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BACKGROUND: Insulin antibodies (IAs) affect blood glucose control in patients receiving insulin therapy. AIM: To investigate the relationship between different hypoglycemic treatments and IAs in patients with type 2 diabetes mellitus (T2DM). METHODS: This cross-sectional, retrospective study included 1863 patients with T2DM who were receiving exogenous insulin therapy. All patients received stable antidiabetic therapy in the last 3 months and IA levels were measured using an iodine-125 array. RESULTS: A total of 1863 patients were enrolled. There were 902 (48.4%) patients who had positive IAs (IA level > 5%), with a mean IA level of 11.06% (10.39%-11.72%). IA levels were positively correlated with high fasting blood glucose (odds ratio = 1.069, P < 0.001). The proportion of positive IAs was lowest in patients using glargine only (31.9%) and highest in patients using human insulin only (70.3%), P < 0.001. The IA levels in patients using sulfonylureas/glinides (8.3%), metformin (9.6%), and dipeptidyl peptidase-4 inhibitors (8.2%) were all lower than in patients without these drugs (all P < 0.05). CONCLUSION: Nearly half of patients on insulin therapy have positive IA antibodies, and IA antibody levels are associated with blood glucose control. Insulin glargine and a combination of oral glucose-lowering drugs were correlated with lower IA levels.

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Hirata disease, also known as insulin autoimmune syndrome (IAS), is a rare cause of hypoglycemia, due to the presence of insulin autoantibodies (IAA) in the circulating blood. These antibodies are immunoglobulin G (IgG), making placental transfer to the fetus possible. To our knowledge, no reports of IAS have been previously described in the neonatal population. We present a case report of hypoglycemia due to a secondary IAS in a neonate and discuss the management and treatment of the disease.

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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.

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Insulin autoimmune syndrome (IAS) is a rare cause of spontaneous hypoglycaemia. We discuss a 91-year-old Caucasian lady who presented with syncope and episodic adrenergic and neuroglycopenic symptoms. Despite significantly elevated insulin, C-peptide, and proinsulin levels with the presence of anti-insulin antibodies, a pancreatic mass was not identified. Serum immunoelectrophoresis demonstrated monoclonal gammopathy of undetermined significance (MGUS). Treatment involved high-dose steroids, diazoxide, corn starch and acarbose, however the patient passed away four months later due to worsening co-morbidities. The management of IAS in the setting of MGUS is challenging.

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Exogenous insulin antibody syndrome (EIAS) has until recently been a rarely described complication of exogenous insulin therapy. EIAS results not only in hyperglycemia, but also in hypoglycemia and occasionally in ketoacidosis (DKA). The incidence of EIAS is increasing probably due to an overall increase in autoimmunity associated with the coronavirus disease 2019 (Covid-19) epidemic resulting in increasing binding of insulin by antibodies. Herein, we describe a case of EIAS occurring in an elderly patient with longstanding type 1 diabetes mellitus (T1DM) who had progressive loss of glycemic control. It responded positively, as we have previously described, to oral mycophenolate mofetil and the use of soluble regular insulin delivered by continuous subcutaneous insulin infusion (CSII). Therefore, EIAS is an increasingly frequent cause of hyperglycemia with and without DKA, and hypoglycemia in subjects with T1DM. Once diagnosed, they can be treated with mycophenolate mofetil and soluble insulin in an outpatient setting, which will decrease the rate of hospitalization and lower the expense of therapy.

