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

• DOI: 10.1016/j.molmet.2021.101413
• Publication Date: 2021-12-07T07:42:07Z
• Authors: Chieh-Hsin Yang; Danise Ann-Onda; Xuzhu Lin; Stacey Fynch; Shaktypreya Nadar...; Evan G. Pappas; Xin Liu; John W. Scott; Jonathan S. Oakhill; Sandra Galic; Yanchuan Shi; Alba Moreno-Asso; Cassandra Smith; Thomas Loudovaris; Itamar Levinger; Decio L. Eizirik; D. Ross Laybutt; Herbert Herzog; Helen E. Thomas; Kim Loh
• Keywords: Obstétrique; Male; 0301 basic medicine; 3101 Biochemistry and cell biology; insulin secretion; diabetes management; Institute for Health and Sport; 610; NPY; Glycemic Control; beta cell function; Brief Communication; Arginine; 576; Mice; 03 medical and health sciences; Gynécologie; Insulin-Secreting Cells; 616; Animals; Insulin; Neuropeptide Y; Obesity; Internal medicine; Y1 receptor; Insulin secretion; 3202 Clinical sciences; Type 2 diabetes; RC31-1245; Receptors, Neuropeptide Y; 3. Good health; Mice, Inbred C57BL; Glucose; Diabetes Mellitus, Type 2; Biologie cellulaire; b-Cell; type 2 diabetes; β-Cell

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 neuropeptide Y1 receptor improves islet transplantation outcome 1 (T1D). The aim this study was identify pathophysiological role Y (NPY) system human T2D and further evaluate therapeutic potential using antagonist BIBO3304 improve function survival T2D. gene expression NPY islets from nondiabetic subjects with determined correlated stimulation index. glucose-lowering β-cell-protective effects BIBO3304, selective orally bioavailable antagonist, high-fat diet (HFD)/multiple low-dose streptozotocin (STZ)-induced genetically obese (db/db) mouse models were assessed. In study, we identified more than 2-fold increase NPY1R its ligand, mRNA T2D, which significantly associated reduced insulin secretion. Consistently, pharmacological receptors by protected β cells dysfunction death under multiple diabetogenic conditions islets. preclinical demonstrated led adiposity enhanced action skeletal muscle. Importantly, treatment also improved preserved mass, thereby resulting better both HFD/multiple STZ-induced db/db mice. Our results revealed novel causal link between increased NPY-Y1 failure understanding pathophysiology Furthermore, our demonstrate represents therapy for improving