Novel role of PAQR4 in Pancreatic Beta Cell Function and Type 2 Diabetes

Insulin secretion from pancreatic â-cells is essential for maintaining glucose homeostasis, a process frequently disrupted in obesity-related type 2 diabetes (T2DM). Despite ongoing therapeutic advances, the prevalence of diabetes among U.S. adults rose to 15.8% in 2023, and current treatments, including GLP-1- based therapies, remain limited by side effects and inconsistent responsiveness. PAQR4 is an orphan receptor in the progestin and adiponectin receptor family (PAQR1-11) with a poorly defined role in metabolic diseases. We recently uncovered a novel role of PAQR4 in metabolic regulation by mediating ceramide homeostasis. PAQR4 promotes ceramide accumulation by regulating ceramide synthases. In adipocytes, PAQR4 overactivation impairs adipose tissue function and causes insulin resistance, whereas its deficiency lowers ceramide levels and improves insulin sensitivity in obesity. Elevated ceramides, a class of bioactive sphingolipids, promote lipotoxicity and drive â-cell dysfunction in T2DM. Our preliminary data show that PAQR4 expression in human islets increases with hyperglycemia and correlates negatively with INS (insulin) and GLP1R (GLP-1 receptor) but correlates positively with HbA1c levels. Supporting this, our pilot data in mice show that Paqr4 overexpression specifically in â-cells induces hyperglycemia and reduces insulin secretion and GLP-1 action. Based on these data, we hypothesize that PAQR4 is a key regulator of â-cell function by mediating ceramide metabolism, while chronic metabolic stress disrupts PAQR4-mediated ceramide balance and drives â-cell dysfunction. In Aim1, we will determine the impact of PAQR4 on â-cell function and systemic glucose homeostasis during metabolic stress. We will use human islets alongside our newly developed inducible, â-cell-specific gain- and loss-of-function mouse models to temporally investigate the role of PAQR4 in â-cell function, islet remodeling, and systemic metabolism. In Aim2, we will investigate how PAQR4 influences ceramide homeostasis and GLP-1 signaling in â-cell function. We will examine how PAQR4-mediated ceramide imbalance drives â-cell dysfunction by regulating cellular stress, insulin secretion and cell survival in mouse and human islets, and how activation the PAQR4-ceramide axis affects GLP-1R signaling and whether combining GLP-1R agonists with ceramide-targeting interventions improves â-cell function. Successful results in these studies will provide considerable mechanistic insights into ceramide homeostasis and â-cell function, and establish PAQR4 as a valuable therapeutic target for improving metabolic disorders associated with ceramide dysregulation. Project Number: 1P20GM156679-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Qingzhang Zhu (+1 co-PI) | Institution: UNIVERSITY OF KENTUCKY, LEXINGTON, KY | Award Amount: $269,500 | Activity Code: P20 | Study Section: Special Emphasis Panel[ZGM1 RCB-3 (C1)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11513763