Presence Of Insulin Autoantibodies Research Articles

Long-term follow-up of methimazole-associated insulin autoimmune syndrome: a rare case report

Insulin autoimmune syndrome (IAS) is a rare cause of hypoglycemia and is characterized by the presence of insulin autoantibodies and fasting or late postprandial hypoglycemia. The number of reports on the association of long-term follow-up of IAS in China is limited. We herein report a case of drug-induced IAS in a 44-year-old Chinese woman. She had been taking methimazole for Graves’ disease and had subsequently presented with recurrent hypoglycemic episodes. Laboratory assessments on admission revealed that her serum insulin level was significantly elevated (>1000 µIU/mL) and that she was positive for serum insulin autoantibody, leading to a diagnosis of IAS. Human leukocyte antigen DNA typing identified *04:06/*09:01:02, an immunogenetic determinant associated with IAS. After treatment with prednisone for 2 months, the hypoglycemic episodes disappeared, her serum insulin level gradually declined, and her insulin antibody levels became negative. Clinicians should be aware of the potential for methimazole to trigger autoimmune hypoglycemia in people with a genetic predisposition.

Abstract 160: A tri prong approach in the management of insulin autoimmune syndrome

Insulin autoimmune syndrome (IAS) manifests as transient self-limiting endogenous hyperinsulinemic hypoglycemia. It is characterized by the presence of insulin autoantibodies which bind insulin and the unpredictable release of insulin from insulin-autoantibody complexes resulting in spontaneous hypoglycemia. It needs to be considered in patients with hypoglycemia (in non-diabetic individuals) to avoid unnecessary investigations and surgical interventions. Treatment of Insulin autoimmune syndrome has always been an enigma. We suggest a tri-prong approach, with the pharmacological cocktail of alpha glucose inhibitor, steroids, and diazoxide along with dietary modifications after the elimination of the culprit agent. The targeting of the three major pathogenetic mechanisms when initiated early holds the potential of earlier relief of symptoms and accelerated recovery in severe and refractory hypoglycemia.

Severe Fasting Hypoglycemia Mimicking Insulinoma in Three Patients With Insulin Autoimmune Syndrome

Insulin autoimmune syndrome (IAS) is a rare cause of hypoglycemia characterized by the presence of insulin autoantibodies (IAA) in patients without prior exposure to exogenous insulin. Differential diagnosis with other causes of hypoglycemia may be complex. We report three IAS cases with severe fasting hypoglycemia, referred to our Unit for the diagnostic workup of insulinoma. All three patients (two women and a man, age 66, 44, and 50 years) had history of severe fasting hypoglycemia leading to loss of consciousness along with weight gain. Both insulin and C-peptide were high, but their levels varied greatly among patients, ranging from 24 to 1500 μU/ml (n.v. <16.3) and from 11 to 27 ng/mL (n.v. < 4,2), respectively. Imaging studies for insulinoma were negative. In all patients, evidence of elevated IAA (ranging from 310 to 660 UA, n.v. < 5) allowed diagnosis of IAS. Two patients were taking alpha lipoic acid, a sulphydryl compound consistently associated to IAS, while in the other the HLA-DRB1*0403 haplotype, conferring susceptibility to IAS, was detected. Continuous monitoring glucose (CGM) (iPro2; Medtronic Diabetes, CA, USA) showed in all patients the presence of prolonged hypoglycemia (with time spent with blood glucose below 54 mg/dL ranging from 9 to 20% of total monitoring time), and in one case the coexistence of high glucose levels after meals. One patient responded well to diazoxide treatment, while the others required both chronic steroid therapy and the use of plasmaphereses. Conclusion: Clinical manifestations of IAS vary widely among patients, without a direct correlation between symptoms severity and levels of both insulin and IAA; prandial hyperglycemia may also be present, leading to increases in glycated hemoglobin. Our patients displayed severe fasting hypoglycemic attacks that initially posed the suspicion of insulinoma. The assessment of IAA is thus mandatory in cases of fasting hypoglycemia, before proceeding to more expensive and probably unnecessary diagnostic and therapeutic procedures. CGM is a useful tool in evaluation and management of IAS, allowing the assessment of hypoglycemia duration and the detection of the wide glycemic variability secondary to the complex mechanism of insulin binding to IAA.

