Positive Effects of NPY1 Receptor Activation on Islet Structure Are Driven by Pancreatic Alpha- and Beta-Cell Transdifferentiation in Diabetic Mice

Abstract

Enzymatically stable and specific neuropeptide Y1 receptor (NPYR1) agonists, such as sea lamprey PYY(1-36) (SL-PYY(1-36)), are believed to improve glucose regulation in diabetes by targeting pancreatic islets. In this study, streptozotocin (STZ) diabetic transgenic GluCreERT2;ROSA26-eYFP and Ins1Cre/+;Rosa26-eYFP mouse models have been used to study effects of sustained NPYR1 activation on islet cell composition and alpha- and beta-cell lineage transitioning. STZ induced a particularly severe form of diabetes in Ins1Cre/+;Rosa26-eYFP mice, but twice-daily administration (25 nmol/kg) of SL-PYY(1-36) for 11 days consistently improved metabolic status. Blood glucose was decreased (p < 0.05 - p < 0.001) and both fasted plasma and pancreatic insulin significantly increased by SL-PYY(1-36). In both GluCreERT2;ROSA26-eYFP and Ins1Cre/+; Rosa26-eYFP mice, STZ provoked characteristic losses (p < 0.05 - p < 0.001) of islet numbers, beta-cell and pancreatic islet areas together with increases in area and central islet location of alpha-cells. With exception of alpha-cell area, these morphological changes were fully, or partially, returned to non-diabetic control levels by SL-PYY(1-36). Interestingly, STZ apparently triggered decreased (p < 0.001) alpha- to beta-cell transition in GluCreERT2;ROSA26-eYFP mice, together with increased loss of beta-cell identity in Ins1Cre/+;Rosa26-eYFP mice, but both effects were significantly (p < 0.001) reversed by SL-PYY(1-36). SL-PYY(1-36) also apparently reduced (p < 0.05) beta- to alpha-cell conversion in Ins1Cre/+;Rosa26-eYFP mice and glucagon expressing alpha-cells in GluCreERT2;ROSA26-eYFP mice. These data indicate that islet benefits of prolonged NPY1R activation, and especially restoration of beta-cell mass, are observed irrespective of diabetes status, being linked to cell lineage alterations including transdifferentiation of alpha- to beta-cells.

Beneficial metabolic effects of recurrent periods of beta‐cell rest and stimulation using stable neuropeptide Y1 and glucagon‐like peptide‐1 receptor agonists

“…18 However, the characteristic expansion of alpha-cell area and central internalisation of glucagon positively stained islet cells induced by STZ 48 were reversed only in the combined treatment group. Similar observations have been made previously with sub-chronic NPY1R activation, 21 suggesting restoration of the local islet environment, rather than augmentation of beta-cell mass alone, is a key benefit of NPY1R activation by SL-PYY. Indeed, positive effects on beta-cell turnover were not different between treatment groups and observed effects on beta-cell proliferation and protection against apoptosis agree with earlier studies on the effects of these peptides on beta-cell health.…”

“…In this regard, peptide tyrosine (PYY), a 36 amino acid gut‐derived peptide secreted from L‐cells, binds to neuropeptide Y1 receptors (NPY1Rs) expressed on pancreatic beta cells to induce insulinostatic actions that promote beta‐cell rest 18 . Moreover, NPY1R signalling has been shown to enhance beta‐cell growth and survival, 18,19 as well as evoking positive islet cell transdifferentiation events that enhance beta‐cell mass 20 . To pharmacologically exploit such actions, dipeptidyl peptidase‐4 (DPP‐4) stabilized analogues of human PYY (1–36) were generated through astute amino acid modification, based on current structure/function knowledge for PYY 21 .…”

“…Conversely, investigation of PYY gene structure from phylogenetically ancient fish identified highly conserved PYY sequences with inherent enzymatic stability 19 . In particular, sea lamprey PYY (1–36) replicated the pancreatic beta‐cell benefits of human PYY (1–36), leading to beta‐cell rest together with positive effects on islet cell turnover and lineage transition events 19,20 . Because C‐terminal degradation of PYY peptides abolishes bioactivity, 22,23 substitution of l ‐Arg with its enantiomer d ‐Arg, at position 35 in sea lamprey PYY (1–36), yielded an N‐ and C‐terminally enzyme‐resistant NPY1R compound that retained bioactivity, namely ( d ‐Arg 35 )‐sea lamprey PYY (1–36) (SL‐PYY) 24 …”

“…19 In particular, sea lamprey PYY (1-36) replicated the pancreatic beta-cell benefits of human PYY , leading to beta-cell rest together with positive effects on islet cell turnover and lineage transition events. 19,20 Because C-terminal degradation of PYY peptides abolishes bioactivity, 22,23 substitution of L-Arg with its enantiomer D-Arg, at position 35 in sea lamprey PYY , yielded an Nand C-terminally enzyme-resistant NPY1R compound that retained bioactivity, namely (D-Arg 35 )-sea lamprey PYY (1-36) (SL-PYY). 24 It follows that sequential administration of SL-PYY and liraglutide could represent a useful therapeutic approach to test in diabetes, building on previous positive observations in rodent models.…”

Neuropeptide Y1 receptor antagonism protects β-cells and improves glycemic control in type 2 diabetes

“…Indeed, failure to suppress NPY expression in β cells during metabolic stress was identified to be crucial in accelerating the programming of cell death [ 28 ]. Intriguingly, previous studies reported that treatment of Y receptor agonists, such as PYY administration, appears to protect islet β cells from apoptosis and dedifferentiation triggered by STZ in diabetic mice [ [13] , [14] , [15] , 32 ]. Considering that the administration of PYY in diabetic mice induced significant weight loss, the mechanism underlying PYY's β-cell protective effects is likely attributable to its anorexic effect acting via the Y2 receptor rather than via the Y1 receptor on the hypothalamus.…”