Systemic Metabolic Alterations Correlate with Islet-Level Prostaglandin E2 Production and Signaling Mechanisms That Predict β-Cell Dysfunction in a Mouse Model of Type 2 Diabetes

The transition from beta-cell compensation to beta-cell failure is not well understood. Previous works by our group and others have demonstrated a role for Prostaglandin EP3 receptor (EP3), encoded by the Ptger3 gene, in the loss of functional beta-cell mass in Type 2 diabetes (T2D). The primary endogenous EP3 ligand is the arachidonic acid metabolite prostaglandin E-2 (PGE(2)). Expression of the pancreatic islet EP3 and PGE(2) synthetic enzymes and/or PGE(2) excretion itself have all been shown to be upregulated in primary mouse and human islets isolated from animals or human organ donors with established T2D compared to nondiabetic controls. In this study, we took advantage of a rare and fleeting phenotype in which a subset of Black and Tan BRachyury (BTBR) mice homozygous for the Leptin(ob/ob) mutation-a strong genetic model of T2D-were entirely protected from fasting hyperglycemia even with equal obesity and insulin resistance as their hyperglycemic littermates. Utilizing this model, we found numerous alterations in full-body metabolic parameters in T2D-protected mice (e.g., gut microbiome composition, circulating pancreatic and incretin hormones, and markers of systemic inflammation) that correlate with improvements in EP3-mediated beta-cell dysfunction.

Automated summary

In the transition from beta-cell compensation to beta-cell failure in Type 2 diabetes (T2D), the role of Prostaglandin EP3 receptor (EP3) and its ligand prostaglandin E-2 (PGE(2)) has been demonstrated. By studying a rare genetic model of T2D in mice, researchers found improvements in EP3-mediated beta-cell dysfunction correlated with changes in metabolic parameters and inflammation markers.