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Insulin autoimmune syndrome (IAS) or Hirata disease is a rare condition presenting as recurrent hypoglycemia, and associated with elevated insulin levels in the presence of insulin autoantibodies (IAAs) in patients who were never exposed to exogenous insulin and with no evidence of pancreatic abnormalities. IAS is much more frequent in East Asians, especially the Japanese population, compared to the lower incidence in Caucasians. However, it can be associated with other autoimmune diseases or drug use like methimazole and alpha-lipoic acid (ALA). We report a case of a 47-year-old Caucasian male presenting with a 12-month history of worsening episodes of fasting and post-prandial hypoglycemia associated with symptoms of dizziness, tremors, palpitations, and unconsciousness associated with hypoglycemia. Symptoms resolved with the administration of carbohydrate-containing foods, establishing Whipple's triad. At an outside facility, he had initial labs that showed elevated insulin levels (141 µU/ml) with normal glucose, C-peptide, and proinsulin levels, but there was no availability of an IAA lab assay. Given his symptoms, severity, and frequency of hypoglycemia, he was admitted to the hospital for a 72-hour fast, which showed the lowest glucose level of 64 mg/dl with inappropriately high insulin of 22.2 µU/ml, low C-peptide of 0.57 ng/ml, and undetectable proinsulin of <1.6 pmol/L, but with IAA being >50 U/ml (0.0-0.4 U/ml). He was treated with intensive dietary counseling with a low-carbohydrate diet and prednisone 20 mg twice daily initially. Additionally, he could not tolerate octreotide, diazoxide, and acarbose due to side effects. He is currently on prednisone 10 mg daily and nifedipine with no further hypoglycemic episodes, but still has a high IAA of >50 U/ml and serum insulin levels of 70-112 µU/ml. Our case highlights the importance of recognizing hypoglycemia and checking for IAA levels as first-line diagnostic tests, in the absence of which there could be a delay in diagnosis and leading to unnecessary lab and imaging testing. Our case is unique since it happened in a Caucasian without any prior exposure to a triggering factor and has not undergone self-remission yet, which happens in most of IAS cases.

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Objective: The Scatchard plot of anti-insulin antibodies is curvilinear, indicating heterogeneity in binding sites. However, the relationship between bound insulin (B) and free insulin (F) in patients with anti-insulin antibodies has not yet been elucidated. This study aimed to determine this relationship. Methods: We studied two insulin-treated patients with diabetes who had high titers of anti-insulin antibodies. The B and F levels were measured using daily blood samples. Assuming that the law of mass action is applicable to the reactions between insulin and anti-insulin antibody forms, we plotted the bound-to-free ratio (B/F) vs. B using patient data. We also performed an equilibrium binding assay in vitro. Results: Some of the B/F vs. B plots of the daily variation showed an approximately linear relationship, while the Scatchard plots of in vitro data became curvilinear. Conclusion: Our study suggests that the one-site (high-affinity site) of anti-insulin antibodies accounts, for the most part, for insulin pharmacokinetics within physiological insulin concentrations. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-023-00641-1.

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INTRODUCTION: Exogenous insulin antibody syndrome (EIAS) rarely occurs in type 1 diabetes and should be considered in those with blood glucose levels outside the target range requiring greater than 2 units/kg/day of insulin without obesity. We describe the novel treatment of this condition using mycophenolate mofetil monotherapy in a pediatric patient in the outpatient setting. CASE PRESENTATION: A 17-year-old Caucasian male with type 1 diabetes experienced an abrupt increase in insulin requirements from 1.7 to 3.3 units/kg/day. Total insulin level was 7 µIU/mL with free insulin of 4.8 µIU/mL (68% of the total insulin), suggesting the presence of insulin antibodies. Switching from insulin aspart to glulisine was unsuccessful as insulin requirements increased to 4.4 units/kg/day. Treatment with oral mycophenolate mofetil decreased insulin requirements to 1.4 units/kg/day after 7 months. Total and free insulin levels improved to 5.2 and 4.6 µIU/mL, respectively (free insulin was 88% of total insulin). No adverse effects were encountered. CONCLUSION: Mycophenolate mofetil monotherapy is successful in safely treating EIAS in a pediatric patient.

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Development and characterization of guinea pig anti-insulin polyclonal antibody against a target-specific insulin antigen. In India, an insulin immunogenicity kit for detecting insulin antibodies (neutralizing Nab) is an unmet medical need for diabetic patient's routine diagnosis. Type 1 diabetics rely on insulin injections daily basis for survival; if the body develops anti-insulin antibodies and neutralizes the exogenous recombinant insulin, glucose control is lost, and the patient eventually dies. Antibodies are excellent diagnostic reagents due to the specificity and sensitivity they provide in recognizing specific and unique target antigens. The paper describes the use of insulin as a target antigen and the development of target (insulin) specific antibodies in guinea pigs for use as a positive control for immunogenicity kit validation. Anti-insulin polyclonal antibody was raised against insulin in the Dunkin Hartley guinea pigs host. Anti-insulin antibody titer of all bleeds from four animals was tested using an indirect ELISA assay format. All four animals responded to the target-specific antigen but only one animal (#4) responded with a high-affinity antibody titer. The hyperimmune sera were purified using a protein A column. The purified anti-insulin antibody was characterized through SDS Page and western blot. The specificity, reactivity, and antibody binding efficiency were confirmed through immunoassays. Guinea pig anti-insulin polyclonal antibody developed in this study showed good specificity, reactivity, and efficiency in the immunoassays. This paper describes the development and characterization of anti-insulin antibodies for use as a control in developing a user-friendly insulin immunogenicity kit.

