Diabetes-related Autoantibodies Research Articles

Role of the C1858T polymorphism of protein tyrosine phosphatase non-receptor type 22 (PTPN22) in children and adolescents with type 1 diabetes.

In recent years, increasing interest has been devoted to the susceptibility gene polymorphisms in type 1 diabetes (T1D) as well as in other autoimmune diseases. Among these, a nucleotide polymorphism of the gene encoding for the protein tyrosine phosphatase non-receptor type 22 (PTPN22) has been associated with T1D in several studies. The aim of this study is to define the frequency of the C1858T polymorphism in the PTPN22 gene in a cohort of 113 Caucasian patients (58 males and 55 females) with T1D, and to assess a possible correlation with a group of clinically relevant variables: age at onset, gender, diabetes-related autoantibodies, residual β-cell function and daily insulin requirement (IR) 6 months after diagnosis. Using a PCR-RFLP approach, we evidenced a 17.7% frequency of the PTPN22 C1858T polymorphism in diabetic patients, higher than the frequency showed in the general population. A statistically significant correlation between this polymorphism and higher levels of C-peptide at diagnosis and lower IR at 6 months from diagnosis was observed (P=0.001 and P=0.04). Moreover, 1858T variant carriers were more frequently positive for glutamic acid decarboxylase (GAD) autoantibodies at diagnosis than wild-type subjects (P=0.19). On the other hand, no significant difference regarding age at onset, gender distribution, insulinoma-associated 2 molecule (IA2) and islet cell antibodies (ICA) positivity was found. These findings, if adequately confirmed in the future and extended to larger samples, may characterize a subset of T1D patients with a defined genetic pattern, who may be eligible for trials aimed to preserve residual β-cell function in the coming years.

Towards an Earlier and Timely Diagnosis of Type 1 Diabetes: Is it Time to Change Criteria to Define Disease Onset?

Type 1 diabetes (T1D) is the immune-mediated form of diabetes requiring insulin treatment and affecting both children and adults. The incidence of T1D is increasing dramatically and has doubled in the past 2 decades. In the recent years, significant knowledge on the disease natural history has been gained and, nowadays, diabetes-related autoantibodies make T1D a predictable disease. Despite this great advance in the field of T1D, we still use diagnostic criteria defined by the American Diabetes Association (ADA) in 1997. In other autoimmune endocrine disorders (e.g., Hashimoto's thyroiditis and Addison's disease), that share several features with T1D, diagnosis is made early in the presence of circulating autoantibodies together with subclinical thyroid/adrenal functional impairment and treatments are often provided in the absence of a frank clinical glandular insufficiency. With this review, we propose to anticipate diagnosis also in T1D at the stage in which subjects have circulating multiple islet autoantibodies, are dysglycemic but are still insulin independent. We believe that anticipating T1D diagnosis can lead to better disease management and prevention of secondary complications but can also provide the possibility to perform earlier and likely more effective interventions for a disease that to date has proven controllable but still incurable.

Frequency of partial remission and related factors in children and adolescents diagnosed with type 1 diabetes mellitus

The aim of this study was to determine the frequency of remission and related factors in children and adolescents with T1DM. The medical files of patients, diagnosed at our clinic with T1DM in a sequential 3-year period and followed up for at least one year, were retrospectively reviewed. Measurements of pH, blood glucose, insulin, C-peptide, HbA1c and diabetes related auto-antibodies were recorded at diagnosis along with presence of diabetic keto-acidosis and daily insulin requirements at initial discharge. Subsequent HbA1c values and daily insulin requirements were recorded at follow up visits. Partial remission was defined as the value of adjusted HbA1c of ≤ 9. Adjusted HbA1c is equal to HbA1c (percent) + [4 x insulin dose (units per kilograms per day)]. Patients were evaluated according to age groups (group 1 ≤ 10 years; Group 2 > 10 years). Data of 111 patients (males = 56) were evaluated [mean age 9.4 ± 4.2 years (0.8–16.2)]. Complete remission was observed in none of our patients. Partial remission was observed in 67 patients (60.4 %), and partial remission was observed more frequently in children ≤ 10 years of age (p = 0.043). No correlation was identified between clinical and laboratory characteristics at the time of diagnosis and frequency of partial remission. The frequency of partial remission was higher in younger children during the period of observation. Additionally, clinical and laboratory characteristics at the time of diagnosis were not helpful in predicting the degree of remission in this study group.

