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

Ryan A Lafferty,R Charlotte Moffett,Frank Reimann,Fiona M Gribble,Neil Tanday,Peter R Flatt,Nigel Irwin

doi:10.3389/fendo.2021.633625

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 Ins1 Cre/+;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 Ins1 Cre/+;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 Ins1 Cre/+; 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 Ins1 Cre/+;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 Ins1 Cre/+;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.

Highlights

Recent investigations have confirmed beneficial effects of sustained activation of pancreatic beta-cell neuropeptide Y1 receptors (NPY1R’s) on the growth, survival and overall secretory function of insulin-producing cells [1,2,3,4,5]
STZ induced a decline in body weight in GluCreERT2;Rosa26-eYFP and Ins1Cre/+;Rosa26-eYFP mice (Figures 1A, B)
Multiple low dose STZ administration resulted in characteristic pancreatic islet beta-cell destruction, acute insulin deficiency and elevations of blood glucose in both GluCreERT2; Rosa26-eYFP and Ins1Cre/+;Rosa26-eYFP transgenic mice

Summary

Introduction

Recent investigations have confirmed beneficial effects of sustained activation of pancreatic beta-cell neuropeptide Y1 receptors (NPY1R’s) on the growth, survival and overall secretory function of insulin-producing cells [1,2,3,4,5]. Recent elegant cell lineage tracing studies have highlighted the transitioning ability of mature islet alpha- and betacells, leading to alterations in islet architecture, especially in diabetes [10,11,12,13] Despite their conflicting roles in the control of blood glucose, alpha- and beta-cells share similar transcriptomes [14, 15], and it seems plausible that SL-PYY[136] might influence transdifferentiation of both cell types, to help elicit the observed NPY1R-mediated improvements in pancreatic islet morphology [4, 5, 16]. The present study was conducted using transgenic mice with alpha- and beta-cell lineage tracing capabilities, to investigate the contribution of transdifferentiation of alpha- and beta-cells to SL-PYY[1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36]induced improvements of pancreatic islet architecture in diabetes

Methods

Results

Discussion

Conclusion