Exploring the Role of the E Prostanoid Receptor 3 in Type 2 Diabetes
Authors: Reuter Austin , Wisinski Jackie , Kimple Michelle 
Published: November 2023

Type 2 Diabetes (T2D) is a chronic disease where a person's body is either generating less than the normal amount of insulin and/or the cells of the body are no longer able to use insulin properly to cause glucose uptake. By comparing healthy islets to type 2 diabetic islets, the Kimple lab has discovered that, in T2D, human and mouse pancreatic islets have increased Ptger3 expression, a gene that encodes for Prostaglandin E2 receptor 3 (EP3). The EP3‐selective agonist, sulprostone, inhibits glucose stimulated insulin secretion from T2D mouse and human islets, but has no effect in islets isolated from lean mice or non‐diabetic human islet donors. Furthermore, the EP3‐selective antagonist, L798,106, potentiates glucose‐stimulated insulin secretion from diabetic mouse and human islets. To investigate the pathological upregulation of EP3 and its contribution to T2D pathophysiology, we used the BTBR ob/ob mouse model, which develops morbid obesity and severe T2D by 10 weeks of age. Pancreatic beta‐cell dysfunction in BTBR ob/ob islets is consistent with upregulation of islet EP3 and production of its endogenous ligand, prostaglandin E2 (PGE2). EP3 couples to a unique G protein, Gaz, and Gaz‐null mice are protected from developing hyperglycemia in a number of diabetic mouse models, including BTBR ob/ob. We hypothesized similar results would be found in Ptger3‐null mice, with pancreatic islets retaining a healthy phenotype, preventing or delaying the onset of T2D. In contrast to our hypothesis, Ptger3‐null ob/ob mice developed severe hyperglycemia by 10 weeks of age, just as wild‐type ob/ob mice. Interestingly, lean Ptger3‐null mice had a mild hyperglycemia that was intermediate between wild‐type lean mice and both BTBR ob groups. To explore the role of EP3 in glucose homeostasis, oral glucose and intraperitoneal insulin tolerance tests were performed. Upon insulin challenge at 8 weeks of age, Ptger3‐null ob/ob and wild‐type ob/ob are similarly and severely insulin resistant, while Ptger3‐null lean mice display significant insulin resistance compared to wild‐type lean mice. Oral glucose tolerance tests at 6 weeks of age revealed both Ptger3‐null and wild‐type BTBR ob/ob mice were severely glucose intolerant, while Ptger3‐null lean mice had mild glucose intolerance as compared to wild‐type lean mice. To investigate the islet phenotype more directly, we collected pancreata at 10 weeks of age and compared beta cell fractional area among the four groups, revealing a significant loss of beta‐cell mass in both BTBR ob/ob groups, with a more severe phenotype possible in the Ptger3‐null ob/ob mice. Taken together, our results suggest that EP3 expression in other body tissues besides the pancreatic islet is critically important for maintaining normal glucose homeostasis, and that in its absence, pancreatic beta‐cell loss is exacerbated by uncontrolled hyperglycemia and lipolysis. In sum, broadly targeting EP3 may not be a valid therapeutic strategy for T2D. A pancreatic beta‐cell specific Ptger3 knockout in the BTBR ob/ob model system will ultimately reveal the contribution of islet EP3 to T2D pathogenesis.

Support or Funding Information

NIH and American Diabetes Association