Titres Of Islet Cell Antibodies Research Articles

THU153 Deep Vein Thrombosis As The Presenting Symptom In An Adolescent With New-Onset Type 2 Diabetes

Abstract Disclosure: F.I. Cooper: None. S. Gurnurkar: None. M. Carakushansky: None. Introduction The prothrombin G20210A mutation occurs in a small portion of the population, but usually does not become apparent unless the individual exhibits another risk factor for clotting (such as diabetes in adulthood). In this case report, we discuss a 15-year-old male with extensive deep vein thrombosis (DVT) in the setting of hyperglycemia and a newly-discovered prothrombin G20210A mutation. Case Presentation A previously healthy, obese 15-year-old male presented to the emergency department with two days of left hip pain radiating down to the left calf, and one day of left calf swelling. The patient denied prolonged immobility, recent infections, or recent vaccinations. There was strong maternal family history of diabetes but no history of thrombosis. D-dimer was 2013 ng/mL (0-500 ng/mL). A Computed Tomography of the abdomen and pelvis with contrast revealed thrombi in the inferior vena cava, left common iliac, left external iliac, left internal iliac and left common femoral veins. Initial labs were remarkable for unexpected significant hyperglycemia-- random serum glucose 317 mg/dl (<140 mg/dl).He was started on unfractionated heparin infusion as well as Lantus and Humalog insulins. An echocardiogram did not reveal pulmonary embolism or right heart strain. Hemoglobin A1C was 11.8% (3.4-5.6%) and C-peptide was detectable at 1.2 ng/mL (1.1-4.4 ng/mL), suggesting type 2 diabetes (in addition to negative anti-GAD 65 and islet cell antibody titers, in this child with a BMI of 34 kg/m2). The patient underwent image-guided thrombolysis and thrombectomy from the popliteal vein to the left iliac vessels and received continuous infusion of heparin and tissue plasminogen activator (TPA). As the clot improved over the subsequent days, he underwent image-guided angioplasty and removal of the popliteal sheath. He was then transitioned to enoxaparin and discharged on day 10 of hospitalization. His blood sugars responded well to insulin therapy (85-308 mg/dl). The patient received a staged thrombophilia workup. A heterozygous mutation was found in factor II (prothrombin G20210A) gene which is associated with a 2-4 fold increased risk of venous thromboembolism. The patient was discharged on enoxaparin, as well as Lantus and Humalog. He is followed by the Hematology and Endocrinology departments. Conclusion In this case, we presented the first written occurrence of DVT in a pediatric patient with type 2 diabetes. Our patient’s hyperglycemia caused by his new onset type 2 diabetes may have led to onset of an extensive DVT thrombosis at an usually young age, since he had an underlying prothrombin G20210A mutation. Our case also illustrates the need for a multidisciplinary approach (involving endocrinology, hematology, pediatric intensive care, and interventional radiology) for successful outcomes in these patients. Presentation: Thursday, June 15, 2023

Abstract #1395490: New Onset of Type 1 Diabetes After Severe Acute Respiratory Syndrome Coronavirus 2 Vaccination

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) poses the greatest threat of our times. SARS-CoV-2 vaccines are one of the most effective strategies against this infection. Diabetic ketoacidosis, hyperglycemic hyperosmolar syndrome, and new-onset diabetes as adverse effects of SARS-CoV-2 vaccination have been infrequently described in the literature. We hereby report a rare case of new-onset type 1 diabetes after SARS-CoV-2 vaccination. An 18-year-old male presented to the outpatient office for evaluation of breast pain. On routine laboratory tests, he was noted to have fasting blood glucose of 200 mg/dL. On further questioning, he reported some polyuria, nocturia, and a 10-pound weight loss over the preceding month. He received the initial dose of Pfizer-BioNTech SARS-CoV-2 vaccine in May 2022 and the second dose in June 2022, approximately one month before the onset of symptoms. He denied any earlier viral infections and had no personal or family history of autoimmune conditions. On evaluation, his body mass index was 20 kg/m2, but otherwise, he had a normal physical exam, including a breast exam. Over the next few days, his blood glucose progressively increased to over 300 mg/dl. HbA1c was noted to be elevated at 8.6%, glutamic acid decarboxylase-65 (GAD-65) antibodies were remarkably high >250 IU/ml (normal 5 IU/ml), C-peptide was 1.51 ng/ml (normal 0.80 – 3.85 ng/ml), blood glucose 156 mg/dl, islet-cell antibody titer was 320 (< 1.25 JDF units) and insulin autoantibodies were negative. He was diagnosed with autoimmune Type 1 diabetes and a basal-bolus insulin regimen was initiated to improve glycemic control. On a one-month follow-up, his insulin requirements remained low but persistent and his glycemic control was acceptable. Various viruses are known to play a fundamental role in the onset of type 1 diabetes via a variety of effects on pancreatic beta-cells because of either the direct lytic effects of viral replication or the inflammatory response to the virus, which is mediated by autoreactive T cells. The limited release of islet cell antigens induces molecular mimicry and paves the way for long-term autoimmunity and the development of type 1 diabetes mellitus. Our patient did not report any viral illnesses before the onset of his symptoms. He also did not have a family or personal history of autoimmune diseases. His onset of diabetic symptoms coincided temporally with receiving the SARS-CoV-2 vaccine. The detection of a considerable titer of GAD-65 antibodies proved autoimmunity. Clinicians must stay vigilant about this potential side effect of SARS-CoV2 vaccine so that a timely diagnosis can be made.

