Islet Cell Autoantibodies Research Articles

HLA Genes, Islet Autoantibodies and Residual C-Peptide at the Clinical Onset of Type 1 Diabetes Mellitus and the Risk of Retinopathy 15 Years Later

Aims/HypothesisHLA genes, islet autoantibodies and residual C-peptide were studied to determine the independent association of each exposure with diabetic retinopathy (DR), 15 years after the clinical onset of type 1 diabetes in 15–34 year old individuals.MethodsThe cohort was identified in 1992 and 1993 by the Diabetes Incidence Study in Sweden (DISS), which investigates incident cases of diabetes for patients between 15 and 34 years of age. Blood samples at diagnosis were analyzed to determine HLA genotype, islet autoantibodies and serum C-peptide. In 2009, fundus photographs were obtained from patient records. Study measures were supplemented with data from the Swedish National Diabetes Registry.ResultsThe prevalence of DR was 60.2% (148/246). Autoantibodies against the 65 kD isoform of glutamate decarboxylase (GADA) at the onset of clinical diabetes increased the risk of DR 15 years later, relative risk 1.12 for each 100 WHO units/ml, [95% CI 1.02 to 1.23]. This equates to risk estimates of 1.27, [95% CI 1.04 to 1.62] and 1.43, [95% CI 1.06 to 1.94] for participants in the highest 25th (GADA>233 WHO units/ml) and 5th percentile (GADA>319 WHO units/ml) of GADA, respectively. These were adjusted for duration of diabetes, HbA1c, treated hypertension, sex, age at diagnosis, HLA and C-peptide. Islet cell autoantibodies, insulinoma-antigen 2 autoantibodies, residual C-peptide and the type 1 diabetes associated haplotypes DQ2, DQ8 and DQ6 were not associated with DR.ConclusionsIncreased levels of GADA at the onset of type 1 diabetes were associated with DR 15 years later. These results, if confirmed, could provide additional insights into the pathogenesis of the most common microvascular complication of diabetes and lead to better risk stratification for both patient screenings and DR treatment trials.

A comparison of the baseline metabolic profiles between Diabetes Prevention Trial-Type 1 and TrialNet Natural History Study participants

We assessed whether differing autoantibody screening criteria for type 1 diabetes (T1D) prevention trials result in different baseline metabolic profiles of those who screen positive. Diabetes Prevention Trial-Type 1 (DPT-1) participants were screened for islet cell autoantibodies, whereas TrialNet Natural History Study (TNNHS) participants were screened for biochemical autoantibodies. In both studies, those determined to be autoantibody positive underwent baseline oral glucose tolerance tests (OGTTs) in which glucose and C-peptide were measured. The percentage of those with an OGTT in the diabetic range was higher among the DPT-1 participants (10.0% of 956 vs. 6.4% of 645, p < 0.01). In a logistic regression analysis with adjustments for age and gender, the difference persisted (p < 0.01). Among those in the non-diabetic range (n = 860 for DPT-1 and n = 604 for the TNNHS), glucose levels were similar at all time points, except for higher fasting glucose levels in the TNNHS participants (p < 0.001). There was a higher percentage of impaired fasting glucose (IFG) in the TNNHS participants (10.9 vs. 6.7%, p < 0.01); however, with adjustments for age and gender, there was no longer a significant difference. There was no significant difference in the percentages with impaired glucose tolerance. C-peptide levels were much lower in the DPT-1 cohort at all OGTT time points (p < 0.001 for all). Differing criteria for autoantibody screening can result in marked differences in the baseline metabolic profiles of prospective participants of T1D prevention trials.

