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Assessment and Management of Anti-Insulin Autoantibodies in Varying Presentations of Insulin Autoimmune Syndrome.

ABSTRACT: Context:Insulin autoimmune syndrome (IAS), spontaneous hyperinsulinemic hypoglycemia due to insulin-binding autoantibodies, may be difficult to distinguish from tumoral or other forms of hyperinsulinemic hypoglycemia, including surreptitious insulin administration. No standardized treatment regimen exists. Objectives:To evaluate an analytic approach to IAS and responses to different treatments. Design and Setting:Observational study in the UK Severe Insulin Resistance Service. Patients:Six patients with hyperinsulinemic hypoglycemia and detectable circulating anti-insulin antibody (IA). Main Outcome Measures:Glycemia, plasma insulin, and C-peptide concentrations by immunoassay or mass spectrometry (MS). Immunoreactive insulin was determined in the context of polyethylene glycol (PEG) precipitation and gel filtration chromatography (GFC). IA quantification using ELISA and RIA, and IA were further characterized using radioligand binding studies. Results:All patients were diagnosed with IAS (five IgG, one IgA) based on a high insulin/C-peptide ratio, low insulin recovery after PEG precipitation, and GFC evidence of antibody-bound insulin. Neither ELISA nor RIA result proved diagnostic for every case. MS provided a more robust quantification of insulin in the context of IA. One patient was managed conservatively, four were treated with diazoxide without sustained benefit, and four were treated with immunosuppression with highly variable responses. IA affinity did not appear to influence presentation or prognosis. Conclusions:IAS should be considered in patients with hyperinsulinemic hypoglycemia and a high insulin/C-peptide ratio. Low insulin recovery on PEG precipitation supports the presence of insulin-binding antibodies, with GFC providing definitive confirmation. Immunomodulatory therapy should be customized according to individual needs and clinical response.

SUBMITTER: Church D

PROVIDER: S-EPMC6179165 | biostudies-other | 2018 Oct

REPOSITORIES: biostudies-other

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Assessment and Management of Anti-Insulin Autoantibodies in Varying Presentations of Insulin Autoimmune Syndrome.

Church David D Cardoso Luís L Kay Richard G RG Williams Claire L CL Freudenthal Bernard B Clarke Catriona C Harris Julie J Moorthy Myuri M Karra Efthmia E Gribble Fiona M FM Reimann Frank F Burling Keith K Williams Alistair J K AJK Munir Alia A Jones T Hugh TH Führer Dagmar D Moeller Lars C LC Cohen Mark M Khoo Bernard B Halsall David D Semple Robert K RK

The Journal of clinical endocrinology and metabolism 20181001 10

<h4>Context</h4>Insulin autoimmune syndrome (IAS), spontaneous hyperinsulinemic hypoglycemia due to insulin-binding autoantibodies, may be difficult to distinguish from tumoral or other forms of hyperinsulinemic hypoglycemia, including surreptitious insulin administration. No standardized treatment regimen exists.<h4>Objectives</h4>To evaluate an analytic approach to IAS and responses to different treatments.<h4>Design and setting</h4>Observational study in the UK Severe Insulin Resistance Servi ...[more]

PMID: 30085133

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Project description:BackgroundThe autoimmune regulator (AIRE) gene influences thymic self-tolerance induction. In autoimmune polyendocrinopathy syndrome type 1 (APS1; OMIM 240300), recessive AIRE mutations lead to autoimmunity targetting endocrine and other epithelial tissues, although chronic candidiasis usually appears first. Autoimmunity and chronic candidiasis can associate with thymomas as well. Patients with these tumours frequently also have high titre immunoglobulin G autoantibodies neutralising type I interferon (IFN)-alpha and IFN-omega, which are secreted signalling proteins of the cytokine superfamily involved in both innate and adaptive immunity.Methods and findingsWe tested for serum autoantibodies to type I IFNs and other immunoregulatory cytokines using specific binding and neutralisation assays. Unexpectedly, in 60/60 Finnish and 16/16 Norwegian APS1 patients with both AIRE alleles mutated, we found high titre neutralising immunoglobulin G autoantibodies to most IFN-alpha subtypes and especially IFN-omega (60% homologous to IFN-alpha)-mostly in the earliest samples. We found lower titres against IFN-beta (30% homologous to IFN-alpha) in 23% of patients; two-thirds of these (from Finland only) also had low titres against the distantly related "type III IFN" (IFN-lambda1; alias interleukin-29). However, autoantibodies to the unrelated type II IFN, IFN-gamma, and other immunoregulatory cytokines, such as interleukin-10 and interleukin-12, were much rarer and did not neutralise. Neutralising titres against type I IFNs averaged even higher in patients with APS1 than in patients with thymomas. Anti-type I IFN autoantibodies preceded overt candidiasis (and several of the autoimmune disorders) in the informative patients, and persisted for decades thereafter. They were undetectable in unaffected heterozygous relatives of APS1 probands (except for low titres against IFN-lambda1), in APS2 patients, and in isolated cases of the endocrine diseases most typical of APS1, so they appear to be APS1-specific. Looking for potentially autoimmunising cell types, we found numerous IFN-alpha(+) antigen-presenting cells-plus strong evidence of local IFN secretion-in the normal thymic medulla (where AIRE expression is strongest), and also in normal germinal centres, where it could perpetuate these autoantibody responses once initiated. IFN-alpha2 and IFN-alpha8 transcripts were also more abundant in antigen-presenting cells cultured from an APS1 patient's blood than from age-matched healthy controls.ConclusionsThese apparently spontaneous autoantibody responses to IFNs, particularly IFN-alpha and IFN-omega, segregate like a recessive trait; their high "penetrance" is especially remarkable for such a variable condition. Their apparent restriction to APS1 patients implies practical value in the clinic, e.g., in diagnosing unusual or prodromal AIRE-mutant patients with only single components of APS1, and possibly in prognosis if they prove to predict its onset. These autoantibody responses also raise numerous questions, e.g., about the rarity of other infections in APS1. Moreover, there must also be clues to autoimmunising mechanisms/cell types in the hierarchy of preferences for IFN-omega, IFN-alpha8, IFN-alpha2, and IFN-beta and IFN-lambda1.

