[P3]PP, a stable, long‐acting pancreatic polypeptide analogue, evokes weight lowering and pancreatic beta‐cell‐protective effects in obesity‐associated diabetes.

Aim: To thoroughly investigate the impact of sustained neuropeptide Y4 receptor (NPY4R) activation in obesity‐associated diabetes. Methods: Initially, the prolonged pharmacodynamic profile of the enzymatically stable pancreatic polypeptide (PP) analogue, [P3]PP, was confirmed in normal mice up to 24 h after injection. Subsequent to this, [P3]PP was administered twice daily (25 nmol/kg) for 28 days to high‐fat‐fed mice with streptozotocin‐induced insulin deficiency, known as HFF/STZ mice. Results: Treatment with [P3]PP for 28 days reduced energy intake and was associated with notable weight loss. In addition, circulating glucose was returned to values of approximately 8 mmol/L in [P3]PP‐treated mice, with significantly increased plasma insulin and decreased glucagon concentrations. Glucose tolerance and glucose‐stimulated insulin secretion were improved in [P3]PP‐treated HFF/STZ mice, with no obvious effect on peripheral insulin sensitivity. Benefits on insulin secretion were associated with elevated pancreatic insulin content as well as islet and beta‐cell areas. Positive effects on islet architecture were linked to increased beta‐cell proliferation and decreased apoptosis. Treatment intervention also decreased islet alpha‐cell area, but pancreatic glucagon content remained unaffected. In addition, [P3]PP‐treated HFF/STZ mice presented with reduced plasma alanine transaminase and aspartate transaminase levels, with no change in circulating amylase concentrations. In terms of plasma lipid profile, triglyceride and cholesterol levels were significantly decreased by [P3]PP treatment, when compared to saline controls. Conclusion: Collectively, these data highlight for the first time the potential of enzymatically stable PP analogues for the treatment of obesity and related diabetes. [ABSTRACT FROM AUTHOR]