Uncommon triggers of insulin autoimmune syndrome: a case report.

BACKGROUND: Insulin autoantibody syndrome (IAS), or Hirata disease, is caused by high concentrations of insulin autoantibodies, which result in spontaneous, mainly post-prandial, hypoglycemic episodes. We report a case of a previously healthy 67-year-old man presenting with recurrent fasting hypoglycemia culminating in a diagnosis of insulin autoimmune syndrome linked to omeprazole and probably spices, namely, coriander, and ginger. CASE PRESENTATION: A previously healthy 67-year-old Sinhalese man presented with recurrent syncopal attacks for 3 months, which were found to be hypoglycemic episodes. He experienced mainly fasting hypoglycemic attacks, at a frequency gradually increasing to daily attacks. His cardiovascular, respiratory, abdominal, and neurologic examinations were normal. He was found to have insulin levels > 6000 mU/L and a post-polyethylene glycol insulin recovery of less than 9.5%. Contrast-enhanced computed tomography of the pancreas was normal. The diagnosis of insulin autoantibody syndrome was confirmed by testing for the insulin autoantibody level, yielding a level of > 300 U/mL. With regard to a possible trigger, he had a history of omeprazole intake for 2 weeks, 4 weeks prior to the onset of symptoms. He also consumed an herbal supplement containing coriander and ginger extracts daily for a period of 1 year, approximately 2 years prior to the onset of hypoglycemic attacks. He was commenced on prednisolone 30 mg daily, and hypoglycemic episodes responded dramatically, and thus he was tapered off corticosteroids. CONCLUSION: Omeprazole-induced insulin autoantibody syndrome is likely in this patient; however, the known hypoglycemic effects of coriander and ginger make it worthwhile to consider a possible association with insulin autoantibody syndrome. In addition, this case report highlights the need to consider insulin autoantibody syndrome even in patients presenting with fasting hypoglycemic attacks.

Insulin Autoimmune Syndrome - An After-Meal Roller Coaster Ride.

Hypoglycemic disorders are rare in persons without diabetes, and clinical evaluation to identify its etiology can be challenging. We present a case of insulin autoimmune syndrome induced by carbimazole in a middle-aged Chinese man with underlying Graves' disease, which was managed conservatively with a combination of dietary modification and alpha-glucosidase inhibitor.

Immunogenicity, Efficacy, and Safety of Biosimilar Insulin Glargine (Gan & Lee Glargine) Compared With Originator Insulin Glargine (Lantus) in Patients With Type 1 Diabetes After 26 Weeks Treatment.

OBJECTIVE: To compare the immunogenicity, safety, and efficacy of Gan & Lee insulin glargine (GL Glargine) with that of the originator insulin glargine (Lantus) in patients with type 1 diabetes mellitus (T1DM). METHODS: This was a phase 3, multicenter, randomized, open-label, equivalence study. Five hundred seventy-six subjects with T1DM were randomized 1:1 to receive either GL Glargine or Lantus treatment for 26 weeks. The primary end point was the percentage of subjects in each treatment group who developed treatment-induced anti-insulin antibody after baseline and up to visit week 26, which was evaluated using a country-adjusted logistic regression model. The study also compared the changes in glycated hemoglobin, and adverse events including hypoglycemia. RESULTS: The percentage of subjects positive for treatment-induced anti-insulin antibody by Week 26 was 25.8% in the GL Glargine treatment group and 25.3% in the Lantus treatment group, with a 90% confidence interval (-5.4, 6.5) of the difference in proportions that fell completely between the similarity margins (-11.3, 11.3). The least squares mean difference between treatment groups for changes in glycated hemoglobin was -0.08 (90% confidence interval: -0.23, 0.06), and the other immunogenicity and safety profiles were comparable. CONCLUSION: GL Glargine demonstrated similar immunogenicity, efficacy, and safety compared to Lantus over 26 weeks in patients with T1DM.

Data-Driven Phenotyping of Presymptomatic Type 1 Diabetes Using Longitudinal Autoantibody Profiles.