Prospektive Verlaufsbeobachtungsstudien zur Entstehung des Typ-1-Diabetes im Kindesalter und während der Pubertät

The incidence of type 1 diabetes is increasing rapidly. Detecting the mechanisms underlying the autoimmune disease is a main goal of research. Studies investigating the pathogenesis of type 1 diabetes are working on the identification and characterization of exogenous, endogenous and genetic factors which induce or modify autoimmunity. Islet cell autoimmunity can be detected through screening for islet cell autoantibodies. This quantitative analysis allows the stratification of the individual risk for the development of type 1 diabetes. Prospective observational studies are most suitable to assess persons at risk, either because of the occurrence of type 1 diabetes in the family or because of a genotype associated with increased risk. Age-related factors which are analysed in observational studies include nutrition, increase in height and weight, childhood diseases and vaccinations as well as psychosocial aspects. Identification and characterization of these risk factors will serve as a basis for working on new approaches to prevent or to cure type 1 diabetes. Aim of this article is to provide an overview of the most relevant observational studies.

Successful transfer to sulfonylurea therapy in an infant with developmental delay, epilepsy and neonatal diabetes (DEND) syndrome and a novel ABCC8 gene mutation

Successful transfer to sulfonylurea therapy in an infant with developmental delay, epilepsy and neonatal diabetes (DEND) syndrome and a novel ABCC8 gene mutation

Disease progression and search for monogenic diabetes among children with new onset type 1 diabetes negative for ICA, GAD- and IA-2 Antibodies

BackgroundTo investigate disease progression the first 12 months after diagnosis in children with type 1 diabetes negative (AAB negative) for pancreatic autoantibodies [islet cell autoantibodies(ICA), glutamic acid decarboxylase antibodies (GADA) and insulinoma-associated antigen-2 antibodies (IA-2A)]. Furthermore the study aimed at determining whether mutations in KCNJ11, ABCC8, HNF1A, HNF4A or INS are common in AAB negative diabetes.Materials and methodsIn 261 newly diagnosed children with type 1 diabetes, we measured residual β-cell function, ICA, GADA, and IA-2A at 1, 6 and 12 months after diagnosis. The genes KCNJ11, ABCC8, HNF1A, HNF4A and INS were sequenced in subjects AAB negative at diagnosis. We expressed recombinant K-ATP channels in Xenopus oocytes to analyse the functional effects of an ABCC8 mutation.ResultsTwenty-four patients (9.1%) tested AAB negative after one month. Patients, who were AAB-negative throughout the 12-month period, had higher residual β-cell function (P = 0.002), lower blood glucose (P = 0.004), received less insulin (P = 0.05) and had lower HbA1c (P = 0.02) 12 months after diagnosis. One patient had a heterozygous mutation leading to the substitution of arginine at residue 1530 of SUR1 (ABCC8) by cysteine. Functional analyses of recombinant K-ATP channels showed that R1530C markedly reduced the sensitivity of the K-ATP channel to inhibition by MgATP. Morover, the channel was highly sensitive to sulphonylureas. However, there was no effect of sulfonylurea treatment after four weeks on 1.0-1.2 mg/kg/24 h glibenclamide.ConclusionGAD, IA-2A, and ICA negative children with new onset type 1 diabetes have slower disease progression as assessed by residual beta-cell function and improved glycemic control 12 months after diagnosis. One out of 24 had a mutation in ABCC8, suggesting that screening of ABCC8 should be considered in patients with AAB negative type 1 diabetes.

Effect of HLA Class I and Class II Alleles on Progression From Autoantibody Positivity to Overt Type 1 Diabetes in Children With Risk-Associated Class II Genotypes

OBJECTIVEClass II alleles define the main HLA effect on type 1 diabetes, but there is an independent effect of certain class I alleles. Class II and class I molecules are differently involved in the initiation and effector phases of the immune response, suggesting that class I alleles would be important determinants in the rate of β-cell destruction. To test this hypothesis we analyzed the role of HLA class I and class II gene polymorphisms in the progression from diabetes-associated autoimmunity to clinical disease.RESEARCH DESIGN AND METHODSThe effect of HLA-DR-DQ haplotypes and a panel of class I HLA-A and -B alleles on the progression from autoantibody seroconversion to clinical diabetes was studied in 249 children persistently positive for at least one biochemical diabetes-associated autoantibody in addition to islet cell autoantibody.RESULTSThe progression to clinical disease was separately analyzed after the appearance of the first and the second persistent biochemical autoantibody using Cox regression. Multivariate analysis demonstrated a significant protective effect of the A*03 allele (odds ratio [OR] 0.61, P = 0.042 after the first and OR 0.55, P = 0.027 after the second autoantibody), whereas the B*39 allele had a promoting effect after seroconversion for the second autoantibody (OR 2.4, P = 0.014). When children with the DR3/DR4 genotype were separately analyzed, HLA-B*39 had a strong effect (OR 6.6, P = 0.004 and OR 7.5, P = 0.007, after the appearance of the first and the second autoantibody, respectively). The protective effect of A*03 was seen only among children without the DR3/DR4 combination.CONCLUSIONSThese results confirm that class I alleles affect the progression of diabetes-associated autoimmunity and demonstrate interactions between class I and class II alleles.