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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.

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Background: Exogenous insulin antibody syndrome (EIAS) is an immunological disorder caused by circulating insulin antibodies (IAs), featuring hypersensitivity to exogenous insulin and insulin resistance. With the wide use of recombinant human insulin and insulin analogs, there has been a significant proliferation of EIAS. Case Report: We describe two cases of diabetes mellitus (DM) with hyperinsulinemia and high serum levels of IAs. They had never been exposed to methimazole, glutathione, lipoic acid, and other sulfhydryl drugs, but they all received insulin treatment. The patient in case 1 had recurrent hypoglycemia before hospitalization. A prolonged oral glucose tolerance test (OGTT) showed hypoglycemia with inappropriately high insulin levels. The patient in case 2 was hospitalized for diabetic ketosis. An OGTT indicated hyperglycemia with hyperinsulinemia and low levels of C-peptide. IAs induced by exogenous insulin in the two patients with DM were positive at high titers, prompting a diagnosis of another condition-EIAS. Conclusion: We discussed the differences between these two cases of EIAS in clinical manifestations and treatment and summarized all patients of EIAS treated in our department to date.

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Objective: This study aimed to investigate the clinical implications of fasting serum insulin (FINS) levels in subjects with type 2 diabetes who were receiving insulin therapy. Methods: A total of 1,553 subjects with type 2 diabetes [774 subjects who had never received insulin treatment (N-INS) and 779 subjects who were receiving insulin therapy (constant insulin treatment, C-INS)] admitted to the Department of Endocrinology and Metabolism of Peking University People's Hospital were enrolled in this study. Their FINS levels were measured and those with hyperinsulinemia were identified. The underlying mechanisms of hyperinsulinemia were revealed by measuring insulin antibodies (IAs) and analyzing changes in FINS levels before and after polyethylene glycol (PEG) precipitation. In addition, the clinical characteristics of patients with different types of hyperinsulinemia were compared. Results: Higher FINS levels and a higher incidence (43.8%, 341/779) of hyperinsulinemia (FINS > 15µIU/mL) were observed in subjects with C-INS than in subjects with N-INS. Among subjects with C-INS and hyperinsulinemia, 66.9% (228/341) were IAs positive, and the incidence of IAs was found to be positively associated with FINS level. By performing PEG precipitation, we found that all subjects without IAs (i.e., those with real hyperinsulinemia) and 31.1% of subjects (71/228) with IAs (i.e., those with both real and IAs-related hyperinsulinemia) still had hyperinsulinemia after PEG precipitation, whereas FINS levels in the other 68.9% of subjects (157/228) with IAs were normal (IAs-related hyperinsulinemia) after PEG precipitation. Comparisons between the groups showed that subjects with real hyperinsulinemia showed more obvious insulin resistance characteristics, including higher lipid levels, BMIs, and homoeostasis model assessment2-estimated insulin resistance (HOMA2-IR) index, and were more likely to have hypertension, obesity, and metabolic syndromes (p < 0.05). However, the risk of hypoglycemia and glucose variability increased significantly in subjects with IAs compared with those without IAs. A cutoff of FINS to serum C-peptide ratio (≥ 9.3µIU/ng) could be used to screen IAs in clinical practice with 83.3% sensitivity and 70% specificity. Conclusions: It is necessary to measure FINS in subjects with C-INS to distinguish between types of hyperinsulinemia, which should help to tailor treatment regimens.

