Anti-insulin receptor autoantibodies are not required for type 2 diabetes pathogenesis in NZL/Lt mice, a New Zealand obese (NZO)-derived mouse strain.
The New Zealand obese (NZO) mouse strain shares with the related New Zealand black (NZB) strain a number of immunophenotypic traits. Among these is a high proportion of B-1 B lymphocytes, a subset associated with autoantibody production. Approximately 50% of NZO/HlLt males develop a chronic insulin-resistant type 2 diabetes syndrome associated with 2 unusual features: the presence of B lymphocyte-enriched peri-insular infiltrates and the development of anti-insulin receptor autoantibodies (AIRAs). To establish the potential pathogenic contributions of B lymphocytes and AIRAs in this model, a disrupted immunoglobulin heavy chain gene (Igh-6) congenic on the NZB/BlJ background was backcrossed 4 generations into the NZO/HlLt background and was then intercrossed to produce mice that initially segregated for wild-type versus the mutant Igh-6 allele and thus permitted comparison of syndrome development. A new flow cytometric assay (AIRA binding to transfected Chinese hamster ovary cells stably expressing mouse insulin receptor) showed IgM and IgG subclass AIRAs in serum from Igh-6 intact males, but not in Igh-6null male serum. However, the absence of B lymphocytes and antibodies distinguishing mutant from wild-type males failed to significantly affect diabetes-free survival. The Igh-6null males gained weight less rapidly than wild-type males, probably accounting for a retardation, but not prevention, of hyperglycemia. Thus, AIRA and the B-lymphocyte component of the peri-insulitis in chronic diabetics were not essential either to development of insulin resistance or to eventual pancreatic beta cell failure and loss. A new substrain, designated NZL, was generated by inbreeding Igh-6 wild-type segregants. Currently at the F10 generation, NZL mice exhibit the same juvenile-onset obesity as NZO/HlLt males, but develop type 2 diabetes at a higher frequency (> 80%). Also, unlike NZO/HlLt mice that are difficult to breed, the NZL/Lt strain breeds well and thus offers clear advantages to obesity/diabetes researchers.
McInerney
Marcia F
MF
Department of Medicinal and Biological Chemistry, University of Toledo College of Pharmacy, Toledo, OH 43606, USA. mmciner@utnet.utoledo.edu
Najjar
Sonia M
SM
Brickley
Deanna
D
Lutzke
Mary
M
Abou-Rjaily
George A
GA
Reifsnyder
Peter
P
Haskell
Bradford D
BD
Flurkey
Kevin
K
Zhang
Ying-Jian
YJ
Pietropaolo
Susan L
SL
Pietropaolo
Massimo
M
Byers
James P
JP
Leiter
Edward H
EH
D000818:Animals; D001323:Autoantibodies / Q000378:metabolism*; D001402:B-Lymphocytes / Q000473:pathology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D005803:Genes, Immunoglobulin / Q000235:genetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics; D011972:Receptor, Insulin / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
D001323:Autoantibodies; D011972:Receptor, Insulin