Enhancing the Understanding of Pre-Type 1 Diabetes in the General Population

Type 1 diabetes occurs in ∼90% of patients with no family history of the disease. The majority of studies seeking to identify at-risk subjects have been conducted in first-degree relatives who comprise just 10% of all cases of type 1 diabetes but may have a 20-fold increased risk for type 1 diabetes (1). Although the peak incidence occurs at adolescence, there are data to suggest that 5–10% of all adults diagnosed with type 2 diabetes may actually have type 1 diabetes (latent autoimmune diabetes in adults [LADA]). If type 1 diabetes is to be prevented, significantly enhanced understanding of both the mechanisms leading to type 1 diabetes and the natural history of the pre-diabetic period is essential. Current evidence suggests that type 1 diabetes results from a complex interaction between type 1 diabetes genetic susceptibility (predominantly HLA Class II associations) and environmental exposure(s) leading to a breakdown of tolerance culminating in β-cell autoimmunity and destruction (2). In the process leading to overt type 1 diabetes, both T and B lymphocytes are activated. B-lymphocyte activation is characterized by the emergence of cytoplasmic islet cell autoantibodies (ICAs) and one or more autoantibodies against the β-cell–specific autoantigen insulin, glutamate decarboxylase, the IA-2 protein tyrosine phosphatase, or the zinc transporter ZnT8 (IAA, GADA, IA-2A, and ZnT8A, respectively). For the most part, IAA, GADA, IA-2A, and ZnT8A have replaced ICA, which is measured using indirect immunofluorescence that requires a subjective evaluation of the fluorescence intensity. The IAA, GADA, IA-2A, and ZnT8A analyses require only small amounts of serum (5–20 μl in most assays) and are thus well suited for large-scale studies comprising both infants and small children. Serum samples can be safely stored at −20°C for years before the measurement of the autoantibodies is undertaken, and the samples usually also tolerate repeated freeze-thaw cycles without …

Insulin autoantibody could help to screen latent autoimmune diabetes in adults in phenotypic type 2 diabetes mellitus in Chinese

Latent autoimmune diabetes in adults (LADA) is characterized by a relatively mild diabetes onset, autoantibody positivity, and eventual requirement for insulin therapy. Glutamic acid decarboxylase autoantibodies (GADA) or cytoplasmic islet cell autoantibodies (ICA) play a key role in distinguishing LADA from type 2 diabetes mellitus (T2DM) in clinical practice. The aim of our research was to determine whether insulin autoantibody (IAA) has some additional value in diagnosing LADA. We analyzed IAA, GADA, and IA-2A (antibodies to insulinoma-associated antigen-2) in 1,003 newly diagnosed phenotypic T2DM patients, 110 type 1 diabetes mellitus (T1DM) patients, and 317 normal controls to survey the prevalence of IAA in phenotypic T2DM patients and the overlapping positivity of IAA with other autoantibodies. Sera were drawn within 7 days from the start of insulin therapy. Results showed that 3.39% of the newly diagnosed phenotypic T2DM, 0.95% of normal control (χ(2) = 5.3, P < 0.05), and 21.82% of T1DM (χ(2) = 68.2, P < 0.001) were positive for IAA at diagnosis. The combination frequency of three antibodies was 10.47%, which was higher than any single antibody testing. Combination testing of IAA with GADA and IA-2A could improve LADA diagnose rate by 2.39% than that of GADA and IA-2A. IAA-positive subjects had diabetes family history more common compared to its matched group (67.6% vs. 14.7%, P = 0.000). Postprandial C-peptide in IAA-positive group tended to be lower, but the difference was not statistically significant (P = 0.084). We concluded that IAA can be used to screen LADA in phenotypic T2DM in the Chinese population.

