TY - JOUR
T1 - Neuropeptide Y1 receptor antagonism protects β-cells and improves glycemic control in type 2 diabetes
AU - Yang, Chieh Hsin
AU - Ann-Onda, Danise
AU - Lin, Xuzhu
AU - Fynch, Stacey
AU - Nadarajah, Shaktypreya
AU - Pappas, Evan G.
AU - Liu, Xin
AU - Scott, John W.
AU - Oakhill, Jonathan S.
AU - Galic, Sandra
AU - Shi, Yanchuan
AU - Moreno-Asso, Alba
AU - Smith, Cassandra
AU - Loudovaris, Thomas
AU - Levinger, Itamar
AU - Eizirik, Decio L.
AU - Laybutt, D. Ross
AU - Herzog, Herbert
AU - Thomas, Helen E.
AU - Loh, Kim
N1 - Funding Information:
This work was supported by the National Health and Medical Research Council of Australia in the form of a project grant #1158242 to KL. This work was also supported by a Diabetes Australia Project grant ( Y19G-LOHK ) and Australian Diabetes Society Skip-Martin Fellowships to KL. Supported in part by the Victorian Government's Operational Infrastructure Support Program . We thank all organ donors and their families, Donatelife and the staff of St Vincent's Institute involved in the human islet isolation program.
Publisher Copyright:
© 2021 The Author(s)
PY - 2022/1
Y1 - 2022/1
N2 - Objectives: Loss of functional β-cell mass is a key factor contributing to poor glycemic control in advanced type 2 diabetes (T2D). We have previously reported that the inhibition of the neuropeptide Y1 receptor improves the islet transplantation outcome in type 1 diabetes (T1D). The aim of this study was to identify the pathophysiological role of the neuropeptide Y (NPY) system in human T2D and further evaluate the therapeutic potential of using the Y1 receptor antagonist BIBO3304 to improve β-cell function and survival in T2D. Methods: The gene expression of the NPY system in human islets from nondiabetic subjects and subjects with T2D was determined and correlated with the stimulation index. The glucose-lowering and β-cell-protective effects of BIBO3304, a selective orally bioavailable Y1 receptor antagonist, in high-fat diet (HFD)/multiple low-dose streptozotocin (STZ)-induced and genetically obese (db/db) T2D mouse models were assessed. Results: In this study, we identified a more than 2-fold increase in NPY1R and its ligand, NPY mRNA expression in human islets from subjects with T2D, which was significantly associated with reduced insulin secretion. Consistently, the pharmacological inhibition of Y1 receptors by BIBO3304 significantly protected β cells from dysfunction and death under multiple diabetogenic conditions in islets. In a preclinical study, we demonstrated that the inhibition of Y1 receptors by BIBO3304 led to reduced adiposity and enhanced insulin action in the skeletal muscle. Importantly, the Y1 receptor antagonist BIBO3304 treatment also improved β-cell function and preserved functional β-cell mass, thereby resulting in better glycemic control in both HFD/multiple low-dose STZ-induced and db/db T2D mice. Conclusions: Our results revealed a novel causal link between increased islet NPY-Y1 receptor gene expression and β-cell dysfunction and failure in human T2D, contributing to the understanding of the pathophysiology of T2D. Furthermore, our results demonstrate that the inhibition of the Y1 receptor by BIBO3304 represents a potential β-cell-protective therapy for improving functional β-cell mass and glycemic control in T2D.
AB - Objectives: Loss of functional β-cell mass is a key factor contributing to poor glycemic control in advanced type 2 diabetes (T2D). We have previously reported that the inhibition of the neuropeptide Y1 receptor improves the islet transplantation outcome in type 1 diabetes (T1D). The aim of this study was to identify the pathophysiological role of the neuropeptide Y (NPY) system in human T2D and further evaluate the therapeutic potential of using the Y1 receptor antagonist BIBO3304 to improve β-cell function and survival in T2D. Methods: The gene expression of the NPY system in human islets from nondiabetic subjects and subjects with T2D was determined and correlated with the stimulation index. The glucose-lowering and β-cell-protective effects of BIBO3304, a selective orally bioavailable Y1 receptor antagonist, in high-fat diet (HFD)/multiple low-dose streptozotocin (STZ)-induced and genetically obese (db/db) T2D mouse models were assessed. Results: In this study, we identified a more than 2-fold increase in NPY1R and its ligand, NPY mRNA expression in human islets from subjects with T2D, which was significantly associated with reduced insulin secretion. Consistently, the pharmacological inhibition of Y1 receptors by BIBO3304 significantly protected β cells from dysfunction and death under multiple diabetogenic conditions in islets. In a preclinical study, we demonstrated that the inhibition of Y1 receptors by BIBO3304 led to reduced adiposity and enhanced insulin action in the skeletal muscle. Importantly, the Y1 receptor antagonist BIBO3304 treatment also improved β-cell function and preserved functional β-cell mass, thereby resulting in better glycemic control in both HFD/multiple low-dose STZ-induced and db/db T2D mice. Conclusions: Our results revealed a novel causal link between increased islet NPY-Y1 receptor gene expression and β-cell dysfunction and failure in human T2D, contributing to the understanding of the pathophysiology of T2D. Furthermore, our results demonstrate that the inhibition of the Y1 receptor by BIBO3304 represents a potential β-cell-protective therapy for improving functional β-cell mass and glycemic control in T2D.
KW - Insulin secretion
KW - NPY
KW - Type 2 diabetes
KW - Y1 receptor
KW - β-Cell
UR - https://www.scopus.com/pages/publications/85121996368
U2 - 10.1016/j.molmet.2021.101413
DO - 10.1016/j.molmet.2021.101413
M3 - Article
C2 - 34890851
AN - SCOPUS:85121996368
SN - 2212-8778
VL - 55
JO - Molecular Metabolism
JF - Molecular Metabolism
M1 - 101413
ER -
SDG 3 Good Health and Well-being