Metabolomics Profiling of Patients With A-β+ Ketosis-Prone Diabetes During Diabetic Ketoacidosis

When stable and near-normoglycemic, patients with "A-β+" ketosis-prone diabetes (KPD) manifest accelerated leucine catabolism and blunted ketone oxidation, which may underlie their proclivity to develop diabetic ketoacidosis (DKA). To understand metabolic derangements in A-β+ KPD patients during DKA, we compared serum metabolomics profiles of adults during acute hyperglycemic crises, without (n = 21) or with (n = 74) DKA, and healthy control subjects (n = 17). Based on 65 kDa GAD islet autoantibody status, C-peptide, and clinical features, 53 DKA patients were categorized as having KPD and 21 type 1 diabetes (T1D); 21 nonketotic patients were categorized as having type 2 diabetes (T2D). Patients with KPD and patients with T1D had higher counterregulatory hormones and lower insulin-to-glucagon ratio than patients with T2D and control subjects. Compared with patients withT2D and control subjects, patients with KPD and patients with T1D had lower free carnitine and higher long-chain acylcarnitines and acetylcarnitine (C2) but lower palmitoylcarnitine (C16)-to-C2 ratio; a positive relationship between C16 and C2 but negative relationship between carnitine and β-hydroxybutyrate (BOHB); higher branched-chain amino acids (BCAAs) and their ketoacids but lower ketoisocaproate (KIC)-to-Leu, ketomethylvalerate (KMV)-to-Ile, ketoisovalerate (KIV)-to-Val, isovalerylcarnitine-to-KIC+KMV, propionylcarnitine-to-KIV+KMV, KIC+KMV-to-C2, and KIC-to-BOHB ratios; and lower glutamate and 3-methylhistidine. These data suggest that during DKA, patients with KPD resemble patients with T1D in having impaired BCAA catabolism and accelerated fatty acid flux to ketones-a reversal of their distinctive BCAA metabolic defect when stable. The natural history of A-β+ KPD is marked by chronic but varying dysregulation of BCAA metabolism

Early probiotic supplementation and the risk of celiac disease in children at genetic risk

Abstract Probiotics are linked to positive regulatory effects on the immune system. The aim of the study was to examine the association between the exposure of probiotics via dietary supplements or via infant formula by the age of 1 year and the development of celiac disease autoimmunity (CDA) and celiac disease among a cohort of 6520 genetically susceptible children. Use of probiotics during the first year of life was reported by 1460 children. Time-to-event analysis was used to examine the associations. Overall exposure of probiotics during the first year of life was not associated with either CDA (n = 1212) (HR 1.15; 95%CI 0.99, 1.35; p = 0.07) or celiac disease (n = 455) (HR 1.11; 95%CI 0.86, 1.43; p = 0.43) when adjusting for known risk factors. Intake of probiotic dietary supplements, however, was associated with a slightly increased risk of CDA (HR 1.18; 95%CI 1.00, 1.40; p = 0.043) compared to children who did not get probiotics. It was concluded that the overall exposure of probiotics during the first year of life was not associated with CDA or celiac disease in children at genetic risk

Analgesic antipyretic use among young children in the TEDDY study : No association with islet autoimmunity

Background: The use of analgesic antipyretics (ANAP) in children have long been a matter of controversy. Data on their practical use on an individual level has, however, been scarce. There are indications of possible effects on glucose homeostasis and immune function related to the use of ANAP. The aim of this study was to analyze patterns of analgesic antipyretic use across the clinical centers of The Environmental Determinants of Diabetes in the Young (TEDDY) prospective cohort study and test if ANAP use was a risk factor for islet autoimmunity. Methods: Data were collected for 8542 children in the first 2.5 years of life. Incidence was analyzed using logistic regression with country and first child status as independent variables. Holm's procedure was used to adjust for multiplicity of intercountry comparisons. Time to autoantibody seroconversion was analyzed using a Cox proportional hazards model with cumulative analgesic use as primary time dependent covariate of interest. For each categorization, a generalized estimating equation (GEE) approach was used. Results: Higher prevalence of ANAP use was found in the U.S. (95.7%) and Sweden (94.8%) compared to Finland (78.1%) and Germany (80.2%). First-born children were more commonly given acetaminophen (OR 1.26; 95% CI 1.07, 1.49; p = 0.007) but less commonly Non-Steroidal Anti-inflammatory Drugs (NSAID) (OR 0.86; 95% CI 0.78, 0.95; p = 0.002). Acetaminophen and NSAID use in the absence of fever and infection was more prevalent in the U.S. (40.4%; 26.3% of doses) compared to Sweden, Finland and Germany (p < 0.001). Acetaminophen or NSAID use before age 2.5 years did not predict development of islet autoimmunity by age 6 years (HR 1.02, 95% CI 0.99-1.09; p = 0.27). In a sub-analysis, acetaminophen use in children with fever weakly predicted development of islet autoimmunity by age 3 years (HR 1.05; 95% CI 1.01-1.09; p = 0.024). Conclusions: ANAP use in young children is not a risk factor for seroconversion by age 6 years. Use of ANAP is widespread in young children, and significantly higher in the U.S. compared to other study sites, where use is common also in absence of fever and infection