Progression to Diabetes in Relatives of Type 1 Diabetic Patients: Mechanisms and Mode of Onset

OBJECTIVERelatives of type 1 diabetic patients are at enhanced risk of developing diabetes. We investigated the mode of onset of hyperglycemia and how insulin sensitivity and β-cell function contribute to the progression to the disease.RESEARCH DESIGN AND METHODSIn 328 islet cell autoantibody–positive, nondiabetic relatives from the observational arms of the Diabetes Prevention Trial-1 Study (median age 11 years [interquartile range 8], sequential OGTTs (2,143 in total) were performed at baseline, every 6 months, and 2.7 years [2.7] later, when 115 subjects became diabetic. β-Cell glucose sensitivity (slope of the insulin-secretion/plasma glucose dose-response function) and insulin sensitivity were obtained by mathematical modeling of the OGTT glucose/C-peptide responses.RESULTSIn progressors, baseline insulin sensitivity, fasting insulin secretion, and total postglucose insulin output were similar to those of nonprogressors, whereas β-cell glucose sensitivity was impaired (median 48 pmol/min per m2 per mmol/l [interquartile range 36] vs. 87 pmol/min per m2 per mmol/l [67]; P < 0.0001) and predicted incident diabetes (P < 0.0001) independently of sex, age, BMI, and clinical risk. In progressors, 2-h glucose levels changed little until 0.78 years before diagnosis, when they started to rise rapidly (∼13 mmol · l−1 · year−1); glucose sensitivity began to decline significantly (P < 0.0001) earlier (1.45 years before diagnosis) than the plasma glucose surge. During this anticipation phase, both insulin secretion and insulin sensitivity were essentially stable.CONCLUSIONSIn high-risk relatives, β-cell glucose sensitivity is impaired and is a strong predictor of diabetes progression. The time trajectories of plasma glucose are frequently biphasic, with a slow linear increase followed by a rapid surge, and are anticipated by a further deterioration of β-cell glucose sensitivity.

Testing for monogenic diabetes among children and adolescents with antibody‐negative clinically defined Type 1 diabetes

Monogenic diabetes is frequently misdiagnosed as Type 1 diabetes. We aimed to screen for undiagnosed monogenic diabetes in a cohort of children who had a clinical diagnosis of Type 1 diabetes but were pancreatic autoantibody-negative. We studied 252 patients diagnosed clinically with Type 1 diabetes between 6 months and 17 years of age. Pancreatic autoantibodies [islet cell autoantibodies (ICA), glutamic acid decarboxylase antibodies (GADA) and/or insulinoma-associated antigen-2 antibodies (IA2A)] were absent in 25 cases (9.9%). The most frequent genes involved in monogenic diabetes [KCNJ11 and INS for neonatal diabetes and HNF1A and HNF4A for maturity-onset diabetes of the young (MODY)] were directly sequenced. Two of the 25 (8%) antibody-negative patients had de novo heterozygous mutations in INS; c.94G>A (G32S) and c.265C>T (R89C). The two patients presented with non-ketotic hyperglycaemia at 8 and 11 months of age. In contrast, the four antibody-positive patients who presented at a similar age (6-12 months) had a more severe metabolic derangement, manifested as ketosis in all four cases, with ketoacidosis in two. At ages 15 and 5 years, both INS mutation patients were prescribed a replacement dose of insulin with good glycaemic control [glycated haemoglobin (HbA(1c)) 7.0 and 7.2%]. No mutations were found in KCNJ11, HNF1A or HNF4A. The identification of patients with monogenic diabetes from children with clinically defined Type 1 diabetes may be helped by clinical criteria including the absence of pancreatic autoantibodies.

