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

Abstract

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.

A Peptide Triple Agonist of GLP-1, Neuropeptide Y1, and Neuropeptide Y2 Receptors Promotes Glycemic Control and Weight Loss

“…Interestingly, while administration of GEP12 did not result in a reduction in GLP-1R internalization, when evaluated in the presence of a Y1-R antagonist, it elicited increased insulin secretion in rat islets compared to results obtained with either GEP44 or Ex-4. These findings are consistent with the reduced rates of insulin secretion observed in islets in response to agonism at Y1-R (Yang, Ann-Onda et al 2022).…”

A new machine learning based computational framework identifies therapeutic targets and unveils influential genes in pancreatic islet cells

“…Some of these identified genes have played a key role in understanding the working mechanism of pancreatic cells [33, 34]. In Figure S2.2 in Supplementary Additional File 2, we identified four transcription factors-SP1, HDAC1, EGR1 and E2F1.…”

“…Figure 2 shows the highly connected subgraphs obtained from the PPI network, which include the following 16 genes: PPY, PYY, NPY, GNG12, BSG, HSP90AA1, HSPA8, RBM39, H1-2, HSP90AB1, RRM2, TUBBB, ATP5F1B, ACTB, SLC25A5, and EEF1A1. Some of these identified genes have played a key role in understanding the working mechanism of pancreatic cells [33,34]. In Figure S2.2 in Supplementary Additional File 2, we identified four transcription factors-SP1, HDAC1, EGR1 and E2F1.…”

Profiling of G-protein Coupled Receptors in Adipose Tissue and Differentiating Adipocytes Offers a Translational Resource for Obesity/Metabolic Research

“…Chemokines and chemokine receptors have long been associated with obesity-linked inflammation and insulin resistance and modulation of the chemokine/Chemokine receptor axis is considered a novel approach for the treatment of obesity and associated metabolic disorders (31)(32). Similarly, previous studies have reported increased expression of NPYR1 expression in adipose tissue of obese human subjects and high-fat diet-fed mice (34)(35). Moreover, selective antagonism of pe-ripheral NPYR1 was shown to prevent insulin resistance and other metabolic abnormalities in high-fat diet-fed mice (36)(37).…”

“…Many GPCRs in this list have previously been studied for their role in adipose biology. These include alpha-and beta-adrenergic receptors (11)(12)(13)(14)(15)(16), adenosine receptors (19), free fatty acid receptors (7,17,18), adhesion receptors (20,21), hydroxycarboxylic acid receptors (22,23), gastric inhibitory peptide (27)(28)(29), chemokine receptors (30)(31) and many others (32)(33)(34)(35). Interestingly, many GPCRs with notable expression profiles in adipose tissue and adipocytes have no known role in adipose metabolism.…”