Insulin antibodies (IAs) are prevalent in insulin-treated patients with diabetes and may cause immunological dysglycemia, known as exogenous insulin antibody syndrome (EIAS). This study aims to elucidate the clinical, genetic, and proteomic characteristics of patients with concurrent type 2 diabetes (T2D) and EIAS.

This was a case-control study with 177 IA-positive and 177 IA-negative T2D patients receiving insulin therapy. Among the IA-positive group, 46 patients with hypoglycemia and aberrantly elevated molar ratio of insulin to C-peptide (ICPR > 1) were identified as EIAS cases, followed with human leukocyte antigen (HLA) genotyping and plasma proteomic analysis by Olink platform.

Patients with EIAS exhibited greater glycemic variability than patients in other groups (IA-positive ICPR ≤ 1 or IA-negative). Higher ICPR was associated with increased glycemic variability in the IA-positive group. DRB1*0405-DQA1*03-DQB1*0401, DRB1*0803-DQA1*0103-DQB1*0601, and DRB1*1501-DQA1*0102-DQB1*0502 are the susceptible HLA haplotypes for EIAS. Additionally, nine differentially expressed proteins were identified in EIAS patients, with GALNT3, IL10, and CCL28 showing promising diagnostic performance.

IA-positive patients with remarkably elevated ICPR are prone to glycemic variability and should be evaluated for the diagnosis of EIAS. In this pilot study with limited sample size, EIAS is associated with unique HLA-DR-DQ risk haplotypes and enhanced immunoinflammatory response.

Premixed insulin combines two types of insulin in a single injection. This combination streamlines dosing for patients with type 1 or type 2 diabetes, thereby enhancing convenience. However, patients receiving premixed insulin commonly have less satisfactory blood glucose control. The fixed ratio of insulin in these formulations frequently fails to account for the nuanced demands of individualized glucose-lowering therapy. Moreover, local absorption of mixed insulin and potential systemic autoimmune responses may further compromise glycaemic control. The co-formulation of insulin degludec and insulin aspart introduces a new combination of the two insulin types within a single injection, offering a promising solution for mitigating the limitations inherent in premixed insulin.

Insulin autoimmune syndrome (IAS) is a rare cause of endogenous hyperinsulinemic hypoglycemia triggered by insulin autoantibodies. Through extensive research on IAS in recent years, it has been revealed that the use of exogenous insulin by diabetic patients can result in clinical manifestations similar to those of IAS. This phenomenon is known as exogenous IAS (EIAS). This article describes a case of a patient with EIAS who presented with atypical clinical manifestations. The patient, a middle-aged female with a 17-year history of type 2 diabetes, had been using Insulin Aspart 30 Injection for almost 10 years. She developed severe hyperinsulinemia, low C-peptide levels, positive insulin antibodies, poor postprandial glycemic control, and occasional autonomic nervous system symptoms such as hunger, palpitations, fatigue, and excessive sweating. Despite these symptoms, hypoglycemia was not detected. Switching the type of insulin for two weeks resulted in a significant reduction in insulin dosage, leading to stabilization of fasting and two-hour postprandial blood glucose levels within the target range. This article aims to alert medical professionals about diabetic patients who have hyperinsulinemia, insulin antibodies, and difficulty controlling blood sugar due to EIAS. It is crucial to prevent missed diagnoses, misdiagnoses, and potentially unnecessary surgical interventions through increased awareness.

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.

Insulin autoimmune syndrome (IAS) is a severe manifestation of spontaneous hypoglycemia. It is characterized by elevated levels of immune-reactive insulin and highly potent insulin autoantibodies (IAAs), which are induced by endogenous insulin circulating in the bloodstream. It is distinguished by recurring instances of spontaneous hypoglycemia, the presence of IAA within the body, a substantial elevation in serum insulin levels, and an absence of prior exogenous insulin administration. Nevertheless, recent studies show that both conventional insulin and its analogs can induce IAS episodes, giving rise to the notion of non-classical IAS. Therefore, more attention should be paid to these diseases.