Predictive Characteristics of Diabetes-Associated Autoantibodies Among Children With HLA-Conferred Disease Susceptibility in the General Population

OBJECTIVEAs data on the predictive characteristics of diabetes-associated autoantibodies for type 1 diabetes in the general population are scarce, we assessed the predictive performance of islet cell autoantibodies (ICAs) in combination with autoantibodies against insulin (IAAs), autoantibodies against GAD, and/or islet antigen 2 for type 1 diabetes in children with HLA-defined disease predisposition recruited from the general population.RESEARCH DESIGN AND METHODSWe observed 7,410 children from birth (median 9.2 years) for β-cell autoimmunity and diabetes. If a child developed ICA positivity or diabetes, the three other antibodies were measured in all samples available from that individual. Persistent autoantibody positivity was defined as continued positivity in at least two sequential samples including the last available sample.RESULTSPre-diabetic ICA positivity was observed in 1,173 subjects (15.8%), 155 of whom developed type 1 diabetes. With ICA screening, 86% of 180 progressors (median age at diagnosis 5.0 years) were identified. Positivity for four antibodies was associated with the highest disease sensitivity (54.4%) and negative predictive values (98.3%) and the lowest negative likelihood ratio (0.5). The combination of persistent ICA and IAA positivity resulted in the highest positive predictive value (91.7%), positive likelihood ratio (441.8), cumulative disease risk (100%), and specificity (100%). Young age at seroconversion, high ICA level, multipositivity, and persistent positivity for IAA were significant risk markers for type 1 diabetes.CONCLUSIONSWithin the general population, the combination of HLA and autoantibody screening resulted in disease risks that are likely to be as high as those reported among autoantibody-positive siblings of children with type 1 diabetes.

Pancreatic islet autoantibodies as predictors of type 1 diabetes in the Diabetes Prevention Trial-Type 1.

OBJECTIVEThere is limited information from large-scale prospective studies regarding the prediction of type 1 diabetes by specific types of pancreatic islet autoantibodies, either alone or in combination. Thus, we studied the extent to which specific autoantibodies are predictive of type 1 diabetes.RESEARCH DESIGN AND METHODSTwo cohorts were derived from the first screening for islet cell autoantibodies (ICAs) in the Diabetes Prevention Trial–Type 1 (DPT-1). Autoantibodies to GAD 65 (GAD65), insulinoma-associated antigen-2 (ICA512), and insulin (micro-IAA [mIAA]) were also measured. Participants were followed for the occurrence of type 1 diabetes. One cohort (Questionnaire) included those who did not enter the DPT-1 trials, but responded to questionnaires (n = 28,507, 2.4% ICA+). The other cohort (Trials) included DPT-1 participants (n = 528, 83.3% ICA+).RESULTSIn both cohorts autoantibody number was highly predictive of type 1 diabetes (P < 0.001). The Questionnaire cohort was used to assess prediction according to the type of autoantibody. As single autoantibodies, ICA (3.9%), GAD65 (4.4%), and ICA512 (4.6%) were similarly predictive of type 1 diabetes in proportional hazards models (P < 0.001 for all). However, no subjects with mIAA as single autoantibodies developed type 1 diabetes. As second autoantibodies, all except mIAA added significantly (P < 0.001) to the prediction of type 1 diabetes. Within the positive range, GAD65 and ICA autoantibody titers were predictive of type 1 diabetes.CONCLUSIONSThe data indicate that the number of autoantibodies is predictive of type 1 diabetes. However, mIAA is less predictive of type 1 diabetes than other autoantibodies. Autoantibody number, type of autoantibody, and autoantibody titer must be carefully considered in planning prevention trials for type 1 diabetes.

