Faculty Research 1980 - 1989

Title

The influence of genetic background on the expression of mutations at the diabetes locus in the mouse. IV. Male lethal syndrome in CBA/Lt mice.

Document Type

Article

Publication Date

1981

Keywords

Blood-Glucose: an, Body-Weight, Castration, Diabetes-Mellitus-Experimental: fg, Diet, Female, Gene-Expression-Regulation, Genes-Lethal, Insulin, Islands-of-Langerhans: pa, Male, Mice, Mice-Inbred-CBA: ge, Sex-Factors, Sex-Hormones: du, SUPPORT-NON-U-S-GOVT, SUPPORT-U-S-GOVT-P-H-S

JAX Source

Diabetes. 1981 Dec; 30(12):1035-44.

Grant

AM17631, AM27722

Abstract

To assess whether db-induced pathogenetic changes in beta-cells were restricted to mice with H-2d haplotype, the db gene from BL/Ks was transferred into the CBA/Lt subline (H-2k). A marked sexual dimorphism was observed in the diabetes syndrome in db/db animals. Young adult db/db males exhibited an early onset and completely lethal diabetes (100% mortality by 6 mo). At 3 mo db/db males were moderately obese (43 +/- 4 g) but severely hyperglycemic (475 +/- 69 mg/dl blood glucose) and hyperglucagonemic. Islets were atrophic, showing variable leukocytic infiltration. Although hyperinsulinemic at 2 mo, mutant males had only normal or below normal plasma insulin at 4 mo. Electron microscopic examination confirmed beta-cell necrosis and the appearance, in prenecrotic beta-cells, of numerous intracisternal type A (retrovirus) particles (IAP). In contrast, db/db females became increasingly obese with age but remained healthy, suffering no mortality in 6 mo. These mice were only transiently hyperglycemic and were able to sustain hyperinsulinemia. Light and electron microscopy revealed beta-cell hypertrophy that was not accompanied by increased numbers of IAP or by necrosis. Retrovirus infection therefore seemed a consequence rather than a cause of hyperglycemia. Ovariectomy coupled with testosterone injection failed to induce severe diabetes in females; castration failed to moderate male diabetes. Instead, biweekly injections of 25 micrograms each of 17 beta-estradiol and progesterone effected complete diabetes remission in males. Experiments using cultured CBA/J islet cells did not support the hypothesis that ovarian steroids were directly protective at the beta-cell level. This study shows that db gene-induced pathogenesis is not restricted to mice with the H-2d haplotype, and that sex steroids are important modifiers of syndrome severity.

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