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Diabetologia. 2017 Aug;60(8):1475-1482. doi: 10.1007/s00125-017-4276-5. Epub 2017 Apr 28.

Metabolically inactive insulin analogue does not prevent autoimmune diabetes in NOD mice.

Author information

1
Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases (NIAID) and Clinical Genomics Program, NIAID, National Institutes of Health, Building 10, Room 11D14, 10 Center Drive, Bethesda, MD, 20814, USA.
2
Novo Nordisk Type 1 Diabetes Center, Novo Nordisk Research Center, Seattle, WA, USA.
3
La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA.
4
Wellstat Diagnostics, Gaithersburg, MD, USA.
5
Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases (NIAID) and Clinical Genomics Program, NIAID, National Institutes of Health, Building 10, Room 11D14, 10 Center Drive, Bethesda, MD, 20814, USA. lenardo@nih.gov.

Abstract

AIMS/HYPOTHESIS:

Insulin is widely considered to be a driver antigen in type 1 diabetes in humans and in mouse models of the disease. Therefore, insulin or insulin analogues are candidates for tolerogenic drugs to prevent disease onset in individuals with risk of diabetes. Previous experiments have shown that autoimmune diabetes can be prevented in NOD mice by repeated doses of insulin administered via an oral, nasal or parenteral route, but clinical trials in humans have not succeeded. The hypoglycaemic activity of insulin is dose-limiting in clinical studies attempting tolerance and disease prevention. Here, we aimed to investigate the therapeutic potential of metabolically inactive insulin analogue (MII) in NOD mice.

METHODS:

The tolerogenic potential of MII to prevent autoimmune diabetes was studied by administering multiple i.v. or s.c. injections of MII to non-diabetic 7-12-week-old female NOD mice in three geographical colony locations. The incidence of diabetes was assessed from daily or weekly blood glucose measurements. The effect of MII on insulin autoantibody levels was studied using an electrochemiluminescence-based insulin autoantibody assay. The effect on the number of insulin-reactive CD8+ and CD4+ T lymphocytes in peripheral lymphoid tissue was studied with MHC class I and MHC class II tetramers, respectively.

RESULTS:

We found that twice-weekly s.c. administration of MII accelerates rather than prevents diabetes. High-dose i.v. treatment did not prevent disease or affect insulin autoantibody levels, but it increased the amount of insulin-reactive CD4+ T lymphocytes in peripheral lymphoid tissue.

CONCLUSIONS/INTERPRETATION:

Our data suggest that parenteral MII, even when used in high doses, has little or no therapeutic potential in NOD mice and may exacerbate disease.

KEYWORDS:

Autoimmune diabetes; Insulin; Non-obese diabetic mouse; Tolerance

PMID:
28455654
PMCID:
PMC5661969
DOI:
10.1007/s00125-017-4276-5
[Indexed for MEDLINE]
Free PMC Article

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