Incident Dysglycemia and Progression to Type 1 Diabetes Among Participants in the Diabetes Prevention Trial–Type 1

OBJECTIVEWe studied the incidence of dysglycemia and its prediction of the development of type 1 diabetes in islet cell autoantibody (ICA)-positive individuals. In addition, we assessed whether dysglycemia was sustained.RESEARCH DESIGN AND METHODSParticipants (n = 515) in the Diabetes Prevention Trial–Type 1 (DPT-1) with normal glucose tolerance who underwent periodic oral glucose tolerance tests (OGTTs) were followed for incident dysglycemia (impaired fasting glucose, impaired glucose tolerance, and/or high glucose levels at intermediate time points of OGTTs). Incident dysglycemia at the 6-month visit was assessed for type 1 diabetes prediction.RESULTSOf 515 participants with a normal baseline OGTT, 310 (60%) had at least one episode of dysglycemia over a maximum follow-up of 7 years. Dysglycemia at the 6-month visit was highly predictive of the development of type 1 diabetes, both in those aged <13 years (P < 0.001) and those aged ≥13 years (P < 0.01). Those aged <13 years with dysglycemia at the 6-month visit had a high cumulative incidence (94% estimate by 5 years). Among those who developed type 1 diabetes after a dysglycemic OGTT and who had at least two OGTTs after the dysglycemic OGTT, 33 of 64 (52%) reverted back to a normal OGTT. However, 26 (79%) of the 33 then had another dysglycemic OGTT before diagnosis.CONCLUSIONSICA-positive individuals with normal glucose tolerance had a high incidence of dysglycemia. Incident dysglycemia in those who are ICA positive is strongly predictive of type 1 diabetes. Children with incident dysglycemia have an especially high risk. Fluctuations in and out of the dysglycemic state are not uncommon before the onset of type 1 diabetes.

Novel antigens in type 1 diabetes: The importance of ZnT8

The presence of circulating islet cell autoantibodies distinguishes type 1A diabetes (T1D) from other diabetic syndromes and determination of autoantigen genes and proteins is instrumental in understanding T1D as a clinical entity and in investigating the pathogenesis of the disease. ZnT8 was recently defined as a candidate autoantigen based on a -bioinformatics analysis focused on discovery of beta-cell-specific proteins associated with the regulatory pathway of secretion. The native molecule does not lend itself easily to solution-phase autoantibody assays, but ligands based on the predicted domain structure and molecular modeling have led to robust diagnostic procedures showing high specificities and sensitivities that complement current T1D autoantibody assays and add to the predictive value of their measurement. The incorporation of genetic and structural epitope analysis into ZnT8A determinations adds a further dimension to its diagnostic value and understanding of its role in the autoimmune disease process.

A−β− Subtype of Ketosis-Prone Diabetes Is Not Predominantly a Monogenic Diabetic Syndrome

OBJECTIVEKetosis-prone diabetes (KPD) is an emerging syndrome that encompasses several distinct phenotypic subgroups that share a predisposition to diabetic ketoacidosis. We investigated whether the A−β− subgroup of KPD, characterized by complete insulin dependence, absent β-cell functional reserve, lack of islet cell autoantibodies, and strong family history of type 2 diabetes, represents a monogenic form of diabetes.RESEARCH DESIGN AND METHODSOver 8 years, 37 patients with an A−β− phenotype were identified in our longitudinally followed cohort of KPD patients. Seven genes, including hepatocyte nuclear factor 4A (HNF4A), glucokinase (GCK), HNF1A, pancreas duodenal homeobox 1 (PDX1), HNF1B, neurogenic differentiation 1 (NEUROD1), and PAX4, were directly sequenced in all patients. Selected gene regions were also sequenced in healthy, unrelated ethnically matched control subjects, consisting of 84 African American, 96 Caucasian, and 95 Hispanic subjects.RESULTSThe majority (70%) of the A−β− KPD patients had no significant causal polymorphisms in either the proximal promoter or coding regions of the seven genes. The combination of six potentially significant low-frequency, heterozygous sequence variants in HNF-1α (A174V or G574S), PDX1 (putative 5′–untranslated region CCAAT box, P33T, or P239Q), or PAX4 (R133W) were found in 27% (10/37) of patients, with one additional patient revealing two variants, PDX1 P33T and PAX4 R133W. The A174V variant has not been previously reported.CONCLUSIONSDespite its well-circumscribed, robust, and distinctive phenotype of severe, nonautoimmune-mediated β-cell dysfunction, A−β− KPD is most likely not a predominantly monogenic diabetic syndrome. Several A−β− KPD patients have low-frequency variants in HNF1A, PDX1, or PAX4 genes, which may be of functional significance in their pathophysiology.