Project description:RATIONALE:Insulin autoimmune syndrome (IAS) is a rare endocrine disease characterized by repeated fasting hypoglycemia or episodes of hypoglycemia late after meals, elevated serum insulin, and positivity for insulin autoantibody (IAA) or insulin receptor antibody (IRA). We summarize the clinical manifestations and treatment experiences of 3 patients with IAS. PATIENT CONCERNS:One patient with >20-year history of type 2 diabetes mellitus had irregular episodes of hypoglycemia 2 years of after treatment with insulin. Another patient with a 6-year history of type 2 diabetes mellitus presented irregular episodes of hypoglycemia after 6 months of treatment with insulin. One patient with a history of Graves' disease showed hypoglycemia after administration of thiamazole. DIAGNOSIS:Serum islet cell antibody (ICA) and glutamic acid decarboxylase antibody (GADA) were negative, while antibody insulin autoantibodies were positive in all the 3 patients. Two patients demonstrated diabetes mellitus after an oral glucose tolerance test, while one had normal glucose tolerance. Furthermore, serum insulin levels significantly elevated and did not matched C peptide levels. No abnormalities were found on enhanced MRI of the pancreas, and all 3 patients were clinically diagnosed with IAS. INTERVENTIONS:In case one, insulin aspart 30 injection was withdrawn after admission. In addition, the patient was prescribed sublingual acarbose 3 times daily. Two weeks after admission, prednisone acetate was administered orally once daily at night. In case 2, insulin aspart 30 injection was withdrawn after admission, the patient was prescribed sublingual acarbose 3 times daily with a meal. Five days after admission, oral prednisone acetate was administered once daily at night. In case 3, oral propylthiouracil was prescribed and thiamazole withdrawn after admission, and the patient consumed an extra meal before sleeping. OUTCOMES:At the 3-month follow-up visit, the hypoglycemic episodes had disappeared, serum insulin levels were significantly decreased, and insulin antibody (IA) levels were no longer detectable in all 3 patients. LESSONS:For those patients with high-insulin hypoglycemia, IAA should be evaluated if serum insulin concentrations are inconsistent with C peptide levels. Therapeutically, a lower dose of glucocorticoids with more appropriate medication timing can be used to achieve good results.

Project description:Autoimmune neurological syndromes (AINS) with autoantibodies against the 65 kDa isoform of the glutamic acid decarboxylase (GAD65) present with limbic encephalitis, including temporal lobe seizures or epilepsy, cerebellitis with ataxia, and stiff-person-syndrome or overlap forms. Anti-GAD65 autoantibodies are also detected in autoimmune diabetes mellitus, which has a strong genetic susceptibility conferred by human leukocyte antigen (HLA) and non-HLA genomic regions. We investigated the genetic predisposition in patients with anti-GAD65 AINS. We performed a genome-wide association study (GWAS) and an association analysis of the HLA region in a large German cohort of 1214 individuals. These included 167 patients with anti-GAD65 AINS, recruited by the German Network for Research on Autoimmune Encephalitis (GENERATE), and 1047 individuals without neurological or endocrine disease as population-based controls. Predictions of protein expression changes based on GWAS findings were further explored and validated in the CSF proteome of a virtually independent cohort of 10 patients with GAD65-AINS and 10 controls. Our GWAS identified 16 genome-wide significant (P < 5 × 10-8) loci for the susceptibility to anti-GAD65 AINS. The top variant, rs2535288 [P = 4.42 × 10-16, odds ratio (OR) = 0.26, 95% confidence interval (CI) = 0.187-0.358], localized to an intergenic segment in the middle of the HLA class I region. The great majority of variants in these loci (>90%) mapped to non-coding regions of the genome. Over 40% of the variants have known regulatory functions on the expression of 48 genes in disease relevant cells and tissues, mainly CD4+ T cells and the cerebral cortex. The annotation of epigenomic marks suggested specificity for neural and immune cells. A network analysis of the implicated protein-coding genes highlighted the role of protein kinase C beta (PRKCB) and identified an enrichment of numerous biological pathways participating in immunity and neural function. Analysis of the classical HLA alleles and haplotypes showed no genome-wide significant associations. The strongest associations were found for the DQA1*03:01-DQB1*03:02-DRB1*04:01HLA haplotype (P = 4.39 × 10-4, OR = 2.5, 95%CI = 1.499-4.157) and DRB1*04:01 allele (P = 8.3 × 10-5, OR = 2.4, 95%CI = 1.548-3.682) identified in our cohort. As predicted, the CSF proteome showed differential levels of five proteins (HLA-A/B, C4A, ATG4D and NEO1) of expression quantitative trait loci genes from our GWAS in the CSF proteome of anti-GAD65 AINS. These findings suggest a strong genetic predisposition with direct functional implications for immunity and neural function in anti-GAD65 AINS, mainly conferred by genomic regions outside the classical HLA alleles.

Dataset Information

Assessment and Management of Anti-Insulin Autoantibodies in Varying Presentations of Insulin Autoimmune Syndrome.

Publications

Assessment and Management of Anti-Insulin Autoantibodies in Varying Presentations of Insulin Autoimmune Syndrome.

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