OBJECTIVE: To characterize distinct islet autoantibody profiles preceding stage 3 type 1 diabetes. RESEARCH DESIGN AND METHODS: The T1DI (Type 1 Diabetes Intelligence) study combined data from 1,845 genetically susceptible prospectively observed children who were positive for at least one islet autoantibody: insulin autoantibody (IAA), GAD antibody (GADA), or islet antigen 2 antibody (IA-2A). Using a novel similarity algorithm that considers an individual's temporal autoantibody profile, age at autoantibody appearance, and variation in the positivity of autoantibody types, we performed an unsupervised hierarchical clustering analysis. Progression rates to diabetes were analyzed via survival analysis. RESULTS: We identified five main clusters of individuals with distinct autoantibody profiles characterized by seroconversion age and sequence of appearance of the three autoantibodies. The highest 5-year risk from first positive autoantibody to type 1 diabetes (69.9%; 95% CI 60.0-79.2) was observed in children who first developed IAA in early life (median age 1.6 years) followed by GADA (1.9 years) and then IA-2A (2.1 years). Their 10-year risk was 89.9% (95% CI 81.9-95.4). A high 5-year risk was also found in children with persistent IAA and GADA (39.1%) and children with persistent GADA and IA-2A (30.9%). A lower 5-year risk (10.5%) was observed in children with a late appearance of persistent GADA (6.1 years). The lowest 5-year diabetes risk (1.6%) was associated with positivity for a single, often reverting, autoantibody. CONCLUSIONS: The novel clustering algorithm identified children with distinct islet autoantibody profiles and progression rates to diabetes. These results are useful for prediction, selection of individuals for prevention trials, and studies investigating various pathways to type 1 diabetes.

Immunogenicity, efficacy, and safety of biosimilar insulin glargine (Gan & Lee glargine) compared with originator insulin glargine (Lantus®) in patients with type 2 diabetes after 26 weeks' treatment: A randomized open label study.

AIM: To evaluate the equivalence of immunogenicity, safety and efficacy of Gan & Lee (GL) Glargine (Basalin®; Gan & Lee Pharmaceutical) with that of the reference product (Lantus®) in adult participants with type 2 diabetes mellitus. METHODS: This was a phase 3, multicenter, open-label, equivalence trial conducted across 57 sites. In total, 567 participants with type 2 diabetes mellitus were randomized in a 1:1 ratio to undergo treatment with either GL Glargine or Lantus® for 26 weeks. The primary endpoint was the proportion of participants in each treatment arm who manifested treatment-induced anti-insulin antibodies (AIA). Secondary endpoints included efficacy and safety metrics, changes in glycated haemoglobin levels, and a comparative assessment of adverse events. Results were analysed using an equivalence test comparing the limits of the 90% confidence interval (CI) for treatment-induced AIA development to the prespecified margins. RESULTS: The percentages of participants positive for treatment-induced glycated haemoglobin by week 26 were similar between the GL Glargine (19.2%) and Lantus® (21.3%) treatment groups, with a treatment difference of -2.1 percentage points and a 90% CI (-7.6%, 3.5%) (predefined similarity margins: -10.7%, 10.7%). The difference in glycated haemoglobin was -0.08% (90% CI, -0.23, 0.06). The overall percentage of participants with any treatment-emergent adverse events was similar between the GL Glargine (80.1%) and Lantus® (81.6%) treatment groups. CONCLUSIONS: GL Glargine was similar to Lantus® in terms of immunogenicity, efficacy, and safety, based on the current study.

Comparative assessment of immunogenicity of recombinant insulin Aspart from BioGenomics and its originator NovoRapid® in adult patients with type 2 diabetes mellitus.