Insulin autoimmune syndrome induced by exogenous insulin injection: a four-case series

BackgroundInsulin autoimmune syndrome (IAS) is a rare cause of hypoglycemia and is characterized by the presence of insulin autoantibodies. Patients with IAS usually complain of hypoglycemia without any previous insulin received. Glucocorticoids and immunosuppressants are used to treat IAS.Case presentationWe report four patients with diabetes who were diagnosed with non-classical IAS and describe the treatment of these patients. Moreover, the differential diagnosis with hyperinsulinism is discussed.ConclusionHigh levels of insulin autoantibodies, as well as hyperinsulinemic hypoglycemia, are found in patients with diabetes mellitus and prior exogenous insulin exposure. This situation that we classified as non-classical IAS should be attached importance to.

Recurrent hypoglycemia, a rare case of insulin autoimmune syndrome in a young African American male

Insulin autoimmune syndrome (IAS) is an uncommon cause of spontaneous hypoglycemia from hyperinsulinemia due to autoantibodies against endogenous insulin (Jian-Ping Chu, 2016). These individuals have no prior exposure to exogenous insulin. We report a case of a 35-year-old African American male, who presented to Vaughn Regional Medical Center in Selma, AL, after he was found to have seizures from hypoglycemia, with a blood sugar of 63 on presentation. He was never diagnosed with diabetes in the past, nor did he have a history of seizure disorder. He continued to be hypoglycemic during the initial period of his hospital stay. His fasting insulin level was 27 mIU/l (normal is less than 25, with presence of insulin autoantibodies (IAA), and a negative workup otherwise. This led us to include IAS as one of our differentials for his hypoglycemia.

Insulin autoimmune syndrome: a rare cause of hypoglycemia. The case report of the syndrome in pediatric practice

Insulin autoimmune syndrome (IAS) is characterized by spontaneous hypoglycemia accompanied by an increased insulin level and presence of insulin autoantibodies while no exogenous insulin was used. This disorder is the third leading cause of hypoglycemia in Southeastern Asia. The disorder develops in individuals with a genetic predisposition, mostly after they had administered drugs containing a sulfhydryl moiety, such as methimazole, penicillin g, etc. The syndrome is typical of adults and extremely rare among children. We report the case of developing IAS in a 3.5-year-old Caucasian girl, possibly induced by pyritinol therapy.

Insulin-induced autoimmune syndrome: A case report.

Insulin autoimmune syndrome (IAS) is a disease characterized by hyperinsulinemic hypoglycemia associated with autoantibodies against endogenous insulin. A 56-year-old man was admitted to Ningbo First Hospital for the treatment of spontaneous hypoglycemia. He was found to have elevated fasting insulin level (>1,000 mIU/l) and presence of insulin autoantibodies, and after appropriate workup, was diagnosed with IAS. After treating with prednisone for 2 months, his insulin level started decreasing. In patients with repeated hypoglycemia, IAS should be considered in the differential diagnosis. Prednisone may be effective for the treatment of hypoglycemia in patients with IAS.

β-Cell Autoantibodies and Their Function in Taiwanese Children With Type 1 Diabetes Mellitus

To understand the importance of autoimmunity in the development of type 1 diabetes in Taiwanese children, we evaluated the presence of beta-cell autoantibodies and their correlation with residual beta-cell function. From 1989 to 2006, 157 Taiwanese children with newly diagnosed type 1 diabetes were enrolled in this study. We determined the presence of beta-cell autoantibodies, such as glutamic acid decarboxylase autoantibodies (GADAs), insulinoma antigen 2 autoantibodies (IA-2As), and insulin autoantibodies (IAAs). A 6-minute glucagon test was also performed at diagnosis. At diagnosis, 73% of children tested positive for GADAs, 76% for IA-2As and 21% for IAAs. Ninety-two percent of them had at least one of the beta-cell autoantibodies detected. Positivity for IAAs was more frequent in patients younger than 5 years than in those older than 5 years (45% vs. 13%). Using multiple regression analysis, the presence of GADAs or IAAs, or age of onset of these patients was an independent factor for residual beta-cell function. Younger patients and those with GADAs had less residual beta-cell function at disease onset, whereas those with IAAs had more insulin reserve. Autoimmunity plays an important role in the pathogenesis of type 1 diabetes in Taiwanese children, and the presence of IAAs tends to be more common in younger children.