Sex as a determinant of type 1 diabetes at diagnosis

OBJECTIVE The present study tested the hypothesis that girls have a more aggressive disease process than boys at the diagnosis of type 1 diabetes (T1D). METHODS Demographic and clinical characteristics, the humoral autoantibody profile, and the genetic risk assessed by the presence of human leukocyte antigen DR-DQ haplotypes were analyzed in terms of sex in 4993 children and adolescents diagnosed with T1D between January 2003 and December 2016. RESULTS A clear male preponderance (56.6%) was observed in our cohort and boys were significantly older than girls at clinical diagnosis (mean 8.3 vs 7.7 years, P < .001). Age-adjusted analyses showed a poorer metabolic decompensation in girls than boys at diagnosis. Boys tested more often positive for autoantibodies against insulin autoantibodies (P = .008), islet antigen-2 autoantibodies (P = .033), and zinc transporter 8 autoantibodies (P = .027), whereas girls had a higher frequency of glutamic acid decarboxylase autoantibodies (GADA) (P < .001) and higher GADA (P < .001) and islet cell antibody titers (P = .001). We did not find any significant differences in the genetic risk profile between girls and boys. CONCLUSIONS Our data show that the metabolic derangement is more severe in girls already at diagnosis of T1D and this finding is independent of age. The immunologic aggressiveness of the disease is more variable as the predominance of different autoantibodies varies between sexes with a higher frequency of GADA in girls, while the 3 other biochemical autoantibodies were more common in boys.

Characteristics of Slow Progression to Type 1 Diabetes in Children With Increased HLA-Conferred Disease Risk

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 β-cell destruction and mediate preservation of β-cell function. To identify demographic, genetic, and immunological characteristics of slow progression from seroconversion to clinical T1D. HLA-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. 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. 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.

SUN-275 Azathioprine for Tertiary Prevention of Diabetes in Patients with Newly Diagnosed Type 1 Diabetes

Background: Co-occurrence of type 1 diabetes (T1DM) and autoimmune hepatitis (AIH) is rare1. Older studies on azathioprine for tertiary prevention of T1DM show mixed results and often intolerable side effects. 2,3 There are no recent studies or case reports on the effect of azathioprine on the tertiary prevention of T1DM. Clinical Case: A 6 y.o. M with recently diagnosed AIH on prednisolone taper (15 mg BID; 2mg/kg/day) presented to pediatric endocrinology due to abnormal labs including glucose of 684 mg/dL. He endorsed abdominal pain and polydipsia but was otherwise well. Further workup showed VBG: pH 7.4, bicarbonate 26.7, glucose 653mg/dL, C-peptide 4.7, HgbA1c 6.6%. He was given IV fluids and started on basal/bolus insulin regimen. He was positive for 5/5 diabetes related autoantibodies: Glutamic Acid Decarboxylase Antibody: >250 IU/mL [Ref Range: <5 IU/mL], Insulin Antibody: 8.3 U/mL [Ref Range: <0.4 U/mL], Islet Cell Antibody Screen: POSITIVE [Ref Range: NEGATIVE]; Reflex, Islet Cell Antibody Titer: 80 JDF units [Ref Range: < 1.25 JDF units], IA-2 Antibody: 7.8 U/mL[Ref Range: <0.8 U/mL], ZnT8 Antibody: >500 U/mL [Ref Range: <15 U/ml]. His hepatitis was well controlled and over a period of a few weeks his corticosteroids were weaned and azathioprine was started as treatment for his AIH. As his corticosteroid dose was decreased, his insulin requirements decreased; after he was weaned off corticosteroids he was weaned off insulin a few weeks later. He has not required insulin now for over 1 year since diagnosis, with most recent HgbA1c 5.5%. He is continued on azathioprine for his AIH with good control of his hepatitis and without significant medication side effects. Conclusion: This is one of the first recent case reports showing the possible positive effect of azathioprine in tertiary prevention of T1DM. This patient's results may be more dramatic since the onset of hyperglycemia was associated with corticosteroids. Recent trials of immunotherapy in the prevention and treatment of T1DM have focused more on targeted immunomodulation, but in certain cases azathioprine may still be beneficial.4 More studies of immune modulation therapies for preventing and treating T1DM are needed.

