Estrogenization of insulin by catecholestrogen produced high affinity autoantibodies and altered the normal function of insulin in type 1 diabetes

• Published in: Life sciences (1973) Vol. 256; p. 117910
• Main Authors: Khan, Wahid Ali, Malik, Arshi, Khan, Mohd. Wajid Ali
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01-09-2020; Elsevier BV
• Subjects: 4-Hydroxyestradiol; Adult; Affinity; Antigens; Autoantibodies; Autoantibodies - immunology; Autoantibodies - metabolism; Autontibodies; Binding; Biomarkers; Biomarkers - metabolism; Blood Glucose - analysis; Blood Specimen Collection; Carbohydrates; Competitive Bidding; Diabetes; Diabetes mellitus; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - drug therapy; ELISA; Enzyme-Linked Immunosorbent Assay; Estrogens, Catechol - chemistry; Estrogens, Catechol - therapeutic use; Female; Humans; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - therapeutic use; Insulin; Insulin - chemistry; Insulin - therapeutic use; Insulin Resistance; Male; Middle Aged; Receptor, Insulin - immunology; Receptor, Insulin - metabolism; Sensitivity and Specificity; Titration; Type 1 diabetes; FELASA; 4-OHE2; 4-OHE2-Ins; Autontibodies; T1D; IR; EDTA; Insulin; Ins; CEs; 4-Hydroxyestradiol; BSA; SDS-PAGE; 2-OHE2-Ins; Type 1 diabetes; GADA; 4-OHE2-Ins-IR; 16α-OHE2-Ins; DMF; 4-OHE2-Ins-T1D IgG; Ins-IR; Ins-T1D IgG; ELISA
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2020.117910

Insulin (Ins) covalently modified by catecholestrogens (CEs) was commonly found in diabetic patients who have developed insulin resistance. Estrogenization of insulin altered its molecular function and effect carbohydrates metabolisms in these patients. Insulin resistance is a common phenomenon in diabetes but the exact mechanism remains unknown. In this study, binding specificity and affinity of autoantibodies against estrogenized insulin (4-hydroxyestradiol-insulin; 4-OHE2-Ins) were assayed in the serum of type 1 diabetes (T1D) patients in order to explain the phenomena behind insulin resistance.
Specificity and affinity of autoantibodies from the sera of 66 T1D patients and 41 controls were analyzed by direct binding, competition ELISA and quantitative precipitin titration. Insulin was also estimated in the serum of T1D patients by ELISA.
Estrogenized insulin (4-OHE2-Ins) exhibited high affinity and specificity to T1D autoantibodies in comparison to Ins (p < .05) or 4-OHE2 (p < .001). Estrogenization of insulin alters its interaction with the insulin receptor (IR). The affinity constant of 4-OHE2-Ins with the T1D autoantibodies was found to be 1.41 × 10−7 M.
Estrogenization of insulin by catecholestrogen makes these molecules highly antigenic and produced high-affinity autoantibodies in T1D patients. As a result, patients develop insulin resistance and presented this molecule as a potential biomarker for T1D.
•Estrogenized insulin (4-OHE2-Ins) exhibited high affinity and specificity for T1D autoantibodies.•Estrogenization of insulin alters the normal functions of the insulin in T1D patients•Estrogenization of insulin in the blood produced autoantibodies; as a result insulin resistance is developed in T1D patients