Elevation of plasma interleukin-18 concentration is associated with insulin levels in patients with systemic lupus erythematosus

We previously reported that systemic lupus erythematosus (SLE) patients have a higher risk of insulin resistance and abnormal insulin secretion. Recent studies demonstrated that interleukin (IL)-18, a novel pro-inflammatory cytokine, may be involved in triggering the inflammatory processes in SLE and the concentrations of circulating IL-18 in SLE patients were significantly higher than those in healthy subjects. IL-12 has a synergistic effect with IL-18, and both cytokines are inducers of interferon (IFN)-gamma. The objective of this study was to identify the effect of fasting insulin levels on circulating concentrations of IL-18, IL-12 and IFN-gamma in patients with SLE. Plasma levels of proinflammatory Th-1 cytokines were determined by enzyme-linked immunosorbent assay in a total of 70 female SLE patients and 34 age-matched healthy females. Insulin resistance (IR) and secretion were evaluated by homeostasis model assessment (HOMA). All patients were further classified into subgroups based on the quartiles of fasting insulin levels. SLE patients with fasting insulin levels in the top quartile compared with other quartiles had significantly higher plasma levels of IL-18. The presence of insulin auto-antibodies (IAA) in SLE patients had no influence on plasma levels of IL-18. In addition, fasting insulin levels and HOMA IR were positively correlated with IL-18 in all SLE patients, respectively. In conclusion, elevated circulating IL-18 concentrations corresponded with increases in fasting insulin levels and the status of insulin resistance in patients with SLE.

Functional Genomics in Early Autoimmunity

The molecular mechanisms initiating the autoimmune process in type 1 diabetes mellitus (T1DM) remain unknown, and studies aiming to address this question have been compromised by the difficulty of predicting the disease at an early age both in humans and in animal models. An additional hindrance in selecting individuals at an early age has been the complex genetic inheritance of autoimmune diabetes, implicating not only several genes but also environmental factors. We have previously demonstrated the predictive value of insulin autoantibodies (IAAs) at an early age, between three to five weeks in the NOD mouse. Animals positive for early appearance of IAAs (E-IAAs) develop autoimmune diabetes earlier. We showed a correlation between the presence of IAAs in the mothers during pregnancy, E-IAAs in the litters, and the early appearance of T1DM. NOD mice, E-IAA-positive, within litters from IAA-positive mothers during pregnancy, develop diabetes earlier and at a much greater rate than animals that are IAA-negative and from IAA-negative mothers. The molecular mechanisms responsible for this early autoimmune subphenotype were addressed by a global approach to differential gene expression analysis in the pancreatic lymph nodes (PaLNs). Although the data analysis is currently in progress, gene expression signatures were observed that are characteristic for PaLNs with regard to the presence or absence of IAAs. Overall, these data are consistent with the hypothesis of an early environmental influence from the autoimmune maternal environment on the genetic predisposition of the offspring, characterized by specific gene signatures leading to autoimmune disease.

No Association of INS‐VNTR Genotype and IAA Autoantibodies

Type 1 diabetes is associated with autoimmune responses against insulin, with insulin autoantibodies (IAA) being a hallmark of the disease. Genetic susceptibility to type 1 diabetes is polygenic and includes the INS VNTR-IDDM2 locus, which has been shown to regulate the expression of insulin in the pancreas and thymus. In order to determine whether insulin autoimmunity could be attributed to a genetic susceptibility conferred by the INS-VNTR (IDDM2) locus, we studied the frequency of INS-VNTR alleles and the presence of IAA in 90 patients with new-onset type 1 diabetes. IAA were detected in 49 of 67 class I/I individuals and 19 of 23 class III/X patients, indicating that there is no association between the INS VNTR-IDDM2-susceptible allele and humoral autoimmunity against insulin. This finding does not support the hypothesis of an allele-specific tolerance induction that could determine susceptibility toward autoimmunity against the insulin protein and subsequently the development of type 1 diabetes.