SUN-121 Vitamin D Repletion and Sitagliptin Administration is Associated with an Increase in Serum C-Peptide and a Decrease in GAD-65 Antibody and Hemoglobin A1c in a Patient with Latent Autoimmune Diabetes of Adults

Background: Latent Autoimmune Diabetes of Adults (LADA) is characterized by adult onset and circulating autoantibodies e.g. glutamic acid decarboxylase (GAD-65), islet cell antibodies (ICA), and tyrosine phosphate related islet antigen 2 (IA-2). LADA may be misdiagnosed as it has features of both Type 1 (T1DM) and Type 2 (T2DM) diabetes. Dipeptidyl Peptidase-4 (DPP-4) (CD26) is a transmembrane glycoprotein immunomodulator causing a Th1/Th17 dominant milieu while suppressing anti-autoimmune Th2/Treg expression. Th1 and Th17 secrete pro-inflammatory cytokines that mediate β cell autoreactivity. DPP-4 inhibitors (DPP4I), e.g. sitagliptin (S), preserve β cell function, resulting in higher C-peptide levels, suggesting their potential use in LADA. Sustained remission of T1DM was reported in 2 patients with S and Vitamin D (D), leading us to explore their use in LADA. Clinical Case: Our patient is a 45-year-old Hispanic female with a 2 year history of diabetes. She was presumed to have T2DM and was first treated with diet, exercise and metformin, starting in 07/2016. At diagnosis, BMI was 16.16 kg/m² and HbA1c was 10.5% (<5.7). Glipizide and basal/bolus insulin were added in 08/2016. On 10/06/2016 C-peptide was 0.7ng/ml (0.9-7.1) and serum 25-OH-Vitamin D 25.3 ng/ml (30.0-100.0). On 12/11/2017, GAD-65 antibody titer was 54.9nmol/L (<0.02) and ICA was 40 JDF units (<5). Her age of onset, clinical course, and serology were consistent with LADA. In 01/2018, recognizing that she had either T1DM or LADA, S 100mg daily + ergocalciferol 50,000IU weekly were added to her regimen. On 04/05/2018, C-peptide level rose by 29%, GAD-65 antibody fell by 48%, ICA titer remained at 40 JDF units, and A1c fell by 14%. When seen by her primary care provider in April 2018, S was discontinued as the provider thought it was inappropriate for a “T1DM” patient. Subsequently, A1c rose by 7% on 07/10/2018. S was restarted while continuing ergocalciferol on 07/17/2018. Conclusions: This report supports earlier studies suggesting that S+D may be useful options in LADA or T1DM of relatively short duration. Reports of successful treatment of LADA with saxagliptin, and treatment of psoriasis with S suggest that immunomodulation may be a DPP4I class effect useful against autoimmune disease in general. It is likely that DPP4I and D achieve their observed clinical effects via rebalancing the immune system milieu from a Th1/Th17 dominant state toward a Th2/Treg dominant one. Preclinical studies have shown that D supplementation prevents the development of a number of autoimmune conditions, e.g. inflammatory arthritis, autoimmune thyroiditis, and T1DM, which supports the utility of D in the management of LADA. Based on successful prevention of T1DM in NOD mice with S, future trials to prevent T1DM in antibody positive, non-diabetic siblings of T1DM patients with S and/or D will be of interest.

Sex as a determinant of type 1 diabetes at diagnosis.

