Prostaglandin EP3 receptor signaling is required to prevent insulin hypersecretion and metabolic dysfunction in a non-obese mouse model of insulin resistance.

When homozygous for the mutation (Ob), Black-and-Tan Brachyury (BTBR) mice become morbidly obese and severely insulin resistant, and by 10 wk of age, frankly diabetic. Previous work has shown prostaglandin EP3 receptor (EP3) expression and activity is upregulated in islets from BTBR-Ob mice as compared with lean controls, actively contributing to their β-cell dysfunction. In this work, we aimed to test the impact of β-cell-specific EP3 loss on the BTBR-Ob phenotype by crossing floxed mice with the rat insulin promoter (RIP)-Cre driver strain. Instead, germline recombination of the floxed allele in the founder mouse-an event whose prevalence we identified as directly associated with underlying insulin resistance of the background strain-generated a full-body knockout. Full-body EP3 loss provided no diabetes protection to BTBR-Ob mice but, unexpectedly, significantly worsened BTBR-lean insulin resistance and glucose tolerance. This in vivo phenotype was not associated with changes in β-cell fractional area or markers of β-cell replication ex vivo. Instead, EP3-null BTBR-lean islets had essentially uncontrolled insulin hypersecretion. The selective upregulation of constitutively active EP3 splice variants in islets from young, lean BTBR mice as compared with C57BL/6J, where no phenotype of EP3 loss has been observed, provides a potential explanation for the hypersecretion phenotype. In support of this, high islet EP3 expression in Balb/c females versus Balb/c males was fully consistent with their sexually dimorphic metabolic phenotype after loss of EP3-coupled Gα protein. Taken together, our findings provide a new dimension to the understanding of EP3 as a critical brake on insulin secretion. Islet prostaglandin EP3 receptor (EP3) signaling is well known as upregulated in the pathophysiological conditions of type 2 diabetes, contributing to β-cell dysfunction. Unexpected findings in mouse models of non-obese insulin sensitivity and resistance provide a new dimension to our understanding of EP3 as a key modulator of insulin secretion. A previously unknown relationship between mouse insulin resistance and the penetrance of rat insulin promoter-driven germline floxed allele recombination is critical to consider when creating β-cell-specific knockouts.