Biomarker discovery study design for type 1 diabetes in The Environmental Determinants of Diabetes in the Young (TEDDY) study.

The Environmental Determinants of Diabetes in the Young planned biomarker discovery studies on longitudinal samples for persistent confirmed islet cell autoantibodies and type 1 diabetes using dietary biomarkers, metabolomics, microbiome/viral metagenomics and gene expression. This article describes the details of planning The Environmental Determinants of Diabetes in the Young biomarker discovery studies using a nested case-control design that was chosen as an alternative to the full cohort analysis. In the frame of a nested case-control design, it guides the choice of matching factors, selection of controls, preparation of external quality control samples and reduction of batch effects along with proper sample allocation. Our design is to reduce potential bias and retain study power while reducing the costs by limiting the numbers of samples requiring laboratory analyses. It also covers two primary end points (the occurrence of diabetes-related autoantibodies and the diagnosis of type 1 diabetes). The resulting list of case-control matched samples for each laboratory was augmented with external quality control samples.

Is type 1 diabetes "going viral"?

Although genetic predisposition to type 1 diabetes (T1D) is a key risk factor, it does not explain the recent and rapid rise in incidence of the disease, particularly among children under the age of 5 (1). Changes in the environment and/or how individuals respond to these changes are now widely believed to be responsible for the recent increases in T1D. While viruses have been hypothesized to have an etiological role in T1D for more than five decades, definitive proof has not yet materialized. Nonetheless, a number of candidate viruses have been proposed, including enteroviruses, rotaviruses, herpesviruses, cytomegalovirus, and endogenous retroviruses (2). The strongest and most clinically significant associations point to enterovirus infection. A recent meta-analysis of 26 studies that assessed enteroviral infection using both molecular and immunological assays showed that compared with nondiabetic control subjects, the likelihood of finding evidence of enterovirus is 10-fold higher in T1D patients and fourfold higher in individuals with diabetes-related autoimmunity (3). Despite this evidence, important questions remain. These include whether a viral infection is causal in the development of T1D, whether it acts to accelerate the onset of disease in individuals in whom the process of β-cell destruction has already been initiated, or whether it is simply present because individuals with diabetes are more susceptible to infection. Two articles published in this issue of Diabetes help to address these questions. Ferreira et al. (4) and Kallionpaa et al. (5) used peripheral blood samples from two longitudinal birth cohorts—the BABYDIET cohort (6) and the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study (7), respectively. Both studies monitored development of diabetes-related autoantibodies as well as the onset of T1D in “at-risk” populations, thereby enabling access to samples …

The effect of autoimmunity on the development time of microvascular complications in patients with type 1 diabetes mellitus.

BackgroundType 1 diabetes mellitus (DM) is an autoimmune disease with chronic complications that is becoming more frequent as life expectancy of diabetics has increased owing to improved methods of detection and better management. In this study, we investigated whether the presence of autoimmunity can be used in predicting the development time of microvascular complications.Material/MethodsOur study included 52 patients with type 1 diabetes mellitus (DM). The subjects had developed microvascular complications and they had been tested for anti-GAD (glutamic acid decarboxylase) antibodies and/or islet-cell antibodies (ICA). In the assessment of microvascular complications, we used ocular fundus examination, electromyography (EMG), and 24-h urine microalbuminuria tests.ResultsOf the patients included in the study, 30 were female and 22 were male. Of all patients characterized for the existence of diabetic complications, 36 of 52 had both diabetic retinopathy and diabetic nephropathy, 5 patients had diabetic neuropathy, and 11 patients had diabetic retinopathy only. At the diagnosis of diabetes, 20 in 52 patients tested negative for autoantibodies (anti-GAD and anti-ICA), while 32 of 52 tested positive for anti-GAD and/or anti-ICA. The mean HbA1C level of autoantibody-negative patients was 7.7%, while antibody-positive patients had slightly higher HbA1c levels (7.9%). However, this difference was not statistically significant (p>0.05). The mean development time of microvascular complications in autoantibody-positive patients was calculated as 11: 40±6.46 years, and in patients with negative autoimmunity results it was 10.91±6.70 years.ConclusionsThe presence of diabetes-related autoantibodies (DRAs) in patients with type 1 diabetes mellitus does not have a significant effect on the development time of diabetic microvascular complications.

