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

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.

 

Comments:

The objective of the study described is to investigate the role of the neuropeptide Y (NPY) system in type 2 diabetes (T2D) and evaluate the therapeutic potential of a Y1 receptor antagonist called BIBO3304 in improving beta-cell function and survival in T2D.

The researchers conducted several experiments to achieve their objectives. First, they analyzed the gene expression of the NPY system in human islets obtained from individuals without diabetes and those with T2D. They found that the expression of the NPY1R gene and its ligand, NPY, was more than two-fold higher in islets from subjects with T2D. This increase in gene expression was significantly correlated with reduced insulin secretion.

Next, the researchers examined the effects of BIBO3304, a selective Y1 receptor antagonist, in mouse models of T2D. They used two different models: one induced by a high-fat diet and multiple low-dose streptozotocin (STZ), and the other a genetically obese mouse model (db/db). BIBO3304 treatment led to improved glucose control and enhanced insulin action in skeletal muscle. Importantly, it also protected beta cells from dysfunction and death under the diabetogenic conditions in the islets. The treatment with BIBO3304 preserved functional beta-cell mass and improved beta-cell function in both mouse models, resulting in better glycemic control.

Based on these findings, the researchers concluded that there is a causal relationship between increased expression of the NPY-Y1 receptor in islets and beta-cell dysfunction and failure in human T2D. This insight contributes to the understanding of T2D pathophysiology. Additionally, the study demonstrates that inhibiting the Y1 receptor using BIBO3304 could be a potential therapeutic approach for protecting beta cells, improving functional beta-cell mass, and enhancing glycemic control in T2D.

It's worth noting that this is a summary of a hypothetical study, and the results and conclusions mentioned are fictional. However, it illustrates how the study could be structured and the potential findings that could arise from it.

Related Products

Cat.No. Product Name Information
E0014 BIBO 3304 Trifluoroacetate

BIBO 3304 Trifluoroacetate (BIBO-3304 TFA) is a novel neuropeptide Y Y1 receptor (NPY1R) antagonist with IC50 values of 0.38 nM and 0.72 nM for human Y1 receptor and rat Y1 receptor, respectively. BIBO 3304 shows low affinity for the human Y2 receptor, human and rat Y4 receptor as well as for the human and rat Y5 receptor (IC50 values >1000 nM).

Related Targets

NPY receptor