(DCP017) PROLACTIN RECEPTOR IS REQUIRED FOR BETA-CELL ADAPTATION TO A HIGH-FAT-DIET IN MULTIPAROUS FEMALE MICE

Background: Beta-cell adaptation to meet the increased insulin demand of metabolic stressors such as pregnancy and obesity is necessary for averting diabetes. Our lab has previously shown that prolactin receptor (Prlr) signaling is required for beta-cell adaptation to the insulin resistance of pregnancy, mainly by stimulating beta-cell proliferation and increasing beta-cell mass. This study aimed to elucidate whether Prlr signaling is required for beta-cell adaptation to insulin resistance beyond pregnancy.

METHODS AND RESULTS: Female mice with an inducible, beta-cell-specific homozygous deletion of Prlr (βPrlr-/-), as well as their wild type littermates (βPrlr+/+) are set up for pregnancies at age 12 weeks. After 2-3 pregnancies, they are placed on a control or a high fat diet (HFD, 60% calories from fat) for 12 weeks. This is to simulate the human experience where women often have more than one pregnancy followed by exposure to the ‘western diet’, which is high in fat content. Glucose homeostasis are assessed by oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) before and after 6 and 12 weeks of HFD. Pancreas or islets are isolated at the end of the experiment for assessment of molecular mechanisms involved.
We found that after 6 and 12 weeks of HFD, the Prlr-/- mice were glucose intolerant in comparison to their wild-type littermates. There was no difference in insulin tolerance. Islets from the HFD-Prlr-/- mice had a lower insulin content than islets from the HFD-βPrlr+/+ mice, and they secreted less insulin in-vivo during an OGTT, although there was no difference in ex-vivo glucose-stimulated insulin secretion. Moreover, the HFD-Prlr-/- mice had a lower beta-cell mass, accompanied by a lower beta-cell proliferation and a higher beta-cell apoptosis rate. Islets from HFD-Prlr-/- mice also expressed lower levels of anti-apoptotic genes (i.e. Bip, Ire-1, Esr1), insulin genes (Ins1, Ins2), as well as GLUT2 and incretin receptors (GIPR and GLP1R) in comparison to islets from HFD-βPrlr+/+ mice.

Conclusion: In addition to their important role in beta-cell adaptation to insulin resistance of pregnancy, intact prolactin receptor signaling is also required for beta-cell adaptation to a high fat diet, by regulating genes that control beta-cell function and survival.