OBJECTIVES: To assess and compare the immunogenicity of recombinant Insulin Aspart [manufactured by BioGenomics Limited (BGL-ASP)] with its originator NovoRapid® (manufactured by Novo Nordisk) in adult patients with type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS: BGL-IA-CTP301 study was a randomized, open label, parallel group, multicenter phase-III clinical study to compare the efficacy and safety of recombinant Insulin Aspart 100 U/mL [manufactured by BioGenomics Limited (BGL-ASP)] with its reference medicinal product (RMP); NovoRapid® [manufactured by Novo Nordisk], in adult patients with Type 2 diabetes mellitus (T2DM). The primary objective of the study was to compare the immunogenicity of BGL-ASP and RMP; NovoRapid® in patient serum samples collected from phase-III clinical study. Immunogenicity was studied as the incidence of patients positive for anti-insulin Aspart (AIA) antibodies, developed against BGL-ASP/RMP at baseline, end of 12 week and end of 24 week of the treatment period. The changes in incidence of patients positive for AIA antibodies post-baseline were also studied to assess and compare the treatment-emergent antibody response (TEAR) between the treatment groups (BGL-ASP and RMP). Statistical evaluation was done by Fisher's exact test to compare the overall incidence of patients positive for AIA antibodies and the TEAR positives observed post-baseline in both the treated groups. An in-vitro neutralizing antibody assay (Nab assay) was also performed to study the effect of AIA antibodies in neutralizing the biological activity/metabolic function of the insulin. The neutralizing potential of AIA was studied by its effect on %glucose uptake. We also evaluated the association between AIA antibody levels and its impact on biological activity by studying the correlation between them. RESULTS: Analysis of immunogenicity data suggested that the percentage of patients positive for AIA antibodies until week 24 was similar and comparable in both the treatment groups, BGL-ASP and RMP; NovoRapid®. The changes in incidence of patients positive for AIA post-baseline in terms of TEAR positives were also similar and comparable between the treatment groups. The results of the Nab assay with confirmed positive AIA samples from BGL-ASP- and RMP-treated groups did not have any negative impact on %glucose uptake by the cells in Nab assay, confirming the absence of neutralizing antibodies in both the treatment groups. The correlation studies also showed absence of association between AIA antibody levels and percentage glucose uptake in both BGL-ASP and RMP-NovoRapid® treatment groups. CONCLUSIONS: The immunogenicity assessment based on the overall incidence of patients positive for AIA, changes in incidence of patients positive for AIA post-baseline, TEAR rates and absence of neutralizing antibodies, were found to be apparently similar and comparable in both the treatment groups (BGL-ASP and RMP). We conclude from our studies that the immunogenicity of BGL-ASP is similar and comparable to RMP and the observed immunogenicity in terms of anti-insulin Aspart antibody levels had no impact on the biological activity of insulin.

Sex Differences in Age of Diagnosis, HLA Genotype, and Autoantibody Profile in Children With Type 1 Diabetes.

OBJECTIVE: To examine sex differences in children with newly diagnosed type 1 diabetes (T1D) with respect to age at diagnosis, presence of autoantibodies (GAD antibody [GADA], insulinoma-associated protein 2 [IA-2A], insulin autoantibody [IAA], and zinc transporter 8 autoantibody), and HLA risk. RESEARCH DESIGN AND METHODS: A population-based nationwide sample of 3,645 Swedish children at T1D diagnosis was used. RESULTS: Girls were younger at T1D diagnosis (9.53 vs. 10.23 years; P < 0.001), more likely to be autoantibody-positive (94.7% vs. 92.0%; P = 0.002), more often positive for multiple autoantibodies (P < 0.001), more likely to be positive for GADA (64.9% vs. 49.0%; P < 0.001), and less likely to be positive for IAA (32.3% vs. 33.8%; P = 0.016). Small sex differences in HLA risk were found in children <9 years of age. CONCLUSIONS: The disease mechanisms leading to T1D may influence the immune system differently in girls and boys.

Diagnosis and treatment of anti-insulin antibody-mediated labile glycaemia in insulin-treated diabetes.

