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.

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.

Recurrent hypoglycemic coma and diabetic ketoacidosis caused by insulin antibody. A rare case of type 1 diabetes mellitus.

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: < 5%), and the concentrations of insulin and C-peptide were > 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.

Recurrent hypoglycemic coma and diabetic ketoacidosis caused by insulin antibody: a rare case of type 1 diabetes mellitus / Hipoglicemia hiperinsulinémica causada por anticuerpos antiinsulina: informe de un caso

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.

Tolerant anti-insulin B cells are effective APCs.

Autoreactive B lymphocytes that are not culled by central tolerance in the bone marrow frequently enter the peripheral repertoire in a state of functional impairment, termed anergy. These cells are recognized as a liability for autoimmunity, but their contribution to disease is not well understood. Insulin-specific 125Tg B cells support T cell-mediated type 1 diabetes in NOD mice, despite being anergic to B cell mitogens and T cell-dependent immunization. Using this model, the potential of anergic, autoreactive B cells to present Ag and activate T cells was investigated. The data show that 1) insulin is captured and rapidly internalized by 125Tg BCRs, 2) these Ag-exposed B cells are competent to activate both experienced and naive CD4(+) T cells, 3) anergic 125Tg B cells are more efficient than naive B cells at activating T cells when Ag is limiting, and 4) 125Tg B cells are competent to generate low-affinity insulin B chain epitopes necessary for activation of diabetogenic anti-insulin BDC12-4.1 T cells, indicating the pathological relevance of anergic B cells in type 1 diabetes. Thus, phenotypically tolerant B cells that are retained in the repertoire may promote autoimmunity by driving activation and expansion of autoaggressive T cells via Ag presentation.

IL-10 diminishes CTLA-4 expression on islet-resident T cells and sustains their activation rather than tolerance.

IL-10, a powerful anti-Th1 cytokine, has shown paradoxical effects against diabetes. The mechanism underlying such variable function remains largely undefined. An approach for controlled mobilization of endogenous IL-10 was applied to the NOD mouse and indicated that IL-10 encounter with diabetogenic T cells within the islets sustains activation, while encounter occurring peripheral to the islets induces tolerance. Insulin beta-chain (INSbeta) 9-23 peptide was expressed on an Ig, and the aggregated (agg) form of the resulting Ig-INSbeta triggered IL-10 production by APCs, and expanded IL-10-producing T regulatory cells. Consequently, agg Ig-INSbeta delayed diabetes effectively in young NOD mice whose pathogenic T cells remain peripheral to the islets. However, agg Ig-INSbeta was unable to suppress the disease in 10-wk-old insulitis-positive animals whose diabetogenic T cells have populated the islets. This is not due to irreversibility of the disease because soluble Ig-INSbeta did delay diabetes in these older mice. Evidence is provided indicating that upon migration to the islet, T cells were activated and up-regulated CTLA-4 expression. IL-10, however, reverses such up-regulation, abolishing CTLA-4-inhibitory functions and sustaining activation of the islet T lymphocytes. Therefore, IL-10 supports T cell tolerance in the periphery, but its interplay with CTLA-4 sustains activation within the islets. As a result, IL-10 displays opposite functions against diabetes in young vs older insulitis-positive mice.

Effective use of gamma irradiation for pathogen inactivation of monoclonal antibody preparations.

Gamma irradiation has been used for decades as an effective method of pathogen inactivation of relatively inert materials. Until recently, its application to biologicals has resulted in unacceptable losses in functional activity. In this report we demonstrate that the damaging secondary effects of gamma irradiation can be controlled while maintaining the pathogen inactivation properties due to damage by primary effects. Control is achieved by a combination of protection from free radical damage to a monoclonal antibody through the use of the antioxidant ascorbate and by freeze-drying to minimize the potential for generating free radicals. The data demonstrate a synergy of these two approaches that results in quantitative recovery of functional activity while maintaining the ability to inactivate greater than 5 logs of porcine parvovirus infectivity.

Evaluación del fenómeno autoinmune y de las alteraciones metabolicas consecuentes durante el inicio de la diabetes mellitus insulino dependiente / Evaluation of the autoimmune phenomenon and the metabolies allerations consecuent during of the insulin dependent diabetes mellitus start

La Diabetes Mellitus Insulino Dependiente (DMID), se considera un desorden autoinmune de génesis multifactorial. La participación tumoral y celular en este fenómeno es fundamental, ya que la inactivación total o parcial de la células ß de los Islotes de Langherhans, depende del efecto que causen sobre ellas los diferentes Autoanticuerpos Antiislotes (ICAs), Autoanticuerpos Antiinsulina (IAA) y los Linfocitos Infiltrantes de los Islotes (ICIL). Existen haplotipos del Sistema HLA que confieren susceptibilidad para la DMID y otros que poseen acción protectora. La evaluación de las poblaciones de riesgo debe efectuarse a través de la detección de los citados anticuerpos, de la definición de los HLA (Regiones DR y DQ) y mediante estudios dinámicos que demuestren la reserva metabólica pancreática, tales como la Curva de Tolerancia Glucosada Endovenosa y la detección del Péptido C