Association of subclass distribution of insulin antibody with glucose control in insulin-treated type 2 diabetes mellitus: a retrospective observational study

Abstract

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.

Keywords: glycemic control; insulin antibody (IA); retrospective; subclass; type 2 diabetes.

Figure 1

Venn diagram showing the number of individuals tested positive for subclass-specific insulin antibodies (IgG, IgA, IgE, and IgM) (A) and isotype-specific IgG-IA (IgG1-4) and total IA (B). IA, insulin antibody.

Figure 2

Levels (ECL index) of IgG-IA (IgG1-4) (A) and IgA-IA, IgD-IA, IgE-IA, IgM-IA (B), and frequencies of positivity of different IA isotypes in patients detected positive for total IAs (C). The solid lines represent median values, and the dotted horizontal lines denote the threshold for positivity. ECL, electrochemiluminescence; IA, insulin antibody.

Figure 3

The boxplot showing the median change of FPG (A), 2hPG (B), HbA1c (C), weight (D), serum total insulin (E), and daily insulin dose (F) from baseline in IA-positive patients and IA-negative patients. FPG, fasting plasma glucose; 2hPG, 2-hour postprandial blood glucose; HbA1c, glycated hemoglobin. Data on serum fasting insulin measured before and post-insulin administration were available in 94 IA-positive and 407 IA-negative patients.

Figure 4

The boxplot showing the median change of FPG (A), 2hPG (B), HbA1c (C), weight (D), serum total insulin (E), and daily insulin dose (F) from baseline among different IA subclasses groups. NS, no significance; * P<0.05; ** P<0.005. FPG, fasting plasma glucose; 2hPG, 2-hour postprandial blood glucose; HbA1c, glycated hemoglobin. Data of serum fasting insulin measured prior to and post-insulin administration were available in 94 IA-positive patients.

Figure 5

Frequency of hypoglycemia or injection-site reactions in the IA-positive group and IA-negative group. NS, no significance; *** P < 0.0001; injection-site reaction, referring to skin itching, local redness and swelling, ecchymosis, subcutaneous nodules, and urticaria.

Figure 6

Frequency of hypoglycemia or injection-site reactions in the IA-positive group stratified by IA subclasses. (A) shows 2 of 6 (33.33%), 18 of 48 (37.50%), 4 of 7 (57.14%), and 6 of 37 (16.21%) patients with no subclass, IgG-IA alone, IgG-IA and IgM-IA, or IgG-IA, IgE-IA whether with or without other subclasses had hypoglycemia respectively. (B) shows 4 of 48 (8.30%), and 9 of 37 (24.32%) patients with IgG-IA only, or IgG-IA, IgE-IA, whether with or without other subclasses had injection-site reactions, respectively; other groups had no local responses.