Expression of Innate Immunity Genes and Damage of Primary Human Pancreatic Islets by Epidemic Strains of Echovirus: Implication for Post-Virus Islet Autoimmunity

Three large-scale Echovirus (E) epidemics (E4,E16,E30), each differently associated to the acute development of diabetes related autoantibodies, have been documented in Cuba. The prevalence of islet cell autoantibodies was moderate during the E4 epidemic but high in the E16 and E30 epidemic. The aim of this study was to evaluate the effect of epidemic strains of echovirus on beta-cell lysis, beta-cell function and innate immunity gene expression in primary human pancreatic islets. Human islets from non-diabetic donors (n = 7) were infected with the virus strains E4, E16 and E30, all isolated from patients with aseptic meningitis who seroconverted to islet cell antibody positivity. Viral replication, degree of cytolysis, insulin release in response to high glucose as well as mRNA expression of innate immunity genes (IFN-b, RANTES, RIG-I, MDA5, TLR3 and OAS) were measured. The strains of E16 and E30 did replicate well in all islets examined, resulting in marked cytotoxic effects. E4 did not cause any effects on cell lysis, however it was able to replicate in 2 out of 7 islet donors. Beta-cell function was hampered in all infected islets (P<0.05); however the effect of E16 and E30 on insulin secretion appeared to be higher than the strain of E4. TLR3 and IFN-beta mRNA expression increased significantly following infection with E16 and E30 (P<0.033 and P<0.039 respectively). In contrast, the expression of none of the innate immunity genes studied was altered in E4-infected islets. These findings suggest that the extent of the epidemic-associated islet autoimmunity may depend on the ability of the viral strains to damage islet cells and induce pro-inflammatory innate immune responses within the infected islets.