AIMS: Anti-insulin antibodies in insulin-treated diabetes can derange glycaemia, but are under-recognised. Detection of significant antibodies is complicated by antigenically distinct insulin analogues. We evaluated a pragmatic biochemical approach to identifying actionable antibodies, and assessed its utility in therapeutic decision making. METHODS: Forty people with insulin-treated diabetes and combinations of insulin resistance, nocturnal/matutinal hypoglycaemia, and unexplained ketoacidosis were studied using broad-specificity insulin immunoassays, polyethylene glycol (PEG) precipitation and gel filtration chromatography (GFC) with or without ex vivo insulin preincubation. RESULTS: Twenty-seven people had insulin immunoreactivity (IIR) below 3000 pmol/L that fell less than 50% after PEG precipitation. Insulin binding by antibodies in this group was low and judged insignificant. In 8 people IIR was above 3000 pmol/L and fell by more than 50% after PEG precipitation. GFC demonstrated substantial high molecular weight (HMW) IIR in 7 of these 8. In this group antibodies were judged likely significant. In 2 people immunosuppression was introduced, with a good clinical result in one but only a biochemical response in another. In 6 people adjustment of insulin delivery was subsequently informed by knowledge of underlying antibody. In a final group of 5 participants IIR was below 3000 pmol/L but fell by more than 50% after PEG precipitation. In 4 of these GFC demonstrated low levels of HMW IIR and antibody significance was judged indeterminate. CONCLUSIONS: Anti-insulin antibodies should be considered in insulin-treated diabetes with unexplained glycaemic lability. Combining immunoassays with PEG precipitation can stratify their significance. Antibody depletion may be beneficial, but conservative measures often suffice.

Gastrointestinal Infections Modulate the Risk for Insulin Autoantibodies as the First-Appearing Autoantibody in the TEDDY Study.

OBJECTIVE: To investigate gastrointestinal infection episodes (GIEs) in relation to the appearance of islet autoantibodies in The Environmental Determinants of Diabetes in the Young (TEDDY) cohort. RESEARCH DESIGN AND METHODS: GIEs on risk of autoantibodies against either insulin (IAA) or GAD (GADA) as the first-appearing autoantibody were assessed in a 10-year follow-up of 7,867 children. Stool virome was characterized in a nested case-control study. RESULTS: GIE reports (odds ratio [OR] 2.17 [95% CI 1.39-3.39]) as well as Norwalk viruses found in stool (OR 5.69 [1.36-23.7]) at <1 year of age were associated with an increased IAA risk at 2-4 years of age. GIEs reported at age 1 to <2 years correlated with a lower risk of IAA up to 10 years of age (OR 0.48 [0.35-0.68]). GIE reports at any other age were associated with an increase in IAA risk (OR 2.04 for IAA when GIE was observed 12-23 months prior [1.41-2.96]). Impacts on GADA risk were limited to GIEs <6 months prior to autoantibody development in children <4 years of age (OR 2.16 [1.54-3.02]). CONCLUSIONS: Bidirectional associations were observed. GIEs were associated with increased IAA risk when reported before 1 year of age or 12-23 months prior to IAA. Norwalk virus was identified as one possible candidate factor. GIEs reported during the 2nd year of life were associated with a decreased IAA risk.

Association of subclass distribution of insulin antibody with glucose control in insulin-treated type 2 diabetes mellitus: a retrospective observational study.

Objective: To examine the distribution and effects of the subclass of insulin antibodies on glucose control and side events in patients with type 2 diabetes treated with premixed insulin analog. Methods: A total of 516 patients treated with premixed insulin analog were sequentially enrolled from the First Affiliated Hospital of Nanjing Medical University from June 2016 to August 2020. Subclass-specific insulin antibodies (IAs) (IgG1-4, IgA, IgD, IgE, and IgM) were detected in IA-positive patients by electrochemiluminescence. We analyzed glucose control, serum insulin, and insulin-related events between IA-positive and IA-negative groups, as well as among patients with different IA subclasses. Results: Overall, 98 of 516 subjects (19.0%) were positive for total IAs after premixed insulin analog therapy; of these participants, 92 had subclass IAs, and IgG-IA was the predominant subclass, followed by IgE-IA. IAs were associated with serum total insulin increase and local injection-site reactions but not glycemic control and hypoglycemia. In the subgroup analysis in patients with IA-positive, the IgE-IA and IA subclass numbers were more associated with increased serum total insulin levels. Additionally, IgE-IA might be correlated more strongly with local responses and weakly with hypoglycemia, while IgM-IA might be correlated more strongly with hypoglycemia. Conclusion: We concluded that IAs or IA subclasses might be associated with unfavorable events in patients receiving premixed insulin analog therapy, which can be used as an adjunctive monitoring indicator in clinical insulin trials.

