Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes.
ABSTRACT: The risk determinants of type 1 diabetes, initiators of autoimmune response, mechanisms regulating progress toward beta cell failure, and factors determining time of presentation of clinical diabetes are poorly understood. We investigated changes in the serum metabolome prospectively in children who later progressed to type 1 diabetes. Serum metabolite profiles were compared between sample series drawn from 56 children who progressed to type 1 diabetes and 73 controls who remained nondiabetic and permanently autoantibody negative. Individuals who developed diabetes had reduced serum levels of succinic acid and phosphatidylcholine (PC) at birth, reduced levels of triglycerides and antioxidant ether phospholipids throughout the follow up, and increased levels of proinflammatory lysoPCs several months before seroconversion to autoantibody positivity. The lipid changes were not attributable to HLA-associated genetic risk. The appearance of insulin and glutamic acid decarboxylase autoantibodies was preceded by diminished ketoleucine and elevated glutamic acid. The metabolic profile was partially normalized after the seroconversion. Autoimmunity may thus be a relatively late response to the early metabolic disturbances. Recognition of these preautoimmune alterations may aid in studies of disease pathogenesis and may open a time window for novel type 1 diabetes prevention strategies.
Project description:The pathogenesis of type 1 diabetes is different from that of type 2 diabetes, and anti-glutamic acid decarboxylase antibody (GADA) helps to diagnose autoimmune type 1 diabetes. Some studies reported that GADA seroconversion occurs during the clinical course of type 2 diabetes, leading to development of "type 1 on type 2 diabetes". To clarify the clinical characteristics and triggers of GADA seroconversion, we performed a nationwide questionnaire survey for clinical cases identified by literature search, and obtained information on 38 cases (24 with insulin therapy and 14 without it). The diabetes duration up to determination of GADA seroconversion was significantly longer in the group with insulin therapy than that without it. This finding was particularly noted in insulin-treated non-obese patients with lower serum C-peptide levels. In these patients, insulin therapy could have masked sudden increases in plasma glucose and HbA1c levels, possibly leading to delayed determination of GADA seroconversion. In non-obese patients without insulin therapy, an abrupt rise in the plasma glucose and HbA1c levels was observed at immediately before the determination, a finding which may help to predict GADA seroconversion. From the results of the present survey, we could not determine apparent triggers of GADA seroconversion. Thus, physicians may need to consider the possibility of concurrent type 1 diabetes during the therapeutic course of type 2 diabetes; GADA measurement should be considered when non-obese type 2 diabetic patients not receiving insulin therapy experience unexpected abrupt hyperglycemia and when those receiving insulin therapy show low serum C-peptide levels.
Project description:A 64-year-old woman developed type 1 diabetes 23 years after the diagnosis of idiopathic CD4 lymphocytopenia. To investigate the etiological interaction between idiopathic CD4 lymphocytopenia and type 1 diabetes, we carried out a longitudinal analysis related to islet-specific autoimmunity. Anti-glutamic acid decarboxylase antibody had been already weakly positive for at least 16 years and started rising at 6 months before the onset of type 1 diabetes. The seroconversion of anti-insulinoma-associated antigen-2 antibody and insulin autoantibody occurred at the time of onset. The ratio of CD8/CD4 had been gradually increasing for 8 years before type 1 diabetes onset. Notably, islet-specific glucose-6-phosphatase catalytic subunit-related protein-reactive CD8+ T cells were detected at type 1 diabetes onset, and the frequency was higher than that in 15 non-diabetic controls (6.75% vs 0.49 ± 0.78%, mean ± SD). The present type 1 diabetes patient, presented with idiopathic CD4 lymphocytopenia and showed an elevated number of CD8+ T cells, including the islet antigen-specific CD8+ T cells that might contribute to autoimmune destruction of pancreatic β-cells.
