Chromogranin A and catestatin regulate pancreatic islet homeostasis, endocrine function, and neurotransmitter signaling.

Chromogranin A (CgA), a neuroendocrine pro-hormone, is proteolytically cleaved into bioactive peptides, most notably catestatin (CST) and pancreastatin (PST), which exert opposing effects on metabolic and inflammatory processes. Using CgA- and CST knockout (KO) mice, we investigated the roles of these peptides in pancreatic endocrine function, morphology, neurotransmitter dynamics, and systemic glucose homeostasis. CST-KO mice displayed impaired insulin secretion in vivo (but not ex vivo), disrupted islet architecture, and elevated catecholamine levels. In contrast, CgA-KO mice, which lack both CST and PST, exhibited reduced beta-cell mass but improved insulin sensitivity due to absence of PST. Peptide supplementation experiments in CgA-KO mice revealed that CST suppressed gluconeogenesis and enhanced glucagon regulation, whereas PST promoted insulin resistance and glucose production. Spatial mass spectrometry further demonstrated altered neurotransmitter and polyamine profiles in KO islets, implicating disrupted nerve-immune-islet crosstalk as a contributor to the observed metabolic phenotypes. Collectively, these findings identify CgA-derived peptides as critical regulators of islet function and highlight CST as a promising therapeutic candidate for diabetes and metabolic-inflammatory disorders.