Islet Autoantibody Standardization Program: interlaboratory comparison of insulin autoantibody assay performance in 2018 and 2020 workshops.

AIMS/HYPOTHESIS: The Islet Autoantibody Standardization Program (IASP) aims to improve the performance of immunoassays measuring autoantibodies in type 1 diabetes and the concordance of results across laboratories. IASP organises international workshops distributing anonymised serum samples to participating laboratories and centralises the collection and analysis of results. In this report, we describe the results of assays measuring IAA submitted to the IASP 2018 and 2020 workshops. METHODS: The IASP distributed uniquely coded sera from individuals with new-onset type 1 diabetes, multiple islet autoantibody-positive individuals, and diabetes-free blood donors in both 2018 and 2020. Serial dilutions of the anti-insulin mouse monoclonal antibody HUI-018 were also included. Sensitivity, specificity, area under the receiver operating characteristic curve (ROC-AUC), partial ROC-AUC at 95% specificity (pAUC95) and concordance of qualitative/quantitative results were compared across assays. RESULTS: Results from 45 IAA assays of seven different formats and from 37 IAA assays of six different formats were submitted to the IASP in 2018 and 2020, respectively. The median ROC-AUC was 0.736 (IQR 0.617-0.803) and 0.790 (IQR 0.730-0.836), while the median pAUC95 was 0.016 (IQR 0.004-0.021) and 0.023 (IQR 0.014-0.026) in the 2018 and 2020 workshops, respectively. Assays largely differed in AUC (IASP 2018 range 0.232-0.874; IASP 2020 range 0.379-0.924) and pAUC95 (IASP 2018 and IASP 2020 range 0-0.032). CONCLUSIONS/INTERPRETATION: Assay formats submitted to this study showed heterogeneous performance. Despite the high variability across laboratories, the in-house radiobinding assay (RBA) remains the gold standard for IAA measurement. However, novel non-radioactive IAA immunoassays showed a good performance and, if further improved, might be considered valid alternatives to RBAs.

Evaluation among trace elements, clinical parameters and type 1 diabetes according to sex: A new sight of auxiliary prediction in negative insulin auto-antibodies population.

BACKGROUND: Type 1 diabetes (T1D) exhibited sex-specific metabolic status including oxidative stress with dynamic change of trace elements, which emphasized the importance of the evaluation of trace elements according to sex. Besides, the most significant characteristic, insulin auto-antibodies, could not be found in all T1D patients, which needed the auxiliary prediction of clinical parameters. And it would benefit the early detection and treatment if some high-risk groups of T1D could predict and prevent the occurrence of disease through common clinical parameters. Hence, there was an urgent need to construct more effective and scientific statistical prediction models to serve clinic better. This study aimed to evaluate the sex-specific levels of trace elements and the relationship between trace elements and clinical parameters in T1D, and construct sex-specific auxiliary prediction model combined with trace elements and clinical parameters. METHODS: A total of 105 T1D patients with negative insulin auto-antibodies and 105 age/sex-matched healthy individuals were enrolled in First Hospital of Jilin University. Inductively Coupled Plasma Mass Spectrometry was performed for the measurement of calcium (Ca), magnesium (Mg), zinc (Zn), copper (Cu), iron (Fe), selenium (Se) in the serum, and the data of clinical parameters were received from medical record system. The lambda-mu-sigma method was used to evaluate the relationship between abnormal clinical parameters and trace elements. Training set and validation set were divided for the construction of predictable models in males and females: clinical parameters model, trace element model and the combined model (clinical parameters and trace elements). Goodness fit test, decision curve analysis and other related statistical methods were used to perform data analysis. RESULTS: Lower levels of Mg, Ca, Fe in the serum were found in T1D population in females compared with healthy population, while levels of Fe, Zn and Cu of serum in T1D individuals were higher than those of healthy population in males. Levels of serum Mg, Fe and Cu in T1D group were found with significant sex difference for (P < 0.05), and the levels of Fe and Cu in serum of males were higher than those of females, level of serum Mg in males was lower than those of females. Levels of serum Mg and Zn showed fluctuation trend with increased numbers of abnormal clinical parameters (NACP) in males. Serum Zn in females showed consistent elevated trend with NACP; serum Se increased first and then decreased with NACP in males and females. The auxiliary prediction model (Triglyceride, Total protein, serum Mg) was found with the highest predicted efficiency in males (AUC=0.993), while the model in females (Apolipoprotein A, Creatinine, Fe, Se, Zn/Cu ratio) showed the best predicted efficiency (AUC=0.951). The models had passed the verification in validation set, and Chi-square goodness-of-fit test, DCA results both confirmed their satisfactory clinical applicability. CONCLUSION: Sex-specific difference were found in serum Mg, Fe and Cu in T1D. The combination of triglyceride, total protein and serum Mg for males, and apolipoprotein A, creatinine, Fe, Se, Zn/Cu ratio for females could effectively predict T1D in patients with negative anti-bodies, which would provide alarm for the population with high-risk of T1D and serve the T1D prediction in patients with negative anti-bodies.

