Diabetologia

, Volume 60, Issue 8, pp 1475–1482

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

  • Juha Grönholm
  • Philippe P. Pagni
  • Minh N. Pham
  • Claire B. Gibson
  • Paul F. Macomber
  • José Luis Vela
  • Matthias von Herrath
  • Michael J. Lenardo
Article

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 

Abbreviations

APC

Antigen presenting cell

ECL

Electrochemiluminescence

HEL

Hen egg lysozyme

IGRP

Islet-specific glucose-6-phosphatase catalytic subunit-related protein

MII

Metabolically inactive insulin analogue

NNRC

Novo Nordisk Research Center

PD-L1

Programmed death-ligand 1

RICD

Re-stimulation-induced cell death

Supplementary material

125_2017_4276_MOESM1_ESM.pdf (577 kb)
ESM 1(PDF 576 kb)

Copyright information

© Springer-Verlag (outside the USA) 2017

Authors and Affiliations

  • Juha Grönholm
    • 1
  • Philippe P. Pagni
    • 2
    • 3
  • Minh N. Pham
    • 2
  • Claire B. Gibson
    • 2
  • Paul F. Macomber
    • 4
  • José Luis Vela
    • 2
  • Matthias von Herrath
    • 2
  • Michael J. Lenardo
    • 1
  1. 1.Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases (NIAID) and Clinical Genomics Program, NIAIDNational Institutes of HealthBethesdaUSA
  2. 2.Novo Nordisk Type 1 Diabetes CenterNovo Nordisk Research CenterSeattleUSA
  3. 3.La Jolla Institute for Allergy and ImmunologyLa JollaUSA
  4. 4.Wellstat DiagnosticsGaithersburgUSA

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