Impact of Ghrelin on Islet Size in Nonpregnant and Pregnant Female Mice

Abstract

Reducing ghrelin by ghrelin gene knockout (GKO), ghrelin-cell ablation, or high-fat diet feeding increases islet size and β-cell mass in male mice. Here, we determined if reducing ghrelin also enlarges islets in females, and if pregnancy-associated changes in islet size are related to reduced ghrelin. Islet size and β-cell mass were larger (P=0.057 for β-cell mass) in female GKO mice. Pregnancy was associated with reduced ghrelin and increased LEAP2 [a ghrelin receptor (GHSR) antagonist] in WT mice. Ghrelin deletion and pregnancy each increased islet size (by ∼19.9-30.2% and ∼34.9-46.4%, respectively), percentage of large islets (>25 µm2 x 103, by ∼21.8-42% and ∼21.2-41.2%, respectively) and β-cell mass (by ∼15.7-23.8% and ∼65.2-76.8%, respectively). Neither islet cross-sectional area, β-cell cross-sectional area, nor β-cell mass correlated with plasma ghrelin, although all positively correlated with LEAP2 (P=0.081 for islet cross-sectional area). In ad lib-fed mice, there was an effect of pregnancy, but not ghrelin deletion, to change (raise) plasma insulin without impacting blood glucose. Similarly, there was an effect of pregnancy, but not ghrelin deletion, to change (lower) blood glucose area under the curve during a glucose tolerance test. Thus, genetic deletion of ghrelin increases islet size and β-cell cross-sectional area in female mice, similar to males. Yet, despite pregnancy-associated reductions in ghrelin, other factors appear to govern islet enlargement and changes to insulin sensitivity and glucose tolerance in the setting of pregnancy. In the case of islet size and β-cell mass, one of those factors may be the pregnancy-associated increase in LEAP2.