Emerging therapeutic potential for peptide YY for obesity-diabetes

Peptide YY (1–36) peptides from phylogenetically ancient fish targeting mammalian neuropeptide Y1 receptors demonstrate potent effects on pancreatic β‐cell function, growth and survival

“…However, the ability of sea lamprey PYY to restore both disturbed insulin and glucagon levels in diabetes is of significant clinical relevance. Thus, acute administration of NPYR1‐specific peptides is associated with insulinostatic actions and β‐cell rest, whereas prolonged activation of β‐cell NPYR1s promotes cell growth and survival, leading to significant elevations in basal and glucose‐stimulated insulin concentrations . Plasma CRP levels were unchanged, indicating lack of adverse inflammatory responses to fish peptides.…”

“…In conclusion, the present study has demonstrated that PYY (1–36) peptide sequences from phylogenetically ancient fish represent enzymatically stable, human NPYR1 modulators. The highly beneficial β‐cell effects of chronic NPYR1 activation were exemplified by sea lamprey PYY (1–36) treatment in STZ‐induced insulin deficient mice, and importantly lacked any proinflammatory effects. Further studies are required to assess the time‐course of these effects and relative contribution of β‐cell regeneration and β‐cell protection/recovery (both stimulated by PYY) to the final improved β‐cell mass and glucose response in the mice.…”

“…Indeed, there is a suggestion that the impressive endocrine pancreatic benefits following Roux‐en‐Y gastric bypass surgery are linked to altered PYY secretion and enhanced NPYR1 activity . As such, confirmed pancreatic effects of NPYR1 activation include inhibition of glucose‐stimulated insulin secretion to induce β‐cell rest, as well as promoting growth and survival of β cells . Since both major forms of diabetes mellitus, type 1 and type 2, are associated with β‐cell loss and/or dysfunction, agents mimicking the action of PYY (1–36) on pancreatic β cells could have distinct therapeutic usefulness.…”

“…14 As such, confirmed pancreatic effects of NPYR1 activation include inhibition of glucose-stimulated insulin secretion to induce β-cell rest, as well as promoting growth and survival of β cells. 13,15 Since both major forms of diabetes mellitus, type 1 and type 2, are associated with β-cell loss and/or dysfunction, 16,17 agents mimicking the action of PYY on pancreatic β cells could have distinct therapeutic usefulness. Consequently, N-terminally stabilized PYY (1-36) peptide analogues, resistant to DPP-4 degradation to maintain NPYR1 activity, are of particular interest.…”

Y1 receptor deficiency in β-cells leads to increased adiposity and impaired glucose metabolism

“…Although activation of Y1 receptor likely reduces insulin secretion from β-cells, which could be beneficial in type 2 diabetes 61 , this is unlikely to be the main factor to impaired glucose homeostasis in high fat fed Y1 lox/lox /INS2 cre/+ mice. On the other hand, the role of insulin in lipogenesis has been extensively studied using several animal models of obesity 62,63 .…”