DC2421 - Sex Difference in Beta cell Adaptation to Metabolic Stress

Blinded Abstract: Beta-cell adapts to metabolic stressors by increasing insulin secretion to prevent diabetes. We have shown that prolactin receptor (Prlr) is required for β-cell adaptation to insulin resistance of pregnancy. Moreover, when multiparous Prlr-null (βPrlr-/-) female mice were challenged with a high fat diet (HFD), they became glucose intolerant. Interestingly, while Prlr signaling regulates beta-cell proliferation during pregnancy, Prlr signaling appears to regulate insulin content and incretin receptor expression in response to obesity. Whether Prlr signaling is also required for beta-cell adaptation to obesity in males is unknown. This study aimed to determine whether there are sex differences in the requirement of Prlr signaling in beta-cell adaptation to obesity. Using a transgenic mouse with an inducible, beta-cell-specific Prlr deletion, wild type (βPrlr+/+) and homozygous mutant (βPrlr-/-) multiparous female mice and male mice were placed on 12 weeks of HFD. In both females and male mice, we observed no difference in glucose tolerance between βPrlr+/+ and βPrlr-/- before starting on HFD, but males had significantly worse glucose tolerance than females. In comparison to βPrlr+/+ mice, female βPrlr-/- mice developed glucose intolerance after 6 weeks of HFD, a difference that persisted for the 12-week HFD treatment. Interestingly, we also observed a progressive worsening of glucose tolerance in βPrlr-/- mice given a control diet. In male βPrlr-/- mice, glucose tolerance deteriorated after 6 weeks of HFD but recovered by week-12 of HFD. These results suggest that Prlr signaling has an important but different role in beta-cell adaptation to HFD in both sexes.