Hypoglycemia Caused by Exogenous Insulin Antibody Syndrome: A Large Single-Center Case Series From China.

CONTEXT: Exogenous insulin antibody syndrome (EIAS) can lead to unexpected and potentially life-threatening recurrent hypoglycemia. OBJECTIVE: We aimed to better define autoimmune hypoglycemia caused by EIAS in patients with diabetes and shed light on the improvements in the identification and intervention for this rare but possibly life-threatening condition. METHODS: We summarized the clinical characteristics of autoimmune hypoglycemia caused by EIAS in 23 patients with diabetes. Furthermore, we performed human leukocyte antigen (HLA) genotyping of 10 patients. RESULTS: We identified a high frequency of autoimmune comorbidities (21.7%), food or drug allergy (48%), insulin allergy (30%), lipodystrophy at the insulin injection sites (22%), and antinuclear antibodies (25%) in the patients. Alternation between hyperglycemia and hypoglycemia was observed in more than 90% of the patients. Most patients showed a high insulin autoantibody titer (>90%) and inappropriately increased insulin concentration (insulin/C-peptide molar ratio >7, >85%). We detected similar frequencies of DRB1*0405-DQB1*0401 and DRB1*0901-DQB1*0303 compared with previously reported frequencies in type 1 diabetes, and a lower frequency of DRB1*0406 compared with insulin autoimmune syndrome. The spontaneous remission rate exceeded 70%. CONCLUSION: Predisposing factors for autoimmune hypoglycemia caused by EIAS include a strong autoimmune background. Susceptible HLA genotypes for type 1 diabetes or insulin autoimmune syndrome might not explain susceptibility to this condition. Additionally, insulin autoantibodies and the insulin/C-peptide molar ratio are reliable screening options. The prognosis for this condition is favorable. Monitoring of insulin and insulin autoantibodies may contribute to treatment effectiveness.

Insulin autoimmune syndrome caused by esomeprazole in a Chinese patient.

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Type 1 diabetes complicated with cyclic vomiting syndrome and exogenous insulin antibody syndrome: A case report.