The Evolution of Type 1 Diabetes

T YPE 1 DIABETES (T1D) OCCURS IN INDIVIDUALS WITH a genetic predisposition to the disease, predominantly from a human leukocyte antigen (HLA)related immunogenotype that accounts for approximately 60% of the genetic influence. In these individuals who are genetically at risk, an environmental trigger is thought to initiate an immune response targeting the insulin-secreting pancreatic islet cells. The initial immune response also may engender secondary and tertiary immune responses that contribute to the impairment of -cell function and destruction of cells. The rate of development of T1D varies, probably related to non-HLA genetic factors and additional environmental factors beyond the triggering exposure. The initial laboratory manifestation of -cell injury is seroconversion, the appearance of diabetes-related autoantibodies. These autoantibodies likely do not mediate -cell injury but rather are markers of such injury. With progressive impairment of -cell function, metabolic abnormalities become measurable, initially either as loss of early insulin response to intravenous glucose or as reduced -cell sensitivity to glucose resulting in decreased insulin secretion. Subsequently, glucose abnormalities manifest as dysglycemia, either impaired fasting glucose (plasma glucose concentration of 100125 mg/dL) impaired glucose tolerance (2-hour plasma glucose concentration of 140-199 mg/dL following an oral glucose test), or indeterminate glucose tolerance (plasma glucose concentration of 200 mg/dL at 30, 60, or 90 minutes following an oral glucose test). Eventually, overt diabetes presents with glucose concentrations meeting current criteria, fasting plasma glucose concentration of 126 mg/dL or 2-hour plasma glucose concentration of 200 mg/dL. At the point of development of overt diabetes there is still evidence of persistent -cell function shown through measurement of C-peptide. C-peptide is a component of the insulin precursor molecule proinsulin, which is secreted by cells on an equimolar basis as insulin but is not contained in commercial insulin preparations, thus allowing measurement of -cell function even in patients treated with insulin. After diagnosis of T1D, however, there is a progressive decline in C-peptide as -cell function becomes more impaired or absent. Nonetheless, even many years after diagnosis, some patients with T1D may have low detectable levels of C-peptide. Since the sequence of events leading to T1D involves immunogenotypes detectable at birth or in infancy, several groups have followed birth cohorts with the genetic risk. Working together, Ziegler and colleagues analyzing cohorts in Colorado, Finland, and Germany report in this issue of JAMA the risk of progression to T1D from the time of seroconversion by measuring detectable diabetes autoantibodies. Remarkably, the results are similar in all 3 cohorts. Among 585 children who developed 2 or more diabetes-related autoantibodies, nearly 70% (280 of 401 available for follow-up) had developed T1D within 10 years, and 84% (299 of 355 available for follow-up) had developed T1D within 15 years. This is the first reportof a longitudinal cohort followed frominfancy throughthedevelopmentofT1D.Because theparticipantswere recruited from both the general population (in Colorado and Finland) and offspring of parents with T1D (in Germany), the similar findings take on added significance, suggesting that the same sequence of events occurs in individuals with socalled sporadic T1D and in relatives of individuals with T1D. The findings in this report raise additional questions. The basis for the differential progression to T1D according to the type of single autoantibody and the pattern of multiple autoantibodies should be explored. Also, the nearly 2-fold higher prevalence of HLA DR3/DR4-DQ8 in participants with multiple autoantibodies (n=331) than in those with a single autoantibody, and the similar prevalence between participants with a single autoantibody and those with no autoantibodies need to be better understood. In addition, would the identification of those with higher titers provide even a greater likelihood of progression to T1D? Muchattention inrecentyearshas focusedonwhetherT1D can be prevented. To that end, studies have been conducted in individualswith thegenetic riskalone(primaryprevention) and in individuals who have autoantibodies (secondary prevention). Although no study has of yet convincingly demonstrateddelayorpreventionofT1D,someevidencesuggests this may be possible. Primary prevention studies have shown the potential todelay theappearanceof autoantibodiesbyvarying infant formula used at the time of weaning from breast milk, either by eliminating cow’s milk and instead using a formula with casein hydrolysate or by removing bovine insulin from the formula. It is unknown whether such actions will delay progression to T1D, but an international effort—the National InstituteofChildHealthandHumanDevelopment–sponsored Trial toReduceInsulin-DependentDiabetesMellitus intheGenetically At-Risk (TRIGR) study—is under way to test the casein hydrolysate formula, with results expected in 2017.

The use of intermediate endpoints in the design of type 1 diabetes prevention trials.

This paper presents a rationale for the selection of intermediate endpoints to be used in the design of type 1 diabetes prevention clinical trials. Relatives of individuals diagnosed with type 1 diabetes were enrolled on the TrialNet Natural History Study and screened for diabetes-related autoantibodies. Those with two or more such autoantibodies were analysed with respect to increased HbA1c, decreased C-peptide following an OGTT, or abnormal OGTT values as intermediate markers of disease progression. Over 2 years, a 10% increase in HbA1c, and a 20% or 30% decrease in C-peptide from baseline, or progression to abnormal OGTT, occurred with a frequency between 20% and 41%. The 3- to 5-year risk of type 1 diabetes following each intermediate endpoint was high, namely 47% to 84%. The lower the incidence of the endpoint being reached, the higher the risk of diabetes. A diabetes prevention trial using these intermediate endpoints would require a 30% to 50% smaller sample size than one using type 1 diabetes as the endpoint. The use of an intermediate endpoint in diabetes prevention is based on the generally held view of disease progression from initial occurrence of autoantibodies through successive immunological and metabolic changes to manifest type 1 diabetes. Thus, these markers are suitable for randomised phase 2 trials, which can more rapidly screen promising new therapies, allowing them to be subsequently confirmed in definitive phase 3 trials.

