VDRF (FokI) single nucleotide polymorphisms using a minisequencing reaction. RESULTS: A few borderline significant associations were observed with both approaches used. In the case-control association analyses we found significant differences between cases and controls in frequencies of VDRB (P=0.024, all subjects and P=0.016, HLA DQB1*0302-positive subjects) and VDRF (P=0.0063, Turku cohort). In the total family set a decreased (39.3%) transmission of the VDRA-VDRB-VDRF haplotype 1-1-2 and an increased (60.3%) transmission of haplotype 2-1-2 to sons was seen (P=0.0059 and P=0.024 respectively). Transmission of the haplotype 2-2-1 to daughters was decreased (37.6%, P=0.022). Interestingly, we also observed significant differences in allele frequencies of the polymorphisms studied between populations from three different regions in Finland. CONCLUSIONS: All these differences disappeared after correction for multiple testing. We conclude that the single nucleotide polymorphisms analysed are unlikely to be associated with type 1 diabetes in the Finnish population.

Oral supplementation corrects plasma lysine concentrations in lysinuric protein intolerance.

In lysinuric protein intolerance (LPI), intestinal absorption and renal tubular reabsorption of arginine, ornithine, and lysine are impaired due to a defective cationic amino acid transporter. Deficiency of arginine and ornithine restricts the function of the urea cycle, leading to hyperammonemia after protein load, and to strong protein aversion. Mealtime supplements of citrulline, another urea cycle intermediate that uses other transport mechanisms, prevent postprandial hyperammonemia and improve protein tolerance. Deficiency of lysine, an essential amino acid, most probably also contributes to the symptoms of LPI. We investigated possibilities to improve the availability of lysine for tissues by increasing plasma lysine concentration. Six patients with LPI were started on short-term oral lysine supplementation that was administered with their regular citrulline doses and standard low-protein meals. L-Lysine in consecutive doses of 0.55 and 1.1 mmol/kg caused profuse diarrhea in first 3 patients. To avoid gastrointestinal side effects, the 3 other patients were started on smaller lysine supplements of only 0.05 mmol/kg per dose, given 3 times daily for 3 days. All pre- and postprandial plasma lysine concentrations remained within normal range in 2 of the 3 patients studied. Even after the larger doses, no significant effects on the urea cycle were seen. We conclude that low-dose oral lysine supplementation normalizes plasma lysine concentration in patients with LPI, and is safe and well tolerated at least in short-term use.