Physiologic and Endocrinologic Characterization of Male Sex-Biased Diabetes in C57BLKS/J Mice Congenic for the fat Mutation at the Carboxypeptidease E Locus

Abstract

The fat gene in mice represents a recessive mutation at the carboxypeptidase E (Cpe) locus. The mutant allele (Cpe ^fat ) encodes a highly unstable enzyme and produces an obesity phenotype characterized by attenuated processing of prohormones such as proinsulin that require this exopeptidase for full maturation. This article presents a preliminary physiologic and endocrinologic characterization of the stock of C57BLKS/LtJ-Cpe ^fat /Cpe ^fat mice at the backcross generation (N10) currently distributed by The Jackson Laboratory. Although previously reported not to be diabetogenic at N5, an additional five backcrosses to the C57BLKS/J background resulted in a male-biased development of both obesity and diabetes. Major differences distinguishing this mutant stock from the phenotypes produced by either the diabetes (Lepr ^db ) or obese (Lep ^ob ) mutations on the same inbred strain back-ground are lack of hyperphagia and hypercorticism, sensitivity of diabetic males to exogenous insulin, and a milder and male-biased diabetes syndrome that is not associated with widespread β-cell necrosis and islet atrophy, and that often remits with age.