Early and Quantal (by Litter) Expression of Insulin Autoantibodies in the Nonobese Diabetic Mice Predict Early Diabetes Onset

Aiming to study the early stages of type 1 diabetes phenotype, before insulitis appears, we measured insulin autoantibodies (IAA) between 3 and 5 wk of age in the NOD mouse (early-IAA (E-IAA)). We report that IAA are found as early as at 3 wk of age, at weaning, and their expression is a quantal phenotype. Maternal autoantibody status influences this early phenotype, because animals of litters issued from IAA-positive ante partum mothers develop E-IAA with a significantly higher incidence than animals issued from IAA-negative mothers. These E-IAA represent synthesized rather than transplacental autoantibodies, as evidenced by higher levels in many offspring compared with maternal IAA, and negative as well as positive offspring in the same litters and it correlates with early diabetes onset, defining the first autoimmune window in diabetes pathogenesis. Therefore, autoimmune processes leading to type 1 diabetes initiate early in life, are influenced by maternal autoantibody status, and can be revealed by the presence of IAA. Our data suggest that the mechanisms responsible for the breakdown of self-tolerance are subjected not only to genetic predisposition, but also to the physiological status of the mother. Pathological progression to autoimmunity is marked by the presence of immunological windows relating early steps with final disease onset.

The HLA-DRB, -DQB polymorphism and anti-insulin antibody response in Slovenian patients with type 1 diabetes.

A combination of specific HLA class II antigens and the presence of type 1 diabetes (T1D)-related antibodies has a high positive predictive value for T1D but low sensitivity. The aim of the present study was to determine the frequencies of HLA-DRB-DQB deduced haplotypes associated with susceptibility and protection in Slovenian patients with established T1D, to evaluate the relationship between the HLA-DRB1-QBP-DQB1 haplotypes and the presence of insulin autoantibodies (IAA) and glutamic acid decarboxylase antibodies (GADA), and to access the possible impact of polymorphic QBP promoters on this relationship. A cohort of 135 patients with T1D (age 17.5 +/- 7.0 years, duration of T1D 9.14 +/- 6.3 years) was investigated. HLA-DRB1 and DQB1 alleles were typed using the polymerase chain reaction (PCR)-reverse line blot method. QBP promoter region alleles were determined using PCR-sequence-specific oligonucleotide hybridization (SSO) and PCR-sequence-specific primers (SSP). IAA and GADA antibodies were determined by enzyme-linked immunosorbent assay (ELISA). The chi-square test with Yates' correction was used for statistical analysis. Deduced haplotypes DRB1*0301-DQB1*0201 (P = 0.0001, OR = 3.4), DRB1*0401-DQB1*0302 (P = 0.0001, OR = 29.8), and DRB1*0402-DQB1*0302 (P = 0.008, OR = 4.7) were significantly more common, and DRB1*1501-DQB1*0602 (P = 0.0001, OR = 0.03) significantly less common in the investigated cohort than in a Slovenian control group. The highest risk and the strongest protective HLA-DR-DQ haplotypes found in Slovenian patients with T1D did not differ from those found in other Caucasian populations. While the DRB1*0301-QBP2.1-DQB1*0201 haplotype, where QBP2.1 did not help to further distinguish DQB1*0201-possessing haplotypes in IAA-positive and IAA-negative patients, was strongly associated with the presence of IAA, the DRB1*0101-QBP5.12-DQB1*0501 haplotype, although not protective compared to the control population, was associated with an absence of IAA in the investigated cohort. It is suggested that there may be a combined influence of the QBP5.12 promoter and the DQB1*0501 functional molecule on reduced IAA production.

Transient Insulin Autoantibody Expression Independent of Development of Diabetes: Comparison of NOD and NOR Strains

NOD mice spontaneously develop anti-insulin autoantibodies associated with the subsequent development of diabetes. NOD mice that express insulin autoantibodies at 8 weeks of age have a diabetes risk exceeding 90%, while mice that do not express autoantibodies by 16 weeks have a risk of less than 20%. NOD female mice expressed insulin autoantibodies more often than male mice (13/15+vs. 6/15+). Autoantibodies characteristically developed between 8 and 20 weeks and then for most mice became negative at diabetes onset in NOD mice. In the diabetes-free strain NOR mice, spontaneous expression of insulin autoantibodies was observed in less mice (female 8/15+, male 3/10+) compared to NOD mice. The expression of autoantibodies was transient in NOR mice and followed the same time-course as for NOD mice and they were all negative by 28 weeks (without progression to diabetes). No correlation was found in NOR mice between the levels of autoantibodies and insulitis. The program of insulin autoantibody expression is regulated over approximately 5 months for both NOD and NOR mice with only NOD mice developing diabetes, indicating that depending upon genetic combination, the presence of insulin autoantibodies does not always predict diabetes development. In addition, this data is not consistent with the hypothesis that the time-course of autoantibodies simply reflects the destruction of β-cells with development of diabetes.