Project description:OBJECTIVE: To compare the ages and sequence in which antibodies associated with type 1 diabetes and celiac disease appear and overt diseases develop in children with an HLA-conferred susceptibility to both diseases. RESEARCH DESIGN AND METHODS: We observed 2,052 children carrying genetic risks for both type 1 diabetes and celiac disease from birth until the median age of 5.7 years and analyzed diabetes- and celiac disease-associated antibodies in serum samples collected at 3- to 12-month intervals. Diabetes was confirmed by World Health Organization criteria and celiac disease by duodenal biopsies. RESULTS: Altogether 342 children seroconverted to positivity for at least one diabetes-associated autoantibody and 88 to positivity for at least one celiac disease-associated antibody at the median ages of 3.0 and 1.5 years, respectively (P < 0.001). If only children with biochemically defined diabetes-associated autoantibodies against insulin, GAD, or IA-2A protein (n = 146) and children with tissue transglutaminase autoantibodies were compared (n = 86), the median seroconversion ages were 2.5 and 3.0 years (P = 0.011). Fifty-one children progressed to overt diabetes at 4.5 years and 44 children to celiac disease at 4.3 years (P = 0.257). Of the 19 children who developed both diabetes- and celiac disease-associated antibodies, 3 progressed to both diabetes and celiac disease. CONCLUSIONS: Children with HLA-conferred susceptibility to type 1 diabetes and celiac disease develop celiac disease-associated antibodies mostly at a younger age or the same age at which they develop diabetes-associated autoantibodies. Clinical diabetes and celiac disease are commonly diagnosed at the same median age.
Project description:Viruses are candidate causative agents in the pathogenesis of autoimmune (type 1) diabetes. We hypothesised that children with a rapid onset of type 1 diabetes may have been exposed to such agents shortly before the initiation of islet autoimmunity, possibly at high dose, and thus study of these children could help identify viruses involved in the development of autoimmune diabetes.We used next-generation sequencing to search for viruses in plasma samples and examined the history of infection and fever in children enrolled in The Environmental Determinants of Diabetes in the Young (TEDDY) study who progressed to type 1 diabetes within 6 months from the appearance of islet autoimmunity, and in matched islet-autoantibody-negative controls.Viruses were not detected more frequently in plasma from rapid-onset patients than in controls during the period surrounding seroconversion. In addition, infection histories were found to be similar between children with rapid-onset diabetes and control children, although episodes of fever were reported less frequently in children with rapid-onset diabetes.These findings do not support the presence of viraemia around the time of seroconversion in young children with rapid-onset type 1 diabetes.
Project description:To evaluate the feasibility of using self-collected capillary blood samples for islet autoantibody testing to identify risk in relatives of people with Type 1 diabetes.Participants were recruited via the observational TrialNet Pathway to Prevention study, which screens and monitors relatives of people with Type 1 diabetes for islet autoantibodies. Relatives were sent kits for capillary blood collection, with written instructions, an online instructional video link and a questionnaire. Sera from capillary blood samples were tested for autoantibodies to glutamic acid decarboxylase, islet antigen-2, insulin and zinc transporter 8. 'Successful' sample collection was defined as obtaining sufficient volume and quality to provide definitive autoantibody results, including confirmation of positive results by repeat assay.In 240 relatives who returned samples, the median (range) age was 15.5 (1-49) years and 51% were male. Of these samples, 98% were sufficient for glutamic acid decarboxylase, islet antigen-2 and zinc transporter 8 autoantibody testing and 84% for insulin autoantibody testing and complete autoantibody screen. The upper 90% confidence bound for unsuccessful collection was 4.4% for glutamic acid decarboxylase, islet antigen-2 and/or zinc transporter 8 autoantibody assays, and 19.3% for insulin autoantibodies. Despite 43% of 220 questionnaire respondents finding capillary blood collection uncomfortable or painful, 82% preferred home self-collection of capillary blood samples compared with outpatient venepuncture (90% of those aged <8 years, 83% of those aged 9-18 years and 73% of those aged >18 years). The perceived difficulty of collecting capillary blood samples did not affect success rate.Self-collected capillary blood sampling offers a feasible alternative to venous sampling, with the potential to facilitate autoantibody screening for Type 1 diabetes risk.
Project description:BACKGROUND:Islet autoantibody testing provides the basis for assessment of risk of progression to type 1 diabetes. We set out to determine the feasibility and acceptability of dried capillary blood spot-based screening to identify islet autoantibody-positive relatives potentially eligible for inclusion in prevention trials. MATERIALS AND METHODS:Dried blood spot (DBS) and venous samples were collected from 229 relatives participating in the TrialNet Pathway to Prevention Study. Both samples were tested for glutamic acid decarboxylase, islet antigen 2, and zinc transporter 8 autoantibodies, and venous samples were additionally tested for insulin autoantibodies and islet cell antibodies. We defined multiple autoantibody positive as two or more autoantibodies in venous serum and DBS screen positive if one or more autoantibodies were detected. Participant questionnaires compared the sample collection methods. RESULTS:Of 44 relatives who were multiple autoantibody positive in venous samples, 42 (95.5%) were DBS screen positive, and DBS accurately detected 145 of 147 autoantibody-negative relatives (98.6%). Capillary blood sampling was perceived as more painful than venous blood draw, but 60% of participants would prefer initial screening using home fingerstick with clinic visits only required if autoantibodies were found. CONCLUSIONS:Capillary blood sampling could facilitate screening for type 1 diabetes prevention studies.