Plasmacytoid Dendritic Cells Are Proportionally Expanded at Diagnosis of Type 1 Diabetes and Enhance Islet Autoantigen Presentation to T-Cells Through Immune Complex Capture

OBJECTIVE—Immune-mediated destruction of β-cells resulting in type 1 diabetes involves activation of proinflammatory, islet autoreactive T-cells, a process under the control of dendritic cells of the innate immune system. We tested the hypothesis that type 1 diabetes development is associated with disturbance of blood dendritic cell subsets that could enhance islet-specific autoimmunity.RESEARCH DESIGN AND METHODS—We examined blood dendritic cells (plasmacytoid and myeloid) in 40 patients with recent-onset diabetes (median duration 28 days) and matched control subjects. We also examined the relative ability of different dendritic cell subsets to process and present soluble or immune complexed islet cell autoantigen (the islet tyrosine phosphatase IA-2) to responder CD4 T-cells.RESULTS—The balance of blood dendritic cells was profoundly disturbed at diabetes diagnosis, with a significantly elevated proportion of plasmacytoid and reduction of myeloid cells compared with control subjects. Dendritic cell subset distribution was normal in long-standing disease and in patients with type 2 diabetes. Both dendritic cell subsets processed and presented soluble IA-2 to CD4 T-cells after short-term culture, but only plasmacytoid dendritic cells enhanced (by as much as 100%) autoantigen presentation in the presence of IA-2+ autoantibody patient serum.CONCLUSIONS—The plasmacytoid subset of dendritic cells is overrepresented in the blood close to diabetes onset and shows a distinctive ability to capture islet autoantigenic immune complexes and enhance autoantigen-driven CD4 T-cell activation. This suggests a synergistic proinflammatory role for plasmacytoid dendritic cells and islet cell autoantibodies in type 1 diabetes.

New-onset diabetes in an obese adolescent: diagnostic dilemmas

A 14-year-old, obese, African American boy presented to his pediatrician with polyuria, polydipsia, and a significant unintentional weight loss. He was dehydrated, with high levels of blood sugar and urinary ketones. He had no history of previous illnesses and was not taking any medications. He had a family history of type 2 diabetes mellitus. Physical examination included assessing stigmata of insulin resistance, and measuring blood pressure, pulse, and BMI. Blood samples were obtained for measurement of venous blood pH, bicarbonate, serum glucose, electrolytes, HbA(1C), aminotransferases and lipids. Urine was sampled for measurement of ketones. Subsequently, measurements of fasting C-peptide and immunoassays for insulin autoantibodies (IAA), islet-cell autoantibodies (ICA-512) and glutamic acid decarboxylase autoantibodies (GAD-65) were performed. New-onset diabetes mellitus with diabetic ketoacidosis, initially diagnosed as type 2 diabetes mellitus, but later determined as type 1 diabetes mellitus. After treatment of diabetic ketoacidosis with hydration and insulin infusion, the patient was discharged on subcutaneous insulin. He was diagnosed with type 2 diabetes mellitus and was transferred to oral insulin-sensitizing agents. He re-presented 18 months later with an insulin requirement during an asthma exacerbation treated with steroids. Due to the worsening of his diabetic symptoms, the patient was tested for islet autoantibodies and was found to be positive for GAD-65 and IAA, that is, diagnostic of type 1 diabetes mellitus. He has continued to require subcutaneous insulin.

