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Ann N Y Acad Sci. 2006 Oct;1079:122-9.

Long-term prevention of diabetes and marked suppression of insulin autoantibodies and insulitis in mice lacking native insulin B9-23 sequence.

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  • 1Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, P.O. Box 6511, Aurora, CO 80045, USA.


We analyzed double native insulin gene knockout NOD mice with a mutated (B16:alanine) proinsulin transgene at multiple ages for the development of insulin autoantibodies, insulitis, and diabetes. In contrast to mice with at least one copy of a native insulin gene that expressed insulin antibodies, only 2 out of 21 (10%) double native insulin gene knockout mice with a mutated insulin transgene developed insulin autoantibodies. Of 21 double insulin knockout mice sacrificed between 10 to 48 weeks of age, only 5 showed minimal insulitis versus 100% of wild-type NOD and more than 90% of insulin 1 knockout mice. Consistent with robust suppression of insulin autoantibodies and insulitis, no double insulin knockout mice developed diabetes. In that the B9-23 peptide with B16A is an altered peptide ligand inducing Th2 responses, we analyzed transfer of splenocytes into NOD.SCID mice. There was no evidence for regulatory T cells able to inhibit transfer of diabetes by diabetogenic NOD splenocytes. Insulin peptide B9-23 is likely a crucial target for initiation of islet autoimmunity and further mutation of the sequence will be tested to attempt to eliminate all anti-islet autoimmunity.

[PubMed - indexed for MEDLINE]
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