Mechanisms of genetically-determined diabetes resistance and susceptibility in db/db mice

Aims/Hypothesis: Leptin receptor-deficient db/db mice are a commonly used research model and it is known that the genetic background, on which the mutation is bred, modulates the mice's phenotype. While diabetes-resistant strains exhibit persistent hyperinsulinemia, susceptible backgrounds show progressive hyperglycemia and islet involution. The primary mechanisms of this phenotypic difference however are not known. Differences in insulin resistance, beta cell function, proliferation and apoptosis possibly contribute. We hypothesized that following the phenotypic divergence between two strains of db/db mice with different susceptibility to diabetes would allow us to address this issue.

Methods: We studied C57BLKS/J (diabetes-susceptible) and C57BL/6 (diabetes-resistant) db/db mice and heterozygous controls from 5 to 12 weeks of age. We measured body weight, fasting blood glucose, plasma insulin, beta cell mass, beta cell proliferation and apoptosis.

Results: Comparable insulin resistance developed in the two db/db strains, which was well compensated for in both groups until 7 weeks of age. At 9 weeks C57BLKS/J mice became hyperglycaemic while a further increase of beta cell mass secured fasting hyperinsulinemia and normoglycaemia in C57BL/6. Correspondingly, a high rate of beta cell proliferation was sustained and islet cell apoptosis was low in this strain. Basal beta cell function was not significantly different between the two genetic backgrounds.

Conclusions: Genetically-determined diabetes resistance in db/db mice results from a continuous beta cell mass adaptation facilitated by sustained hyperproliferation and a low rate of apoptosis. Conversely, the age-dependent failure of this compensation is a major factor of diabetes susceptibility in this model.