Clinical, genetic, and proteomic characteristics of type 2 diabetes complicated with exogenous insulin antibody syndrome: a case-control study

Abstract

<p>Aims: 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. Methods: 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. Results: 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. Conclusions: 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.</p>