Family psychological stress early in life and development of type 1 diabetes: The ABIS prospective study

AimsThis study investigated whether psychological stress in the family during the child's first year of life are associated with the risk of childhood type 1 diabetes (T1D). According to the beta-cell stress hypothesis all factors that increase the need for, or the resistance to, insulin may be regarded as risk factors for T1D. MethodsAmong 8921 children from the general population with questionnaire data from one parent at child's birth and at 1 year of age, 42 cases of T1D were identified up to 11–13 years of age. Additionally 15 cases with multiple diabetes-related autoantibodies were detected in a sub-sample of 2649 children. ResultsCox regression analyses showed no significant associations between serious life events (hazard ratio 0.7 for yes vs. no [95% CI 0.2–1.9], p=0.47), parenting stress (0.9 per scale score [0.5–1.7], p=0.79), or parental dissatisfaction (0.6 per scale score [0.3–1.2], p=0.13) during the first year of life and later diagnosis of T1D, after controlling for socioeconomic, demographic, and diabetes-related factors. Inclusion of children with multiple autoantibodies did not alter the results. ConclusionsNo association between psychological stress early in life and development of T1D could be confirmed.

Low C-peptide levels and decreased expression of TNF and CD45 in children with high risk of type 1 diabetes

Type 1 diabetes (T1D) patients have numeral and functional defects in peripheral immune cells, but the pre-diabetic period is fairly uncharacterized. Our aim was to analyze expression of immunological markers in T1D high risk children and relate it to clinical/immunological parameters. Children from ABIS (All Babies in Southeast Sweden) with ≥2 diabetes related autoantibodies were considered at high risk. Age-matched controls and new-onset T1D patients were included. Expression of genes related to immune cell function and different arms of the immune system was assessed in peripheral blood mononuclear cells using PCR array. Risk children had lower TNF and CD45, and although there were few differences between the groups, expression of many genes differed when comparing children with regard to residual insulin secretion. Hence, expression of immune related genes seemed related not only to the autoimmune process but rather to residual β-cell function, which was decreased already during the pre-diabetic phase.

Fulminant type 1 diabetes with robust recovery of insulin secretion: A case report

In fulminant type 1 diabetes (FT1D), irreversible destruction of pancreatic beta-cells occurs abruptly, leading to sudden diabetic ketoacidosis (DKA) in the absence of diabetes-related autoantibodies. This is the first case report of FT1D in which beta-cell was rescued with the commencement of insulin therapy during the evolution of FT1D.

Fulminant Type 1 diabetes in a pregnant woman as an initial manifestation of the insulin autoimmune syndrome

Fulminant Type 1 diabetes is a subtype of Type 1 diabetes characterized by (1) abrupt onset of diabetes, (2) very short duration of hyperglycaemia with mildly elevated HbA(1c) (< 69 mmol/mol, 8.5%), (3) rapid progression to diabetic ketoacidosis, (4) very low C-peptide level, and (5) often associated with elevated serum pancreatic enzymes, and absence of diabetes-related autoantibodies. We encountered a case of fulminant Type 1 diabetes that developed with an initial manifestation of the insulin autoimmune syndrome and rapidly progressed to diabetic ketoacidosis during pregnancy. A 31-year-old Korean woman presented with recurrent sudden onset of sweating and change of consciousness during sleep at 19 weeks gestation. During a 72-h fasting test, hypoglycaemia (1.72 mmol/l) occurred at 4 h after the start of the test. At that time, there was a high insulin level (370.2 μU/ml), a paradoxically low C-peptide level (0.01 nmol/l) and a positive insulin autoantibody test. An oral glucose tolerance test revealed postprandial hyperglycaemia. She was initially diagnosed as the insulin autoimmune syndrome. On the day 5 of admission, she developed diabetic ketoacidosis. Her HbA(1c) was 62 mmol/mol (7.8%). The rapid progression of diabetic ketoacidosis altered the diagnosis to fulminant Type 1 diabetes. This case differed from typical fulminant Type 1 diabetes because it presented with hypoglycaemia, and positive insulin and anti-phospholipid antibody tests. Her HLA typing was HLA-DQA1*0302, 0501, HLA-DRB1*0301 (DR3), 0901(DR9). Her glucose level was subsequently very well controlled with multiple insulin injections and she successfully delivered a healthy baby.

