Internal medicine

Cell

Receptor

Prostaglandin

Ageing

Diabetes mellitus

Biology

Endocrinology

Type 2 diabetes

Insulin resistance

Insulin

Prostaglandin E

Prostaglandin E2

Blockade

Glucose homeostasis

Senescence

Biochemistry

Medicine

Nature Metabolism

β-cell dysfunction is a hallmark of type 1 and type 2 diabetes. Type 2 diabetes is strongly associated with ageing-related β-cell abnormalities that arise through unknown mechanisms. Here we show better β-cell identity, less β-cell senescence, enhanced glucose-stimulated insulin secretion and improved glucose homeostasis in global microsomal prostaglandin E synthase-2 (mPGES-2)-deficient mice challenged with a high-fat diet or bred with a genetic model of type 2 diabetes (db/db mice). Furthermore, the function of mPGES-2 in β-cells is validated using mice with β-cell-specific mPGES-2 deficiency or overexpression. Mechanistically, the protective role of mPGES-2 deletion is induced by antagonizing β-cell senescence via interference of the PGE2–EP3–NR4A1 signalling axis. We also discover an inhibitor of mPGES-2, SZ0232, which protects against β-cell dysfunction and diabetes, similar to mPGES-2 deletion. We conclude that mPGES-2 contributes to ageing-associated β-cell senescence and dysfunction via the PGE2–EP3–NR4A1 signalling axis. Pharmacologic blockade of mPGES-2 might be effective for treating ageing-associated β-cell dysfunction and diabetes. Zhong, Wan and Cai et al. show that deficiency of the microsomal prostaglandin E synthase-2 (mPGES-2) in pancreatic β-cells improves glucose metabolism and insulin secretion in mice by inhibiting β-cell senescence and dysfunction during diabetes.

mPGES-2 blockade antagonizes β-cell senescence to ameliorate diabetes by acting on NR4A1