Imaging of the Buffering Effect of Insulin Antibodies in the Autoimmune Hypoglycemic Syndrome1

Insulin autoimmune hypoglycemia is characterized by recurrent hypoglycemia and high levels of immunoreactive insulin in the presence of insulin autoantibodies. The mechanisms inducing hypoglycemia are largely unknown. An [123I]insulin scintigraphic scanning was performed to directly demonstrate the effect of antibodies on insulin biodistribution in one patient with this syndrome both before and after treatment. The patient had insulin autoantibodies IgG3 lambda, which had a single site dissociation constant (Kd = 10(-7) mol/L, by Scatchard analysis), a very fast dissociation rate of immune complexes, and a very rapid association of [125I]insulin. Insulin receptors on red blood cells were down-regulated. The [123I]insulin scintigraphic study imaged the buffering effect of antibodies on insulin bioavailability. [123I]Insulin was not removed from the blood, and no liver or kidney uptake of the hormone occurred. The frequency and severity of hypoglycemic episodes required treatment. Insulin antibody levels decreased and [123I]insulin biodistribution improved after treatment with plasmapheresis and prednisone. Improved hormone bioavailability was further evidenced by the reduction in the hypoglycemic delay after i.v. insulin from 90 min before any treatment to 60 min after plasmapheresis and 30 min after steroid administration. Glucose tolerance was normal after treatment. Plasmapheresis followed by steroid treatment can lower the insulin antibody concentration, abolish severe hypoglycemia, and improve insulin biodistribution and glucose tolerance in insulin autoimmune hypoglycemia.

Diabetes Mellitus

Diabetes Mellitus

Reactivity of islet cell antibodies (ICA) to recombinant glutamic acid decarboxylase (GAD)

To study the heterogeneity of islet cell antibodies (ICA), recombinant rat and human GAD65 expressed as bacterial fusion proteins were used to inhibit ICA reactivity in sera from recent onset type 1 diabetic children and ICA-positive first degree relatives of diabetic patients. Rat GAD65 was expressed as a fusion protein in the expression vector RSET and inhibited ICA (GAD+ICA) in 26% of 23 recent onset patients, 29% of 14 ICA positive first degree relatives (FDR) who progressed to diabetes (prediabetics) and 50% of 20 FDR who did not progress to diabetes 18 months to 5 years (31 +/- 14 months) after collection of the sample. GAD+ICA were inversely associated with the presence of insulin autoantibodies (IAA) (P = 0.006). GAD antibodies (GAD-Ab) were also detected by immunoprecipitation of in vitro transcribed and translated [35S] methionine-labelled human GAD65. GAD-Ab were present in 83% of recent onset patients, 86% of prediabetics and 95% of the relatives who did not progress to diabetes. The level of GAD-Ab was higher in the presence of GAD+ICA (1.39 +/- 0.57 vs 0.79 +/- 0.6 index units; P = 0.001). ICA levels were higher in GAD-Ab negative than in GAD-Ab positive sera (377 +/- 256 vs 195 +/- 231 JDFU; P = 0.03). Our results confirm that a recombinant GAD65 fusion protein can be used to detect ICA heterogeneity. However, neither inhibition of ICA with recombinant GAD, nor direct detection of GAD-Ab improved the prediction of progression to clinical diabetes in ICA positive FDR.

