Objective:The current study aimed to investigate the role of β and α1-adrenoceptors in pancreatic regulation of glucose homeostasis, apoptosis, and fibrosis in a rat model of dexamethasone-induced insulin resistance. Introduction:Insulin resistance is a hallmark of metabolic syndrome and is often linked to glucocorticoid excess. β- and α1-adrenoceptors are key modulators of glucose metabolism and tissue remodeling, yet their roles in pancreatic dysfunction under metabolic stress remain incompletely understood. Emerging evidence highlights β-arrestin2 as a key mediator of apoptosis and fibrosis beyond classical G protein signaling. Methods:Insulin resistance was induced in rats by subcutaneous dexamethasone (10 mg/kg/day) for 7 days. The therapeutic effects of carvedilol, phenylephrine, phenylephrine + carvedilol, propranolol, doxazosin, and doxazosin + propranolol were evaluated in relation to glucose homeostasis and pancreatic apoptotic/fibrotic signaling. Results and Conclusion:Dexamethasone impaired glucose homeostasis, expanded islet mass, and triggered pancreatic cell apoptosis and fibrosis via upregulated BAX/Bcl-2 expression ratio, downregulated cAMP, upregulated PKA, ERK1/2, and CREB expression with elevated PKB activity and reduced FOXO1 expression. % Level of β-arrestin2 was reduced in pancreatic islets and elevated in exocrine pancreas in relation to the aforementioned modulations. Blockade of β- or α1-adrenoceptors significantly ameliorated these effects, with combined blockade yielding superior benefits. Carvedilol’s effects were largely β-mediated, with minor α1 involvement. Low-dose phenylephrine yielded modest improvement, supporting a context-dependent, protective role of α1-adrenoceptor activation during metabolic stress. The dependence of drugs’ effects on β-arrestin2 highlights its potential as a central regulator of pancreatic remodeling and a promising target in IR-linked pathologies.