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Experimental Diabesity Research
Volume 5 (2004), Issue 3, Pages 177-185
http://dx.doi.org/10.1080/15438600490478029

Anti-Insulin Receptor Autoantibodies Are Not Required for Type 2 Diabetes Pathogenesis in NZL/Lt Mice, a New Zealand Obese (NZO)-Derived Mouse Strain

1Departments of Medicinal and Biological Chemistry and Pharmacology, College of Pharmacy, University of Toledo, 2801 W. Bancroft Street, BO 2833, Mail Stop 606, Toledo, OH 43606, USA
2Department of Pharmacology and Therapeutics, Medical College of Ohio, Toledo, Ohio, USA
3The Jackson Laboratory, Bar Harbor, Maine, USA
4University of Pittsburgh School of Medicine Diabetes Institute, Pittsburgh, Pennsylvania, USA

Received 30 March 2004; Accepted 24 April 2004

Copyright © 2004 Hindawi Publishing Corporation. 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.

Abstract

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 (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-6nullmales 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 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.