Surface Plasmon Resonance Reveals a Different Pattern of Proinsulin Autoantibodies Concentration and Affinity in Diabetic Patients

Type 1 diabetes mellitus (DM) is characterized by autoimmune aggression against pancreatic beta cells resulting in absolute deficiency of insulin secretion. The first detectable sign of emerging autoimmunity during the preclinical asymptomatic period is the appearance of diabetes-related autoantibodies. In children at risk for type 1 DM, high-affinity Insulin autoantibodies reactive to proinsulin, are associated with diabetes risk. Autoantibodies are usually measured by radioligand binding assay (RBA) that provides quasi-quantitative values reflecting potency (product between concentration and affinity) of specific autoantibodies. Aiming to improve the characterization of the specific humoral immune response, we selected surface plasmon resonance (SPR) as an alternative method to measure proinsulin autoantibodies (PAA). This novel technology has allowed real time detection of antibodies interaction and kinetic analysis. Herein, we have employed SPR to characterize the PAA present in sera from 28 childhood-onset (mean age 8.31±4.20) and 23 adult-onset diabetic patients (≥65 years old, BMI<30) in terms of concentration and affinity. When evaluating comparatively samples from both groups, childhood-onset diabetic patients presented lower PAA concentrations and higher affinities (median 67.12×10−9 M and 3.50×107 M−1, respectively) than the adults (median 167.4×10−9 M and 0.84×107 M−1, respectively). These results are consistent with those from the reference method RBA (Standard Deviation score median 9.49 for childhood-onset group and 5.04 for adult-onset group) where the binding can be directly related to the intrinsic affinity of the antibody, suggesting that there is a different etiopathogenic pathway between both types of clinical presentation of the disease. This technology has shown to be a useful tool for the characterization of PAAs parameters as an alternative to radioimmunoassay, with high versatility and reproducibility associated to low occupational and environmental risk. However, this technology is not eligible for routine marker screening, but this is a powerful technique for a fine description of the thermodynamic parameters of antigen-antibody interaction.

Effectiveness of the glucagon test in estimating islet function for liraglutide treatment in a lean diabetic patient with impaired insulin response to glucose

A 52-year-old lean woman was admitted to hospital for a medical examination in July 2010. A 75 g oral glucose test (75 g OGTT) revealed postprandial hyperglycemia (above 200 mg/dl at 120 min) and she was diagnosed with diabetes mellitus. She was negative for diabetes-related autoantibodies. The 75 g OGTT also revealed a very low insulinogenic index (I.I.) of 0.024 μU/ml/mg/dl; however, her plasma C-peptide immunoreactivity (CPR) response to glucagon was preserved (0.94 and 5.56 at 0 and 6 min, respectively). At the same time, she also suffered from Fe-deficiency anemia due to endometriosis, for which treatment with leuprorelin was initiated after hospitalization in August 2010. Meanwhile, her postprandial plasma glucose level continued to increase. Subsequently, on November 30, 2010, alogliptin therapy at a dose of 6.25 mg was initiated, which was increased to 25 mg on December 28, 2010. Leuprorelin therapy was discontinued on January 14, 2011; however, her plasma glucose level remained high despite the alogliptin therapy. Administration of 0.3 mg liraglutide was initiated on March 15, 2011, and the dose was increased to 0.6 mg on June 7, 2011. The plasma glucose level, glycosylated hemoglobin (HbA1c) level, and 1.5 anhydroglucitol level gradually improved, as did her I.I. Moreover, fasting plasma glucagon levels were suppressed by liraglutide. Her fasting serum CPR to plasma glucose ratio and homeostasis model assessment (HOMA-R) were low both before and after liraglutide administration. These results suggest that the fasting CPR to glucose ratio may underestimate residual islet function in lean patients with high insulin sensitivity. Thus, a glucagon test may be useful to estimate residual islet function when administering liraglutide treatment in lean diabetes patients.