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Purpose: This study aimed to further quantify the relationship between insulin antibodies (IAs) and the 2-hour insulin to C-peptide molar ratio (2h-ICPR) using a multiple linear regression model in T2DM patients. Methods: A total of 274 T2DM patients from April 2019 to December 2022 in Xiang'an Hospital of Xiamen University were included in this study. Multiple Linear Model Fitting was conducted on the candidate independent variables (age, BMI, HbA1c, and 2h-ICPR) for the multiple linear regression. The linear relationship between insulin antibodies (IAs) and the significant independent variables was presented by making multiple linear regression equations. Results: The total demographic characteristics of the included patients were as follows: age (51.92±13.10 years), BMI (24.94±3.99 kg/m2), HbA1c (9.70±2.39%), 2h-ICPR (0.12±0.11), and IAs (0.37±1.12COI). Linear relationships of independent variables: age (r=0.163, p=0.007), 2h-ICPR (r=0.259, p=0.001), BMI (r=0.007, p=0.907) and 2h-ICPR (r=0.092, p=0.129). Multiple linear regression: age (unstandardized ß=0.014, 95% CI: 0.004-0.024, p=0.004), 2h-ICPR (unstandardized ß=2.758, 95% CI: 1.555-3.962, p≤0.001). The regression equation: . Conclusion: The quantitative relationship between 2h-ICPR and insulin antibodies was . 2h-ICPR can be a preliminary screening indicator for insulin antibody testing in patients with type 2 diabetes.

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For diabetes patients, especially elderly diabetes patients, insulin is widely used as an important treatment to control hyperglycemia.However, since a high percentage of elderly diabetes patients use high doses of insulin, it is common to incur issues such as increased insulin resistance and inappropriate treatment.Exogenous insulin-induced autoantibody production is associated with severe insulin resistance and refractory hyperglycemia and hypoglycemia and is referred to as exogenous insulin antibody syndrome.With hypoglycemia, high insulin levels may be inconsistent with C-peptide levels.Increasing the dose of insulin to control blood glucose may be counterproductive.It is necessary to quickly and accurately make a diagnosis and make personalized adjustments to the glucose-lowering regimen to avoid serious consequences.

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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.

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Insulin antibodies (IAs) can cause glycemic variability. Islet transplantation (ITx) is a treatment for insulin-deficient diabetes that aims to establish on-target glycemic control in the absence of hypoglycemia. To date, there has not been a detailed case study of the association between ITx and IA levels. In this study, we identified a unique profile of IA titers, which differed from glutamic acid decarboxylase antibody titers, in four ITx patients. IA levels decreased with intensified immunosuppressive therapy, whereas glutamic acid decarboxylase antibodies increased transiently after ITx. These data suggest the possibility that IAs, unlike other islet autoantibodies, were eliminated due to immunosuppression after transplantation therapy. The disappearance of IAs, as well as the restoration of regulated insulin secretion after ITx, might have a positive effect on glycemic control in recipients with diabetes. Furthermore, this unique feature is suggestive of immunological pathogenesis and has implications for the treatment of IA-causing disease conditions.

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Single nucleotide polymorphisms (SNPs) in insulin and insulin receptor genes may influence the interaction between the two molecules, as may anti-insulin antibodies (IAs), commonly found in patients with type 1 diabetes mellitus (T1D) or type 2 diabetes mellitus (T2D) treated with exogenous insulin. We examined the impact of two SNPs in the human insulin gene (INS), rs3842752 and rs689, and two in the insulin receptor gene (INSR) rs2245649 and rs2229429, on disease susceptibility, glycaemic control, and IAs formation in 100 T1D patients and 101 T2D patients treated with insulin. 79 individuals without diabetes were typed as healthy controls. The minor alleles of rs3842752 and rs689 in INS protected against T1D (OR: 0.50, p = 0.01 and OR: 0.44; p = 0.002, respectively). The minor alleles of both rs2245649 and rs2229429 in INSR were risk factors for poor glycaemic control (HbA1c ≥ 80 mmol/mol) in T1D (OR: 5.35, p = 0.009 and OR: 3.10, p = 0.01, respectively). Surprisingly, the minor alleles of rs2245649 and rs2229429 in INSR associated strongly with the absence of IAs in T1D (OR = 0.28, p = 0.008 and OR = 0.30, p = 0.002, respectively). In conclusion, the minor alleles of the investigated INS SNPs protect against T1D, and the minor alleles of the investigated INSR SNPs are associated with poor glycaemic control and the absence of IAs in T1D.