The present study tested the hypothesis that girls have a more aggressive disease process than boys at the diagnosis of type 1 diabetes (T1D). Demographic and clinical characteristics, the humoral autoantibody profile, and the genetic risk assessed by the presence of human leukocyte antigen DR-DQ haplotypes were analyzed in terms of sex in 4993 children and adolescents diagnosed with T1D between January 2003 and December 2016. A clear male preponderance (56.6%) was observed in our cohort and boys were significantly older than girls at clinical diagnosis (mean 8.3 vs 7.7 years, P < .001). Age-adjusted analyses showed a poorer metabolic decompensation in girls than boys at diagnosis. Boys tested more often positive for autoantibodies against insulin autoantibodies (P = .008), islet antigen-2 autoantibodies (P = .033), and zinc transporter 8 autoantibodies (P = .027), whereas girls had a higher frequency of glutamic acid decarboxylase autoantibodies (GADA) (P < .001) and higher GADA (P < .001) and islet cell antibody titers (P = .001). We did not find any significant differences in the genetic risk profile between girls and boys. Our data show that the metabolic derangement is more severe in girls already at diagnosis of T1D and this finding is independent of age. The immunologic aggressiveness of the disease is more variable as the predominance of different autoantibodies varies between sexes with a higher frequency of GADA in girls, while the 3 other biochemical autoantibodies were more common in boys.

Teasing Diabetes Apart, One Locus at a Time.

Although most organ-specific autoimmune diseases show middle-age onset and a range of severity, type 1 diabetes appears to be relatively atypical given its striking severity and childhood onset. But the discovery of islet cell antibodies (ICA) as a disease hallmark by the recently deceased Franco Bottazzo in 1974 posed interesting conundrums (1). Not everyone with type 1 diabetes had ICA, and not everyone with ICA had diabetes; indeed, they were also found in a fraction of patients with type 2 diabetes. Further, the higher the ICA titer, the more likely one was to get the disease and to get it early. It followed that individuals with low-titer ICA could develop diabetes in adulthood, while others escaped diabetes altogether (2,3). The passing years have illuminated these points, with tracking of multiple autoantibodies with disease progression (4). Type 1 diabetes is a classic example of a complex trait with a strong genetic basis. However, a differential impact of genetic and nongenetic factors is encapsulated in the “threshold hypothesis”—more of one, less of the other, and vice versa (2). In children, diabetes has a high heritability, but data suggests it declines with increasing age of onset (5), reflecting declining HLA impact. The appearance of multiple high-titer diabetes autoantibodies, likely secondary to environmental events around birth, presage early-onset type 1 diabetes (2,6) (Fig. 1). But a second wave of serum autoantibodies, which appear in subjects for up to 10 more years, presents with different immunogenetic characteristics (Fig. 1). In those cases, autoantibodies are often single, low-titer, and raised to glutamic acid decarboxylase, with enrichment of HLA DR3/DQ2 without depletion of protective HLA genotypes (6). We do not know how these “second-wave” autoantibodies in …

Characterisation of rapid progressors to type 1 diabetes among children with HLA-conferred disease susceptibility.

In this study, we aimed to characterise rapid progressors to type 1 diabetes among children recruited from the general population, on the basis of HLA-conferred disease susceptibility. We monitored 7410 HLA-predisposed children participating in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study for the development of beta cell autoimmunity and type 1 diabetes from birth over a median follow-up time of 16.2years (range 0.9-21.1years). Islet cell antibodies (ICA) and autoantibodies to insulin (IAA), GAD (GADA) and islet antigen 2 (IA-2A) were assessed as markers of beta cell autoimmunity. Rapid progression was defined as progression to clinical type 1 diabetes within 1.5years of autoantibody seroconversion. We analysed the association between rapid progression and demographic and autoantibody characteristics as well as genetic markers, including 25 non-HLA SNPs predisposing to type 1 diabetes. Altogether, 1550 children (21%) tested positive for at least one diabetes-associated autoantibody in at least two samples, and 248 (16%) of seroconverters progressed to type 1 diabetes by the end of 2015. The median time from seroconversion to diagnosis was 0.51years in rapid progressors (n=42, 17%) and 5.4years in slower progressors. Rapid progression was observed both among young (<5years) and early pubertal children (>7years), resulting in a double-peak distribution of seroconversion age. Compared with slower progressors, rapid progressors had a higher frequency of positivity for multiple (≥2) autoantibodies and had higher titres of ICA, IAA and IA-2A at seroconversion, and there was a higher prevalence of the secretor genotype in the FUT2 gene among those carrying the high-risk HLA genotype. Compared with autoantibody-positive non-progressors, rapid progressors were younger, were more likely to carry the high-risk HLA genotype and a predisposing SNP in the PTPN22 gene, had higher frequency of ICA, IAA, GADA and IA-2A positivity and multipositivity, and had higher titres of all four autoantibodies at seroconversion. At seroconversion, individuals with rapid progression to type 1 diabetes were characterised by a younger age, higher autoantibody titres, positivity for multiple autoantibodies and higher prevalence of a FUT2 SNP. The double-peak profile for seroconversion age among the rapid progressors demonstrates for the first time that rapid progression may take place not only in young children but also in children in early puberty. Rapid progressors might benefit from careful clinical follow-up and early preventive measures.