Diabetes-Related Autoantibodies in Children With Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is the most common subtype of leukemia in children. Although ALL and type 1 diabetes appear to be biologically unrelated, there are common threads in both epidemiology and etiology. Rising incidence rates of both ALL (1) and type 1 diabetes (2) observed over recent decades in many Western countries seem to support common etiological factors (3). In the current study, we report on diabetes-related autoantibodies (Abs) in a group of patients with ALL. Thirty-four consecutive children (19 males and 15 females, mean age 6.2 ± 4.6 years) were referred to our institution in 2004 for newly diagnosed ALL. Patients were tested for Abs to islet and thyroid antigens. After the initial investigation and treatment, 31/34 (91%) patients (3 died in the mean time) were followedup for 6 years to evaluate the evolution of the autoimmune markers and progression toward type 1 diabetes. Glutamic acid decarboxylase (GAD) Abs by direct …

Could the social environment trigger the induction of diabetes related autoantibodies in young children?

The onset and progression of the autoimmune process leading to type 1 diabetes is partly dependent on genetic predisposition and partly on environmental factors. We have implemented a study design where 1-year-old children, from two equally sized, neighbouring but socioeconomically different cities, were compared for the induction of beta-cell autoantibodies. This study comprises 2448 newborn infants, all living in the urban parts of the twin cities, followed prospectively with regular biological samples and questionnaires in a major population-based study. Of these, a random sample of 1497 children were tested for tyrosine phosphatase (IA-2A) and 1409 children for glutamic acid decarboxylase (GADA). Other documented risk factors of beta-cell autoimmunity and type 1 diabetes, such as family characteristics, dietary factors, and psychosocial factors were also included in the analysis. The risk for diabetes-related autoantibodies, both against GADA and IA-2A (>95% cut off), was significantly higher (p<0.0001) among children from the blue-collar than from the white-collar city. This difference persisted still after adjustment for other previously documented risk factors. Some of these previously known risk factors remained significant in the multivariate analysis as independent explanatory factors, in addition to living in a blue-collar city. Factors in the social environment could trigger the induction of diabetes-related autoantibodies in 1-year-old children. These results point out that our present knowledge of factors influencing the autoimmune process might be widen to also include factors in the social environment of the community.

Asthma and allergic symptoms and type 1 diabetes-related autoantibodies in 2.5-yr-old children