Every fifth individual with type 1 diabetes (T1D) suffers from an additional autoimmune disorder due to shared genetic factors and dysregulated immunity. Here we report an extremely rare case of T1D complicated with cyclic vomiting and hypoglycaemia. A 27-year-old Chinese woman with 14-year history of T1D was periodically hospitalized for severe vomiting of more than 30 times a day without apparent organic causes. The vomiting developed acutely and remitted spontaneously after 2-3 days, followed with intractable hypoglycaemia for another 3-4 days during the hospitalization. A few weeks after discharge, she was admitted once again with the same symptoms and disease course. Cyclic vomiting syndrome (CVS) was diagnosed according to the Rome IV criteria, a system developed to define the functional gastrointestinal disorders. Dynamic association and disassociation of exogenous insulin and insulin antibodies (IAs) were identified in her blood during hypoglycaemia, leading to the diagnosis of exogenous insulin antibody syndrome (EIAS). Treatment with rituximab to suppress the IAs was associated with a striking amelioration of hypoglycaemia. Unexpectedly, the episodes of cyclic vomiting were also dramatically reduced. In conclusion, we identified the first case with alternating CVS and EIAS in the setting of T1D. Dynamic measurements of free and total insulin are helpful for the diagnosis of EIAS. CVS is likely to be a latent autoimmune disorder considering the good response to rituximab treatment.

Hirata's disease (insulin autoimmune syndrome) following envenomation by a common krait.

Snakebite envenomation is known to cause local as well as systemic haematological, myotoxic and neurological effects. Adverse effects on the endocrine system following envenomation are rarely reported. Hirata's disease, also known as insulin autoimmune syndrome (IAS) is a rare disorder that causes hypoglycaemia due to excessive production of insulin autoantibodies. This report describes a rare case of IAS which developed in a snakebite victim following envenomation by a common krait and antivenom treatment. The patient was initially treated with dextrose and corticosteroids, although plasmapheresis was required to reduce the concentration of insulin antibodies and normalise the patient's glucose level. The patient then made an uneventful recovery without permanent sequelae. This report demonstrates the impacts of envenomation by a common krait on developing Hirata's disease and creates awareness among clinicians who treat snakebite envenomation.

[MERCAPTIZOL INDUCED HYPOGLYCEMIA - A CASE REPORT].

INTRODUCTION: This is a case study of a 25-year-old female, Ashkenazy Jewish, previously healthy, presented with a complaint of weakness. Her sugar level on the glucometer was 50 mg% and she felt better after ingestion of a small amount of sugar. Two weeks earlier, while traveling in Peru, she developed thyrotoxicosis and began taking Mercaptizol 30 mg a day and Atenolol 100 mg. She didn't drink iodine (iodinated preparations for water purification) while traveling and had no pain or fever. Her physical examination showed no goiter or exophthalmos. While I saw her she was already euthyroid and felt quite good except for fatigue. In the literature, we found a few case reports of Mercaptizol and PTU-induced insulin autoantibodies which cause symptomatic hypoglycemia. Most cases were described in the Asian population (especially Japanese people) and resolved a few weeks after stopping intake of the drug. In our patient, the hypoglycemia resolved after only one episode and discontinuation of Mercaptizol. Insulin antibodies were negative, and insulin levels (C-peptide) were relatively high. My conclusion is that physicians should be aware of Mercaptizol and PTU-induced hypoglycemia which can be life-threatening.

Case Report: Recurrent Autoimmune Hypoglycemia Induced by Non-Hypoglycemic Medications.

We present a case of recurrent autoimmune hypoglycemia induced by non-hypoglycemic agents. We review reported cases of autoimmune hypoglycemia related to non-hypoglycemic agents, and discuss the effects of different detection methods for insulin autoantibodies on the results obtained. We aim to provide information for clinicians and a warning for medication usage. Considering the increasing number of clopidogrel-induced AIH cases and the hypoglycemia-induced increase in the risk of cardiovascular events, we recommend that cardiovascular disease patients being treated with clopidogrel be informed of this rare side effect and that clinicians be vigilant for the possibility of autoimmune hypoglycemia in this patient population.

Insulin antibodies are prevalent in adults with type 1 diabetes referred for islet cell transplantation and are modified by islet transplantation and immunosuppression: an Australian experience.

We have analysed insulin antibodies in 149 adults with type 1 diabetes and 2859 people without diabetes. We have determined that insulin antibody levels are higher in adults with, versus without, diabetes and that the levels are falling, and more patients are becoming antibody-negative post islet cell transplantation.