Total plasma antioxidants in first-degree relatives of patients with insulin-dependent diabetes.

Insulin-dependent diabetes mellitus (IDDM) is a chronic disorder that results from autoimmune destruction of the pancreatic beta-cells. Recent evidence suggests that oxidative damage, resulting from both cytokine-induced production of toxic free radicals and low antioxidant capacity of the beta-cell plays a significant role in the pathogenesis of IDDM. Islet cell antibodies (ICA) have been the best validated marker of risk for the development of IDDM in predisposed individuals, i.e. first-degree relatives of patients with IDDM. We investigated the total plasma antioxidant status (TAS) in both ICA-positive and ICA-negative first-degree relatives of patients with IDDM, to assess the level of overall protection against oxidative damage. TAS was significantly lowered in ICA-positive when compared to both ICA-negative and healthy subjects (p < 0.001), while no significant difference was found in comparison to recently diagnosed patients with IDDM. TAS values were not significantly influenced by gender, age and smoking habits in all groups, as well as by ICA titers in the group of ICA-positive subjects. Results indicate that prediabetic condition, apart from well-established immunological and metabolic alterations, could be associated with biochemical changes revealing complex disturbances of the antioxidative defence system. Although TAS is a functional rather than specific marker, its measurement is likely to be a valuable tool for understanding the mechanisms of specific beta-cell injury.

Insulin-Autoantikörper und Inselzellantikörper bei neu aufgetretenem Diabetes mellitus Typ I: Assoziation mit Manifestationsalter und HLA-Phänotyp

Insulin autoantibody (IAA) and islet cell antibody (ICA) titres were measured in 108 newly diagnosed type I diabetics (49 male, 59 female, mean age 20 [1-38] years) and 103 non-diabetic controls (41 male, 62 female, mean age 23 [16-46] years). IAA titres in the controls were normally distributed, with a mean of 5 +/- 11 nU/ml. The upper limit of normal was established as 49 nU/ml (mean + 4 standard deviations). Raised IAA and ICA titres were present in 45% and 44% of type I diabetics, respectively, with 59% positive for either IAA or ICA or both. IAA were markedly age-dependent, being positive in 70% (26 out of 37) of diabetics under the age of 15 years, and in 32% (23 out of 71) at the age of 15 years or more (P = 0.0004). There was a less marked difference for ICA titres (positive in 62% of patients less than 15 years, and in 35% of those of 15 years of older; P less than 0.01). IAA were significantly more common in HLA DR4 positive patients than in HLA DR4 negative patients (56% vs 11%; Pc less than 0.00015). With regard to age a significant association between IAA and HLA DR phenotype was present only in homozygous (Pc less than 0.03) and heterozygous (P less than 0.0003) patients aged 15 years or older. By contrast, ICA was not significantly correlated with HLA phenotype. These data suggest a genetic predisposition for the development of IAA.

Increased Frequency of Islet Cell Antibodies in Unaffected Brothers of Children with Type 1 Diabetes

