<p>This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</p> <p>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
ofBlymphocytes and AIRAs in this model, a disrupted immunoglobulin heavy chain gene (<italic>Igh-6</italic>) 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 <italic>Igh-6</italic> 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 <italic>Igh-6</italic> intact males,
but not in Igh6<sup>null</sup> male serum. However, the absence of
B lymphocytes and antibodies distinguishing mutant from
wild-type males failed to significantly affect diabetes-free
survival. The Igh6<sup>null</sup>males gained weight less rapidly than
wild-type males, probably accounting for a retardation, but
not prevention, of hyperglycemia. Thus, AIRA and the Blymphocyte
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 <italic>Igh-6</italic> 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 (&gt; 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.</p>
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Exp Diabesity Res. 2004; 5(3):177-185