[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.

Novel enzyme-resistant pancreatic polypeptide analogs evoke pancreatic beta-cell rest, enhance islet cell turnover, and inhibit food intake in mice.

Pancreatic polypeptide (PP) is a postprandial hormone secreted from pancreatic islets that activates neuropeptide Y4 receptors (NPY4Rs). PP is known to induce satiety but effects at the level of the endocrine pancreas are less well characterized. In addition, rapid metabolism of PP by dipeptidyl peptidase-4 (DPP-4) limits the investigation of the effects of the native peptide. Therefore, in the present study, five novel amino acid substituted and/or fatty acid derivatized PP analogs were synthesized, namely [P3]PP, [K13Pal]PP, [P3,K13Pal]PP, [N-Pal]PP, and [N-Pal,P3]PP, and their impact on pancreatic beta-cell function, as well as appetite regulation and glucose homeostasis investigated. All PP analogs displayed increased resistance to DPP-4 degradation. In addition, all peptides inhibited alanine-induced insulin secretion from BRIN-BD11 beta cells. Native PP and related analogs (10-8 and 10-6 M), and especially [P3]PP and [K13Pal]PP, significantly protected against cytokine-induced beta-cell apoptosis and promoted cellular proliferation, with effects dependent on the NPY4R for all peptides barring [N-Pal,P3]PP. In mice, all peptides, except [N-Pal]PP and [N-Pal,P3]PP, evoked a dose-dependent (25, 75, and 200 nmol/kg) suppression of appetite, with native PP and [P3]PP further augmenting glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK) induced reductions of food intake. The PP peptides had no obvious detrimental effect on glucose tolerance and they did not noticeably impair the glucose-regulatory actions of GLP-1 or CCK. In conclusion, Pro3 amino acid substitution of PP, either alone or together with mid-chain acylation, creates PP analogs with benefits on beta-cell rest, islet cell turnover, and energy regulation that may be applicable to the treatment of diabetes and obesity.

Pancreatic polypeptide revisited: Potential therapeutic effects in obesity-diabetes.

Pancreatic polypeptide (PP), a member of the neuropeptide Y (NPY) family of peptides, is a hormone secreted from the endocrine pancreas with established actions on appetite regulation. Thus, through activation of hypothalamic neuropeptide Y4 (NPY4R or Y4) receptors PP induces satiety in animals and humans, suggesting potential anti-obesity actions. In addition, despite being actively secreted from pancreatic islets and evidence of local Y4 receptor expression, PP mediated effects on the endocrine pancreas have not been fully elucidated. To date, it appears that PP possesses an acute insulinostatic effect, similar to the impact of other peptides from the NPY family. However, it is interesting that prolonged activation of pancreatic Y1 receptors leads to established benefits on beta-cell turnover, preservation of beta-cell identity and improved insulin secretory responsiveness. This may hint towards possible similar anti-diabetic actions of sustained Y4 receptor modulation, since the Y1 and Y4 receptors trigger comparable cell signalling pathways. In terms of exploiting the prospective therapeutic promise of PP, this is severely restricted by a short circulating half-life as is the case for many regulatory peptide hormones. It follows that long-acting, enzyme resistant, forms of PP will be required to determine viability of the Y4 receptor as an anti-obesity and -diabetes drug target. The current review aims to refocus interest on the biology of PP and highlight opportunities for therapeutic development.