Aim: To assess the relation between islet cell antibody (ICA) positivity and demographic characteristics in an extensive series of first-degree relatives of children with type 1 diabetes (T1D). Methods: Family members of children diagnosed with T1D before the age of 16 years and attending one of 27 participating paediatric units in Finland taking care of children with diabetes were invited to volunteer for an ICA screening program aimed at identifying individuals eligible for inclusion in the European Nicotinamide Diabetes Intervention Trial (ENDIT). The final series comprised 2,522 first-degree relatives (1,107 males) with a mean age of 20.4 (range 0.1–51.9) years, out of whom 390 were fathers, 622 mothers, 717 brothers, and 793 sisters of affected cases. Results: Two hundred and four family members (8.1%) tested positive for ICA with levels ranging from 3 to 564 (median 18) Juvenile Diabetes Foundation (JDF) units. One hundred and five relatives (4.2%) had an ICA level of 18 JDF units or more. Males had detectable ICA more often than females (9.6 vs. 6.9%; p = 0.02). Antibody-positive family members under the age of 20 years had higher ICA levels than the older ones [median 18 (range 3–514) JDF units vs. 10 (range 3–564) JDF units; p = 0.008]. Among the adult relatives (≧20 years of age) antibody-positive females had higher ICA levels than the males [median 10 (range 5–564) JDF units vs. 9 (range 3–130) JDF units; p = 0.04]. Siblings had an increased frequency of high-titre ICA (≧18 JDF units) when compared to the parents (4.8 vs. 3.2%; p = 0.05). Among siblings, we found a higher frequency of ICA positivity in brothers than in sisters (10.8 vs. 6.9%; p = 0.01), and this was also true for high-titre ICA (6.0 vs. 3.8 %; p = 0.04). Geographically, the highest ICA prevalence was seen among relatives living in the middle of Finland (10.4 vs. 7.2% in the other parts of Finland; p = 0.01). Conclusions: These results imply that male gender and young age favour positive ICA reactivity among family members of children with T1D. Siblings test positive for high ICA titres (≧18 JDF units) more frequently than parents. Accordingly, judged from demographic characteristics, the yield of ICA screening in first-degree relatives would be maximized by targeting young brothers of affected cases.

Screening strategies for the identification of multiple antibody-positive relatives of individuals with type 1 diabetes.

The objective of this study was to determine the extent to which different screening strategies could identify a population of nondiabetic relatives of a proband with type 1 diabetes who had two or more immunologic markers from the group consisting of islet cell antibodies (ICA), micro insulin autoantibodies (MIAA), GAD65 autoantibodies (GAA), and ICA512 autoantibodies (ICA512AA). Relatives of subjects with type 1 diabetes were screened for ICA as part of the Diabetes Prevention Trial-Type 1. A total of 71,148 samples were also tested for GAA and ICA512AA. IAA results were available on 17,207 of these samples using a protein A/protein G MIAA assay as well. The study population was defined to be those in which all four antibodies were tested. There were 1010 (5.9%) relatives with a single autoantibody on initial screening and 394 (2.3%) with two or more autoantibodies. GAA was more sensitive than ICA [GAA, 91% (357 of 394); ICA, 82% (324 of 394)] in the detection of multiple antibody-positive individuals. The addition of ICA512AA to GAA as a screening test increased sensitivity to 97% (381 of 394), whereas adding ICA512AA to ICA as a screening test increased sensitivity to 93% (367 of 394). GAA and ICA identified somewhat nonoverlapping subgroups of multiple antibody-positive subjects. Thus, the substitution of GAA or ICA for the other failed to detect 8-17% of multiple antibody subjects. Higher ICA titers were associated with increased percentages of multiple antibody-positive subjects; 86% of subjects having Juvenile Diabetes Foundation titers of at least 160 were positive for two or more antibodies. A screening strategy combining GAA and ICA512AA resulted in a higher sensitivity than using any marker individually, although statistically it was not significantly higher than using GAA alone. Screening for any three antibodies guaranteed that all multiple antibody-positive subjects were detected. Screening for two antibodies at one time and testing for the remaining antibodies among those who are positive for one resulted in a sensitivity of 99% for GAA and ICA, 97% for GAA and MIAA or GAA and ICA512AA, 93% for ICA512AA and ICA, 92% for MIAA and ICA, and 73% for ICA512AA and MIAA. From a laboratory perspective, screenings for GAA, ICA512AA, and MIAA are semiautomated tests with high throughput that, if used as initial screen, would identify at first testing 67% of the 2.3% of multiple antibody-positive relatives (100% if antibody-positive subjects are subsequently tested for ICA) as well as 4.7% of relatives with a single biochemical autoantibody, some of whom may convert to multiple autoantibody positivity on follow-up. Testing for ICA among relatives with one biochemical antibody would identify the remaining 33% of multiple antibody-positive relatives. Further follow-up and analysis of actual progression to diabetes will be essential to define actual diabetes risk in this large cohort.

The changing presentation of children with newly diagnosed type 1 diabetes mellitus.

