Insulin immunotherapy for pretype 1 diabetes

Abstract

Purpose of review: Loss of tolerance to insulin likely contributes to the immunopathogenesis of type 1 diabetes (T1D). Several large clinical trials and smaller mechanistic studies have failed to demonstrate the efficacy of insulin antigen therapy. The growing awareness of the heterogeneity of T1D likely affects the response to various immune therapies including insulin. Identification of biomarkers of clinical response will provide further insight into mechanisms leading to the disease and classify responders in the quest for personalized therapy.

Recent findings: Several biomarkers have identified subpopulations in posthoc analyses that showed benefit from oral insulin even though the placebo-controlled study was as a whole unsuccessful. High insulin autoantibody titer, low first phase insulin response, and high Diabetes Prevention Trial-Type 1 Risk Score identify at-risk relatives more likely to benefit from oral insulin. Future incorporation of human leukocyte antigen and the variable number of tandem repeats polymorphism located in the insulin gene promoter (INS VNTR) is of interest for both primary and secondary prevention studies.

Summary: Although primary and secondary prevention trials using oral insulin are ongoing, those completed have been largely unsuccessful. However, we believe that oral insulin should be considered in future trials as part of combination therapies as prerandomization biomarker testing is refined.

Trial registration: ClinicalTrials.gov NCT02620072 NCT00336674 NCT02580877 NCT03364868.

Figure 1:

Schematic for determining whether individuals at high risk of progressing to type 1 diabetes (multiple autoantibody positive individuals) should go into a single non-antigen specific immune therapy arm (red box) or into a combination immune therapy arm (green box). The combination would include oral insulin after individuals were tested for the biomarkers (in the circle) that have a high likelihood of predicting those most likely to have success from oral insulin. Intermediate immune efficacy endpoints could be assessed 6–12 months after oral insulin initiation if excellent medication adherence present. If no insulin-specific immune effects are found, then that subject may elect to go to the non-antigen specific immune monotherapy arm to decrease participant burden.