Correlates of Insulin Autoantibodies With Beta Cell Function at the Time of Diagnosis of Diabetes Mellitus

In this article, the author discusses the prevalence of insulin autoantibodies (IAA) and endogenous insulin secretion in Saudi patients at the onset of diabetes. A positive result, defined as a value greater than 3 SD above the mean binding of normal, was found in 8 (7.6%) of 105 of the patients with diabetes and in 3 (5.7%) of 53 of the healthy control subjects. The relation between the presence of IAA and the pancreatic beta cell secretory activity was studied by determining the levels of insulin and C-peptide in the fasting state and 6 minutes after intravenous injection of 1 mg glucagon. All the IAA positive subjects had a response to glucagon stimulation test. A positive correlation was found between basal and after stimulation for both insulin and C-peptide (r = 0.79, P < 0.001; r = 0.85, P < 0.001 for insulin and r = 0.76, P < 0.001; r = 0.81, P < 0.001 for C-peptide, respectively). Therefore, the current finding indicates that there is no direct effect of IAA on the pancreatic beta cell potential activity in Saudi patients with diabetes at the time of diagnosis, suggesting further that these patients have no insulin deficiency or have mild insulin dependency.

Prospective evaluation of β-cell function in insulin antoantibody-positive relatives of insulin-dependent diabetic patients

During the preclinical period of insulin-dependent diabetes mellitus (IDDM), progression to clinical IDDM is characterized by declining β-cell function. Although the presence of insulin autoantibodies (IAA) improves the ability of islet cell antibodies (ICA) to predict subsequent clinical IDDM, few studies have examined the risk of developing IDDM in subjects positive for IAA but negative for both ICA and antibodies to glutamic acid decarboxylase (64kA). To investigate this question, detailed β-cell function tests (acute insulin response to glucose [AIR gluc] and slope of glucose potentiation) were performed on eight IAA-positive first-degree relatives of insulin-dependent diabetics. All eight subjects were negative for ICA, and seven were tested for 64kA and were negative. Five subjects were studied prospectively for 22.4 ± 9.4 months, while three subjects had only initial studies. Initial β-cell function tests were normal in each subject. AIR gluc was 122.2% ± 19.0% of the expected normal response, while slope was 168.6% ± 20.6% of expected normal response. β-cell function remained normal and remarkably stable in the five subjects followed prospectively. AIR gluc did not significantly change from an initial value of 147.9% ± 23.1% of expected to 153.2% ± 22.4% (NS). The slope of glucose potentiation varied little from 165.5% ± 39.4% initially to 159.5% ± 27.3% (NS) at the most recent determination. We conclude that among nondiabetic first-degree relatives of IDDM subjects, the presence of IAA in the absence of ICA and 64kA is not usually associated with and therefore does not reliably predict β-cell dysfunction or progressive deterioration in β-cell function.

17 CELLULAR AND HUMORAL IMMUNE AGGRESSION AND PANCREATIC FUNCTION IMPAIRMENT IN CHLDREN WITH SPORADIC HYPERGLYCEMIA WITHOUT FAMILIAL HISTORY OF TYPE I DIABETES

Diabetes Experimental, Centro de Invsstigaciones Endocrinológicas (CEDIE), Htal de Niños R. Gutiérrez y Sectión Diabetes, Htal. “A, Posadas”, Buenos Aires, Argentina. Forty five children with sporadic hyperglycemias were studied (normal fasting glycemia, with 2 or more sporadic postprandial hyperglycemias). Controls were healthy children without familial history of diabetes or associated autoimmune diseases, Humoral immunity was detected by the presence of insulin autoantibodies (IAA) according to Palmer;all sera higher than X̄ control±3 SD were considered positive. Cellular immune aggression (CIA) was evaluated by coculturing lymphocytes with dispersed rat islet cells (central group:X̄±2 SD: 29.66±3.06 insulin uU/5000 cells/5 min, n=22) according to the immune markers and taken into consideration the pancreatic function (ins. secr. IS;control group:137.6±78.3 insulin uU, min 1±3 post i.v. glucose, X̄+2 SD, n=15) patients ware divided in two groups. Group A:14/24 with normal IS;1/4 IAA+ve;7/14 CIA+ve and 6|14 without any aggressicn. Group B:10/24 with impaired IS (than X̄ central - 2 SD);5/10 IAA+ve; 10/10 CIA+ve and 5/10 with both immune markers + ve. The results showed that in children with sporadic hyperglycemia:1). The presence of CIA is an early marker since it was found in 50% of children without IS inpaiment or IAA and in all these with impaired IS. 2)IAA were present in 7.14% of children with normal IS and in a 50% of those with impaired IS;3)35% of all children with sporadic hyperglycemia shewed IS impairment and CIA+ve, suggesting that this could be a group at risk of developing Type I diabetes.