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Autoantibodies against glutamic acid decarboxylase (GADA), tyrosine phosphatase-related islet antigen 2 (IA2A), insulin (INSA), and islet cells (ICA) are critical for determining the type of diabetes and management strategy in new-onset diabetes mellitus (NODM), but there have been few reports of all diabetes-associated autoantibody (DAA) in Korea. We retrospectively analyzed 193 patients with NODM aged 0 to 18 years who were followed at two tertiary centers in Korea (2017 to 2021). Patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) were 93 (48.2%) and 100 (51.8%), respectively. In T1DM patients, the DAA positivity rate was 94.6%; prevalence of GADA, IA2A, INSA, and ICA was 71.0%, 71.0%, 31.2%, and 10.8%, respectively; and IA2A added 10.7% point autoantibody positivity (83.9% for GADA+INSA+ICA and 94.6% for GADA+INSA+ICA+IA2A). Among the patients with T2DM, 12 (12.0%) were positive for DAA, and all were positive for INSA. These findings suggest that DAA at diagnosis, especially GADA and IA2A, is useful for classifying diabetes in Korean children and adolescents.

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Patients with diabetes mellitus having insulin antibodies (InsAb) with properties of high binding capacity and low affinity, which are observed in insulin autoimmune syndrome (IAS), are known to have greater plasma glucose fluctuations. Glycated albumin (GA) and the GA/HbA1c ratio have been demonstrated to reflect plasma glucose fluctuations. Hence, we hypothesized that GA or the GA/HbA1c ratio in diabetic patients having InsAb with properties of high binding capacity and low affinity may be higher than those in InsAb-negative diabetic patients, and we verified this hypothesis. Subjects were 12 diabetic patients who had InsAb noted while being treated with insulin and were subjected to Scatchard analysis and whose InsAb had properties similar to those of patients with IAS (affinity constant K1 < 0.24 × 1/10-8 M, number of binding sites R1 ≥ 11.5 × 10-8 M) [four cases of type 1 diabetes (T1D) and eight cases of type 2 diabetes (T2D)]. The control group consisted of T1D and T2D cases matched to the T1D and T2D cases, respectively, according to sex, age, BMI, and HbA1c. GA and the GA/HbA1c ratio were compared between both groups. GA and the GA/HbA1c ratio in InsAb-positive patients was significantly higher than that in the control group for both T1D and T2D patients. Diabetic patients having InsAb with properties of high binding capacity and low affinity had higher GA and the GA/HbA1c ratio than those of InsAb-negative patients. Greater plasma glucose fluctuations were suggested in InsAb-positive diabetic patients.

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ABSTRACT Insulin antibodies (IAs) induced by exogenous insulin rarely cause hypoglycemia. However, insulin autoantibodies (IAAs) in insulin autoimmune syndrome (IAS) can cause hypoglycemia. The typical manifestations of IAS are fasting or postprandial hypoglycemia, elevated insulin level, decreased C-peptide levels, and positive IAA. We report a 45-year-old male with type 1 diabetes mellitus (T1DM) treated with insulin analogues suffering from recurrent hypoglycemic coma and diabetic ketoacidosis (DKA). His symptoms were caused by exogenous insulin and were similar to IAS. A possible reason was that exogenous insulin induced IA. IA titers were 61.95% (normal: 300 mU/L and < 0.02 nmol/L when hypoglycemia occurred. Based on his clinical symptoms and other examinations, he was diagnosed with hyperinsulinemic hypoglycemia caused by IA. His symptoms improved after changing insulin regimens from insulin lispro plus insulin detemir to recombinant human insulin (Gensulin R) and starting prednisone.

Los anticuerpos contra la insulina (AI) inducidos por la insulina exógena raramente causan hipoglucemia. No obstante, los autoanticuerpos contra la insulina (AIA) en el síndrome autoinmune de insulina (SAI) pueden causar hipoglucemia. Las manifestaciones típicas del SAI son la hipoglucemia en ayunas o posprandial, niveles elevados de insulina, la disminución del nivel de péptido C y AIA positivos. Presentamos un paciente hombre de 45 años con diabetes mellitus de tipo 1 (DMT1) tratado con análogos de insulina, que sufría comas hipoglucémicos recurrentes y cetoacidosis diabética (CAD). Sus síntomas fueron causados por la insulina exógena y fueron similares al SAI. La posible razón fue que la insulina exógena indujo AI. El título de AI era del 61,95% (Normal: 300 mU/L y < 0,02 nmol/L cuando se producía la hipoglucemia. Basados en sus síntomas clínicos y otros exámenes, se le diagnosticó hipoglucemia hiperinsulinémica causada por la AI. Sus síntomas mejoraron después de cambiar el régimen de insulina de lispro más insulina detemir a insulina humana recombinante (Gensulin R) y de empezar a tomar prednisona.

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