In this case report, we present a rare case of non-classical IAS in an 83-year-old male patient who present with symptoms of a psychiatric disorder. Upon symptom onset, the patient exhibited Whipple's triad (including hypoglycemia, blood glucose level less than 2.8 mmol/L during onset, and rapid relief of hypoglycemic symptoms after glucose administration). Concurrently, his serum insulin level was significantly elevated, which contradicted his C-peptide levels. After a comprehensive examination, the patient was diagnosed with exogenous insulin autoimmune syndrome. Considering that the patient had type 2 diabetes mellitus and a history of exogenous insulin use before disease onset, it was presumed that non classical IAS was induced by this condition. The PubMed database was used to search for previous cases of IAS and non-classical IAS to analyze their characteristics and treatment approaches.

The occurrence of non-classical IAS is associated with exogenous insulin or its analogs, as well as with sulfhydryl drugs. Symptoms can be effectively alleviated through the discontinuation of relevant medications, administration of hormones or immunosuppressants, plasma exchange, and lifestyle adjustments.

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.

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.

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.

Exogenous insulin can induce insulin antibodies that have a low affinity/high binding capacity. Similar to what is observed in insulin autoimmune syndrome, these insulin antibodies can cause fasting hypoglycemia and postprandial hyperglycemia, a phenomenon known as "exogenous insulin antibody syndrome" (EIAS). Cases of EIAS in patients with type 1 and type 2 diabetes have been sporadically reported, mainly in Asia. However, there has been no report on EIAS in patients with diabetes secondary to total pancreatectomy treated with insulin analogs. A 74-year-old man with diabetes after total pancreatectomy had been treated with continuous subcutaneous insulin infusion using an insulin analog, lispro, and developed recurrent early morning hypoglycemia even after discontinuation of nocturnal basal insulin. His fasting serum lispro level was high even approximately 9 h after the last lispro dose. He had a high titer (72.7%) of insulin antibodies, and a Scatchard analysis revealed low affinity/high binding capacity. These findings suggested that the patient's recurrent early morning hypoglycemia was associated with insulin antibodies against lispro, and we, therefore, switched from lispro to another insulin analog, glulisine. His hypoglycemia improved, accompanied by a dramatic decrease in his insulin antibodies and serum glulisine levels. Early morning hypoglycemia in patients with diabetes secondary to total pancreatectomy may often be explained by high glycemic variability, malnutrition, and/or glucagon deficiency. However, in cases of recurrent early morning hypoglycemia, EIAS should be considered as a potential differential diagnosis.

The purpose of our study was to analyze the characteristics of OGTT and the correlation between the insulin to C-peptide molar ratio (ICPR), HOMA-IR and insulin antibodies (IAs) in T2DM patients.

A total of 77 T2DM patients were included and divided into the IA+ group (25 patients) and IA- group (52 patients). The values of serum glucose, insulin, and C-peptide testing during 2-h OGTT were summarized comparatively, and ROC was made to analyze the predictive value of ICPR for IAs.

At each time point of OGTT, there was no significant difference in serum glucose and C-peptide changes (p>0.05). Serum insulin levels in positive patients were elevated or not at different time points of the OGTT but ICPR was significantly different (P<0.05) in the two groups. Spearman correlation coefficient analysis showed that the presence of insulin antibodies was correlated with ICPR, but not with HOMA-IR, and ICPR-2h had a better prediction capacity (AUC=0.735, the optimal cutoff-point=0.11, Se=0.760, Sp=0.635).

T2DM patients with IAs showed no difference in serum glucose and serum C-peptide changes, but elevated or not insulin levels on the OGTTs, compared with negative patients. ICPR-2h can be a preliminary diagnostic index to timely predict IAs in T2DM patients.