A dominance of Th2 cytokine pattern is associated with allergic diseases, whereas a Th1 pattern has been reported in autoimmune type 1 diabetes (T1D). The Th1/Th2 paradigm has led to the interest in the relationship between these diseases. To investigate the association between atopic diseases, asthma and occurrence of T1D-related β-cell autoantibodies in children, we studied 7208 unselected 2.5-yr-old children from the All Babies in Southeast Sweden (ABIS) cohort. The ABIS cohort includes 17 055 (78.3% out of all 21 700) children born from October 1997 to October 1999, and followed prospectively with regular biological samples and questionnaires, at birth, at 1 and 2.5 yr. Risk factors for development of β-cell autoantibodies at the age of 2.5 yr were type of domiciliary, domestic animals (cat and dog) and getting a new brother/sister during first year of life. Maternal smoking during pregnancy [odds ratio (OR) 1.6] and heavy smoking at home (>10 vs. ≤10 cigarettes) implied risk for tyrosine phosphatase autoantibodies (IA-2A) (OR 2.9). Wheezing during the first year of life implied risk for glutamic acid decarboxylase autoantibodies (GADA) (OR 1.9) and double positivity for GADA and IA-2A (OR 9.1). Rash on several locations (at least three times during 12 months) (OR 1.7) as well as allergic symptoms related to fur-bearing animals (OR 2.7) implied risk for IA-2A. Food allergy against egg, cow-milk, fish, nuts/almonds (one or in combination) implied risk for GADA and IA-2A (OR 4.5). In a regression model wheezing during first year of life remained as a risk factor for GADA [OR 2.0, confidence interval (CI) 1.1-3.8; p = 0.031] and both GADA and IA-2A (OR 10.7, CI 3.9-29.4; p = 0.000). We conclude that allergic symptoms are associated with the development of T1D-related autoantibodies during the first years of life.

The PTPN22C1858T gene variant is associated with proinsulin in new-onset type 1 diabetes

BackgroundThe protein tyrosine phosphatase nonreceptor type 2 (PTPN22) has been established as a type 1 diabetes susceptibility gene. A recent study found the C1858T variant of this gene to be associated with lower residual fasting C-peptide levels and poorer glycemic control in patients with type 1 diabetes. We investigated the association of the C1858T variant with residual beta-cell function (as assessed by stimulated C-peptide, proinsulin and insulin dose-adjusted HbA1c), glycemic control, daily insulin requirements, diabetic ketoacidosis (DKA) and diabetes-related autoantibodies (IA-2A, GADA, ICA, ZnT8Ab) in children during the first year after diagnosis of type 1 diabetes.MethodsThe C1858T variant was genotyped in an international cohort of children (n = 257 patients) with newly diagnosed type 1 diabetes during 12 months after onset. We investigated the association of this variant with liquid-meal stimulated beta-cell function (proinsulin and C-peptide) and antibody status 1, 6 and 12 months after onset. In addition HbA1c and daily insulin requirements were determined 1, 3, 6, 9 and 12 months after diagnosis. DKA was defined at disease onset.ResultsA repeated measurement model of all time points showed the stimulated proinsulin level is significantly higher (22%, p = 0.03) for the T allele carriers the first year after onset. We also found a significant positive association between proinsulin and IA levels (est.: 1.12, p = 0.002), which did not influence the association between PTPN22 and proinsulin (est.: 1.28, p = 0.03).ConclusionsThe T allele of the C1858T variant is positively associated with proinsulin levels during the first 12 months in newly diagnosed type 1 diabetes children.

Permanent neonatal diabetes mellitus - the importance of diabetes differential diagnosis in neonates and infants

The differential diagnosis of various types and forms of diabetes is of great practical importance. This is particularly true for monogenic disease forms, where some spectacular applications of pharmacogenetics have recently been described. For many years the distinct character of diabetes diagnosed in the first weeks and months of life remained unnoticed. The results of the search for type 1 diabetes-related autoantibodies, description of the HLA haplotypes distribution and analysis of clinical features in patients diagnosed in the first 6 months of life provided the initial evidence that the etiology of their disease might be different from that of autoimmune diabetes. Over the last decade, mutations in about a dozen of genes have been linked to the development of Permanent Neonatal Diabetes Mellitus (PNDM). The most frequent causes of PNDM are heterozygous mutations in the KCNJ11, INS and ABCC8 genes. Although PNDM is a rare phenomenon (one case in about 200,000 live births), this discovery has had a large impact on clinical practice as most carriers of KCNJ11 and ABCC8 gene mutations have been switched from insulin to oral sulphonylureas with an improvement in glycemic control. In this review we summarize the practical aspects of diabetes differential diagnosis in neonates and infants. Genetic testing should be advised in all subjects with PNDM as it may influence medical care in subjects with these monogenic forms of early onset diabetes.