Established and Emerging Roles Peptide YY (PYY) and Exploitation in Obesity-Diabetes

The antiobesity effects of activation of hypothalamic neuropeptide Y2 receptors (NPYR2) by the gut-derived hormone, peptide YY (PYY), are established. However, more recent insight into the biology of PYY has demonstrated remarkable benefits of sustained activation of pancreatic beta-cell NPYR1, that promises to open a new therapeutic avenue in diabetes. The therapeutic applicability of NPYR2 agonists for obesity has been considered for many years. An alternative pathway for the clinical realisation of PYY-based drugs could be related to the development of NPYR1 agonists for treatment of diabetes. Thus, although stimulation of NPYR1 on pancreatic beta-cells has immediate insulinostatic effects, prolonged activation of these receptors leads to well defined beta-cell protective effects, with obvious positive implications for the treatment of diabetes. In this regard, NPYR1-specific, long-acting enzyme resistant PYY analogues, have been recently developed with encouraging preclinical effects observed on pancreatic islet architecture in diabetes. In agreement, the benefits of certain types of bariatric surgeries on beta-cell function and responsiveness have also been linked to elevated PYY secretion and NPY1 receptor activation. Enzymatically stable forms of PYY, that selectively activate NPYR1, may have significant potential for preservation of beta-cell mass and the treatment of diabetes. [Abstract copyright: Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.]