Diabetes classification: grey zones, sound and smoke: Action LADA 1

Diseases gain identity from clinical phenotype as well as genetic and environmental aetiology. The definition of type 1 diabetes is clinically exclusive, comprising patients who are considered insulin dependent at diagnosis, whilst the definition of type 2 diabetes is inclusive, only excluding those who are initially insulin dependent. Ketosis-prone diabetes (KPD) and latent autoimmune diabetes in adults (LADA) are each exclusive forms of diabetes which are, at least initially, clinically distinct from type 2 diabetes and type 1 diabetes, and each have a different natural history from these major types of diabetes.KPD can be diagnosed unequivocally as diabetes presenting with the categorical clinical feature, ketoacidosis. In contrast, LADA can be diagnosed by the co-occurrence of three traits, not one of which is categorical or exclusive to the condition: adult-onset non-insulin-requiring diabetes, an islet autoantibody such as glutamic acid decarboxylase autoantibodies (GADA) or cytoplasmic islet cell autoantibodies (ICA), and no need for insulin treatment for several months post-diagnosis. But while some would split diabetes into distinct subtypes, there is a strong case that these subtypes form a continuum of varying severity of immune and metabolic dysfunction modified by genetic and non-genetic factors. This article discusses the nature of disease classification in general, and KPD and LADA in particular, emphasizing the potential value and pitfalls in classifying diabetes and suggesting a need for more research in this area.

Retrospective Assessment of Islet Cell Autoantibodies in Pancreas Organ Donors

OBJECTIVE—Of deceased pancreas donors, 3–4% may have autoantibodies (AAb) to pancreatic islet cell antigens; these autoantibodies are well-established markers of type 1 diabetes. We investigated whether donor AAb positivity could affect the outcome of pancreas transplantation.RESEARCH DESIGN AND METHODS—We retrospectively tested AAb in 135 donors whose pancreata and kidneys were transplanted in type 1 diabetes patients. We measured AAb to glutamic acid decarboxylase (GAD-AAb), the tyrosine-phosphatase-like protein IA2 (IA2-AAb), and insulin (insulin-AAb). We then evaluated pancreas transplant outcome data.RESULTS—Four of 135 (2.96%) donors were AAb positive: three donors had GAD-AAb, and one donor had insulin-AAb. Their respective recipients became insulin independent on follow-up. Three of the four recipients had normal, insulin-producing grafts 3–5.8 years after transplant. The recipient of the insulin-AAb–positive donor pancreas developed chronic rejection following discontinuation of immunosuppression 3.3 years after transplant.CONCLUSIONS—Single AAb positivity did not affect the outcome of pancreas transplantation in our study.

Identification of a Molecular Signature in Human Type 1 Diabetes Mellitus Using Serum and Functional Genomics

Understanding active proinflammatory mechanisms at and before type 1 diabetes mellitus (T1DM) onset is hindered in humans, given that the relevant tissues are inaccessible and pancreatic immune responses are difficult to measure in the periphery by traditional approaches. Therefore, we investigated the use of a sensitive and comprehensive genomics strategy to investigate the presence of proinflammatory factors in serum. The sera of recent onset diabetes patients (n = 15, 12 possessing and 3 lacking islet cell autoantibodies), long-standing diabetes patients (n = 12), "at risk" siblings of diabetes patients (n = 9), and healthy controls (n = 12) were used to induce gene expression in unrelated, healthy PBMC. After culture, gene expression was measured with microarrays and normalized expression data were subjected to hierarchical clustering and multidimensional scaling. All recent onset sera induced an expression signature (192 UniGenes; fold change: >1.5, p < 0.01; false discovery rate: <0.01) that included IL-1 cytokine family members and chemokines involved in monocyte/macrophage and neutrophil chemotaxis, as well as numerous receptors and signaling molecules. This molecular signature was not induced with the sera of healthy controls or long standing diabetes patients, where longitudinal analysis of "at risk" siblings (n = 3) before and after onset support the hypothesis that the signature emerges years before onset. This study supports prior investigations of serum that reflect disease processes associated with progression to T1DM. Identification of unique inflammatory mediators may improve disease prediction beyond current islet autoantibodies. Furthermore, proinflammatory serum markers may be used as inclusion criteria or endpoint measures in clinical trials aimed at preventing T1DM.