Project description: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.
Project description:There is controversy as to whether type 2 diabetes genetic susceptibility contributes to type 1 diabetes, and it is not known what proportion of islet autoantibody-negative new onset subjects have type 2 diabetes risk alleles.We designed this study to evaluate whether two type 2 diabetes-associated single nucleotide polymorphisms (SNPs) of transcription factor 7-like 2 (TCF7L2) gene are associated with the development of islet autoantibody-negative diabetes vs. islet autoantibody-positive diabetes in young patients and whether these SNPs are associated with specific clinical phenotypes.Autoantibody against glutamic acid decarboxylase 65, islet cell antibody 512bdc (form of IA-2), insulin, ZnT8 transporter, and cytoplasmic islet cell antibody were assayed in patients with new onset diabetes seen at the Barbara Davis Center using sera obtained within 2 wk of diagnosis. We genotyped two noncoding variants in the TCF7L2 gene, rs12255372 and rs7903146, in diabetic subjects and normal controls.A total of 140 patients (15.7%) were negative for all islet autoantibodies among 893 subjects less than age 25 at the onset of diabetes. The allele and genotype frequencies of two SNPs showed that these are associated (odds ratio up to 4) with the development of diabetes in the autoantibody-negative diabetic cohort, but not in the autoantibody-positive diabetic cohort.TCF7L2 type 2 diabetes susceptibility alleles are associated with islet autoantibody-negative but not autoantibody-positive new onset diabetes in young patients.
Project description:Relatives with single positive islet autoantibodies have a much lower risk of progression to diabetes than those with multiple autoantibodies.TrialNet subjects positive for single autoantibody to insulin (mIAA) (n?=?50) or single autoantibody to glutamic acid decarboxylase (GADA) (n?=?50) were analyzed using new electrochemiluminescence (ECL) assays (ECL-IAA and ECL-GADA, respectively) at their initial visit and longitudinally over time. Affinity assays were performed on a subset of single autoantibody-positive subjects at initial and most recent visits.After a mean follow-up of 5.3 years, 20 subjects developed type 1 diabetes. Among either single GADA or single mIAA subjects, those who were positive in the ECL assay showed higher affinity at the initial visit, and affinity results stayed consistent over time. No converting events from low to high or high to low affinity were seen over time.Confirmed positivity for ECL is associated with high affinity and can help staging of risk for type 1 diabetes in single autoantibody-positive subjects.
Project description:A decrease in the size of the pancreas is observed in islet autoantibody-positive non-diabetic donors and acute-onset type 1 diabetes irrespective of the diabetes duration. Little is known, however, about the relationship between the size of the pancreas and type 1 diabetes subtypes, including fulminant type 1 diabetes.We examined the pancreatic volume (PV) in 44 adult patients with type 1 diabetes (16 acute-onset type 1 diabetes, 18 slowly progressive type 1 diabetes and 10 fulminant type 1 diabetes) and 39 age- and body mass index-matched non-diabetic controls. PV was measured by computed tomography. The ability to secrete insulin was assessed by stimulated C-peptide after intravenous glucagon administration.PV was significantly correlated with bodyweight in both control participants and type 1 diabetes patients. The PV index (PVI; PV/bodyweight) was decreased by 39% in type 1 diabetes compared with that in controls. PVI was significantly decreased in acute-onset type 1 diabetes patients and slowly progressive type 1 diabetes patients (both P < 0.0001), but not in fulminant type 1 diabetes patients (P = 0.10), compared with control participants. In cases patients with recent-onset type 1 diabetes (0-7 days post-diagnosis), PVI was significantly decreased in acute-onset type 1 diabetes patients (n = 8, P = 0.0005), but not in fulminant type 1 diabetes patients (n = 7, P = 0.44), compared with controls. PVI showed no correlations with the diabetes duration, C-peptide levels, glycated hemoglobin, glutamic acid decarboxylase autoantibody levels, serum amylase or daily total insulin dose in type 1 diabetes subtypes.The present results show that patients with acute-onset type 1 diabetes and slowly progressive type 1 diabetes have small pancreases irrespective of the diabetes duration or C-peptide levels. In contrast to earlier findings on acute-onset type 1 diabetes, we found no reduction of PVI at the onset of fulminant type 1 diabetes.