Although it is known that the incidence of type 1 diabetes mellitus (DM) in childhood is progressively increasing, it is less clear whether the presentation of newly diagnosed DM is changing. The aim of this study was to establish whether any biochemical or clinical presentation parameters have altered over time. A retrospective study was performed comparing newly diagnosed children with DM in two 24 month time intervals, 8 yrs apart (1988-89 and 1995-96). Fifty-seven children were diagnosed with type 1 DM in 1988-89 and 70 children in 1995-96. At presentation, children born in the later cohort had a higher pH (p < 0.001) and lower serum glucose (p < 0.05). Although the frequency of diabetic ketoacidosis (DKA) was higher in the 1988/89 cohort (63% vs. 42% in 1995/96) the absolute number of children with DKA in each time interval was similar (33 subjects in 1988-89 vs. 30 subjects in 1995/96). Islet cell antibody (ICA) levels were very different between the two cohorts; higher antibody levels were found in the 1988/89 group (p < 0.01). DKA was also associated with higher ICA titres (p < 0.05). Hospital admission stay decreased from 6.5 DS to 3.4 DS over the 8-year period (p < 0.0001). At our institution, the presentation of children with type 1 DM is changing with many more children diagnosed before developing DKA. We speculate that a new environmental factor(s) may be responsible for the absolute increase in patients presenting without DKA, while older etiologies (both genetic and environmental) are responsible for the steady, unchanging number of patients with a more severe presentation. Greater awareness of diabetes in children is not the factor contributing to earlier diagnosis before DKA develops.

Screening for preclinical type 1 diabetes in a discrete population with an apparent increased disease incidence.

Environmental agents are proposed to play a role in triggering or exacerbating pancreatic islet autoimmunity in people genetically predisposed to type 1 diabetes. However, with few exceptions, these agents remain enigmatic. Clues to environmental agents may be found by investigating population/geographic clusters or 'hotspots' of high disease incidence. We were alerted to a small community where the incidence of type 1 diabetes appeared to be five-fold higher than expected. Because type 1 diabetes is now recognized to have a subclinical phase during which anti-islet antibodies can be detected, we aimed to identify and characterize a reservoir of children with subclinical disease in this community. Venous blood samples were collected from 1906/2347 (81%) local school children during one week. Islet cell antibodies (ICAs) were detected in 122 (6.4%) children, 18 (0.9%) being high titer (> or = 20 Juvenile Diabetes Foundation units (JDFu)). On retest, 15 months later, the majority of low titer ICAs were undetectable, whereas high-titer ICAs persisted. The latter were found in two distinct age-related, ethnically similar groups. The younger group, aged 6-9 yr, had antibodies to insulin (IAAs), glutamic acid decarboxylase (GAD) and tyrosine phosphatase IA2 in addition to ICA, human leukocyte antigen (HLA) genes associated with susceptibility to type 1 diabetes, and lower first-phase insulin responses (FPIRs) to intravenous glucose. The older group, aged 13-16 yr, the age cohort of the index clinical cases, had few antibodies other than ICA, non-susceptibility HLA genes and normal FPIRs. During follow-up, three children, all from the younger group with multiple antibodies and FPIRs less than the first percentile, developed diabetes 4, 6 and 7 yr after screening. The finding of two age groups of subclinical disease suggests that if environmental agents triggered islet autoimmunity they did not act constantly on the community. Furthermore, the absence of multiple autoantibodies and/or HLA susceptibility genes in the older group, the source of index clinical cases, implies they are a residual subgroup with slow or absent progressive beta-cell destruction. This study illustrates that the natural history of type 1 diabetes may be elucidated by analyzing age-related subclinical disease in the general population.

