The Cohen diabetic (CD) rat is a versatile animal model comprised of 2 rodent strains that manifest many of the common features of type 2 diabetes (T2D) in humans. The sensitive strain (CDs) develops diabetes within 30 days when maintained on a high sucrose/copper poor diet (HSD), whereas the resistant strain (CDr) retains normal blood glucose levels. Neither strain shows any signs of diabetes when provided regular rodent diet (RD). We aimed to conduct protein expression profiling of the CDr and CDs phenotypes, using electrophoresis and bi-directional immunological contrasting, to better understand the critical molecules involved in the disease development process, and to determine their roles in resistance or sensitivity to T2D in this model. Studies were implemented using whole cell extracts were prepared from pancreas, heart, spleen, kidney and muscle tissues obtained from both CDr and CDs rats fed either RD or HSD for 30 days. Using CDr-HSD and CDs-HSD pancreatic extracts and a proprietary immunization strategy, we developed a panel of murine monoclonal antibodies (mAbs) directed against differentially expressed proteins. Of 133 total hybridoma clones, 13 produced mAbs that were uniquely specific for only one of the pancreatic extracts by ELISA(4 against CDr-HSD and 9 against CDs-HSD). Using immunoblotting, we have identified several differentially expressed species: 50 kDa, 55 kDa and 60kDa proteins that are only evident in CDs-HSD pancreas, and a 75 and 80 kDa doublet with down regulated expression in CDs-HSD rats, particularly the 80 kDa isoform. Work is continuing to identify these differentially expressed biomarkers using trypsin digestion and liquid chromatography tandem mass spectrometry in an effort to determine their respective roles in resistance or susceptibility to disease. [ABSTRACT FROM AUTHOR]