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 Type 2 diabetes (T2D). The primary endogenous EP3 ligand is the arachidonic acid metabolite prostaglandin E2 (PGE2). Expression of the pancreatic islet EP3 and PGE2 synthetic enzymes and/or PGE2 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 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.
Highlights
Type 2 diabetes (T2D) is characterized by a systemic loss of blood glucose homeostasis that is primarily linked to obesity, which is often associated with insulin resistance (IR)and systemic inflammation
prostaglandin E2 (PGE2) synthetic and signaling enzymes from WT, normoglycemic obese (NGOB), and T2D islets, where data are relative to β-actin, n = 4–6; and (E) glucose-stimulated insulin secretion from islets stimulated with 1.7 mM glucose or 16.7 mM glucose ±10 nM sulpro(E) glucose-stimulated insulin secretion from islets stimulated with 1.7 mM glucose or 16.7 mM glucose ±10 nM sulprostone
E2 (PGE2 ), a metabolite of arachidonic acid (AA) incorTo date, the BTBRob mouse has been understood as a model of severe T2D secondary porated into plasma membrane phospholipids, and PGE2 excretion have been found to be to β-cell failure, with a consistent, full disease penetrance by 16 weeks of age in both sexes upregulated in islets from T2D mice and humans compared to nondiabetic controls [3,19]
Summary
Type 2 diabetes (T2D) is characterized by a systemic loss of blood glucose homeostasis that is primarily linked to obesity, which is often associated with insulin resistance (IR). One of the most reproducible T2D models utilizes the Leptinob/ob mutation in the Black and Tan BRachyury (BTBR) mouse strain (BTBRob ) [3,4] In these mice, islet Ptger expression and PGE2 synthesis are dramatically upregulated, suppressing insulin secretion [3,4]. What physiological changes might transition islet EP3 signaling from protective to detrimental remain unknown It is well-known that BTBRob mice of both sexes rapidly and reproducibly become hyperglycemic because of underlying defects in both beta-cell function and skeletal muscle insulin sensitivity [6]. Combined with a significant upregulation of islet Ptger expression and the impact of an EP3-selective agonist on GSIS, our results link full-body metabolic derangements with the EP3-mediated β-cell dysfunction of T2D.
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