MON-542 - Stress Receptors and Glucose Metabolism: CRF2 as A Critical Regulator of Pancreatic Islet Function

Overnutrition and stress are recognized contributors to the development of obesity and type 2 diabetes (T2D). Stress can alter eating behaviors and increase the consumption of hyperpalatable foods. The peptide hormones corticotropin-releasing factor (CRF) and urocortins (UCN1–3), along with their two G protein-coupled receptors (GPCRs), CRF1 and CRF2, coordinate the physiological response to stress. CRF2 function is required to restore homeostasis following a stress response. CRF and UCNs also regulate a myriad of biological processes that range from cardiovascular and inflammatory functions to mental health and gastrointestinal disorders.
While UCN2 and UCN3 are known to regulate glucose homeostasis in animal models of T2D, the role of CRF2, the only known cognate receptor for both UCN2 and UCN3 in the pathogenesis of T2D remains uncharacterized. UCN3 is considered a marker for beta-cell maturity and function; it is released from beta-cells in mice and from both alpha-and beta-cells in humans. CRF2 is expressed on delta-cells in both mouse and human islets. The loss of CRF2 disrupts delta-cell influence on alpha- and beta-cells, likely through the reduced or lost function of somatostatin (SST).
Peripheral insulin resistance and insufficient insulin levels are hallmarks of diabetes. Paracrine signaling within the islets between alpha-, beta-, and delta-cells is essential for maintaining physiological glucose levels. Consequently, insulin release from beta-cells is tightly regulated by blood glucose levels and the paracrine and endocrine actions of neuropeptide hormones from the islets and gut. CRF2 signaling in delta-cells is activated by the paracrine action of UCN3 from beta-cells or the endocrine action of UCN2.
In this study, the role of CRF2 in mediating SST, glucagon, and insulin release in a cAMP-dependent manner was ascertained. Our data show that mice lacking CRF2 (Crhr2-/-) exhibit impaired glucose mobilization and fatty liver on standard chow, despite maintaining body weights equivalent to wild-type (WT) non-diabetic littermates; a high-fat diet (HFD) exacerbated these pre-diabetic outcomes. Islets from Crhr2-/- mice showed higher baseline insulin secretion compared to controls. Furthermore, pharmacological blockade of CRF2 in islets from non-diabetic human donors resulted in increased glucagon release following a glucose challenge. Preliminary metabolic analysis revealed that islets from Crhr2-/- mice exhibit a reduced capacity for ATP-linked respiration and an elevated extracellular acidification rate (ECAR), an indicator of lactate production. Additionally, the expression of Pdx-1 and Glut2 was increased in Crhr2-/- islets compared with wild type. Our findings will help elucidate how dysregulated stress receptor function impairs glucagon and insulin secretion, ultimately contributing to the development of metabolic syndrome and diabetes.

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