Systemic metabolic alterations correlate with islet-level prostaglandin E2 production and signaling mechanisms that predict beta-cell dysfunction in a mouse model of type 2 diabetes

ABSTRACT: The transition from β-cell compensation to β-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 β-cell mass in T2D. The primary endogenous EP3 ligand is the arachidonic acid metabolite, prostaglandin E2 (PGE2). Pancreatic islet EP3 expression, expression of PGE2 synthetic enzymes, and/or PGE2 excretion itself have all been shown as up-regulated in primary mouse and human islets isolated from animals or human organ donors with established T2D as compared to non-diabetic 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 Leptinob/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 β-cell dysfunction.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Blood Plasma

DISEASE(S): Type 2 Diabetes Mellitus

SUBMITTER: Yanlong Zhu  

LAB HEAD: Ying Ge

PROVIDER: PXD022624 | Pride | 2021-09-09

REPOSITORIES: Pride