Diabetic autoimmunity in infants and pre-schoolers with type 1 diabetes

The incidence of type 1 diabetes is increasing most rapidly in children under 5 yrs of age, a group where the disease appears to be more accelerated than traditional type 1 diabetes. Little is known about demographics, and markers of diabetes autoimmunity, in infants and pre-schoolers with type 1 diabetes. We report an analysis of 47 children diagnosed with type 1 diabetes prior to 5 yrs of age compared with a representative cohort (n=49) diagnosed after 5 yrs of age, and all were followed at Loma Linda University (LLU) Children's Hospital. Ethnic, familial, seasonal, and autoimmune marker characteristics are outlined. To determine the prevalence of diabetes autoimmune markers, ICA512, GAD65 and insulin autoantibodies (IAA) antibodies were measured. Children with early-onset diabetes had a significantly higher incidence of viral illness symptoms (p=0.005) and diabetic ketoacidosis (DKA; p=0.017) at the time of diagnosis. However, hemoglobin A1C (HbA1c) levels at diagnosis were significantly higher in the later-onset group (p=0.001). A honeymoon period was reported in 14.8% of children diagnosed before 5 yrs of age compared with 42.1% in those diagnosed over 5 yrs of age (p=0.038). Islet-cell antibodies (ICAs) and glutamic acid decarboxylase (GAD) antibody titers were significantly different between early- and later-onset groups. ICA titers were positive in 35.29%, and GAD in 41.38% of the early-onset group versus 70.83 and 71.74% in children with later-onset disease, (p=0.001 and 0.009, respectively). IAA titers, drawn after instituting insulin therapy, were not significantly different between the two groups. GAD and ICA512 antibody results suggest a relative lack of diabetes immune markers in infants and toddlers with new-onset diabetes. This finding, and the apparent shorter pre-clinical phase reflected in the lower HbA1c values, may indicate age-related differences in type 1 diabetes autoimmunity or the existence of non-autoimmune diabetogenic mechanisms in younger children.

Predictive value of islet cell antibody titer at onset of type 1 diabetes for clinical course of the disease

Predictive value of islet cell antibody titer at onset of type 1 diabetes for clinical course of the disease

Interactions of age, islet cell antibodies, insulin autoantibodies, and first-phase insulin response in predicting risk of progression to IDDM in ICA+ relatives: the ICARUS data set. Islet Cell Antibody Register Users Study.

Many studies have examined the role of age, islet cell antibodies (ICAs), insulin autoantibodies (IAAs), and first-phase insulin responses (FPIRs) to an intravenous glucose tolerance test (IVGTT) as markers of risk of progression to IDDM, but a large data set is required for the analysis of the interactions between these markers. The Islet Cell Antibody Register Users Study (ICARUS) register includes 456 first-degree relatives with ICA levels > or = 5 JDF U confirmed in a reference laboratory, 108 of whom have progressed to IDDM in the course of prospective follow-up. Analysis of this data set confirmed the importance of the loss of FPIR, high ICA titer, coexistence of IAA, and young age in enhancing the risk of progression to the disease. The influence of any given marker of risk is modified by the presence or absence of the other markers. Cox regression analysis performed in a subset of 217 subjects for whom IVGTT, ICA, and IAA data were available showed that risk was most strongly associated with loss of FPIR; IAA and ICA titer contributed equally to the model, while age was also an independent risk determinant.

Antibody response to islet antigens in anti-CD4/prednisolone immune intervention of type 1 diabetes

Cytoplasmic islet cell antibodies, glutamic acid decarboxylase autoantibodies, spontaneous insulin autoantibodies, and insulin-induced antibodies were analyzed in a 1-year follow-up study of 12 newly diagnosed patients with insulin-dependent diabetes mellitus aged 14 +/- 2 years (range 7-20 years) who had been initially treated with either multiple injections of insulin alone (control group) or, in addition, anti-CD4 monoclonal antibody/prednisolone (treatment group). Despite individual variations in islet cell antibody titers, there were no significant differences in the prevalence or changes in the mean titers between the two groups. Glutamic acid decarboxylase autoantibodies remained almost unchanged, but correlated with levels of islet cell antibodies. While at initiation of treatment only 50% of the patients from both groups had spontaneous insulin autoantibodies, all patients developed insulin-induced antibodies upon conventional insulin therapy during the course of follow-up. This was not related to islet cell antibody or glutamic acid decarboxylase antibody levels. The insulin requirement was markedly reduced through the period of follow-up, but did not significantly differ between the two groups. A correlation between islet cell antibody levels and insulin requirement was observed in the control group but not in the treatment group. Plasma levels of the antibodies were not associated with changes in stimulated C-peptide or hemoglobin A1 concentrations. Activated T-lymphocytes persisted in both groups of patients, but their mean levels were not significantly different. The reason for the absence of statistically significant differences between treatment and control groups could be due to the small number of patients in the study. In conclusion, short-term immune intervention with anti-CD4 monoclonal antibody in addition to insulin therapy did not suppress autoimmune reactions towards the beta cells.

小児インスリン依存型糖尿病における膵島細胞抗体 (ICA) 陽性率および抗体価の経時的変化に関する検討

小児インスリン依存型糖尿病における膵島細胞抗体 (ICA) 陽性率および抗体価の経時的変化に関する検討