Muntjewerff Elke M, Epremidze Dali, Nezhyva Mariya, Kal Satadeepa, Rohm Theresa V, Tang Kechun, Singh Kailash, Espes Daniel, Jati Suborno, Bootsma Marleen, Mannaa Atef Mahmoud, Ikebuchi Hiromi, Nilsson Anna M, Rajasekaran Mahadevan, Andrén Per E, Jansson Erik T, Mahata Sushil K, Christoffersson Gustaf
Department of Medical Cell Biology, Uppsala University, Sweden.
Department of Pharmaceutical Biosciences, Uppsala University, Sweden.
bioRxiv. 2025 Aug 27:2024.11.29.626063. doi: 10.1101/2024.11.29.626063.
Chromogranin A (CgA), a neuroendocrine pro-hormone, undergoes proteolytic cleavage to yield bioactive peptides, notably catestatin (CST) and pancreastatin (PST), which exert opposing effects on metabolic and inflammatory processes. Using CgA and CST knockout (KO) mice, this study investigated their roles in pancreatic endocrine function, morphology, neurotransmitter dynamics, and systemic glucose homeostasis. CST deficiency induced insulin resistance, altered islet architecture, and heightened catecholamine levels, whereas CgA-KO mice lacking both CST and PST exhibited improved insulin sensitivity due to absence of PST. CST suppressed gluconeogenesis and enhanced glucagon regulation, while PST promoted insulin resistance and glucose production. Spatial mass spectrometry revealed altered neurotransmitter and polyamine profiles in pancreatic islets, implicating disrupted nerve-immune-islet interactions. CST's modulation of catecholaminergic and inflammatory pathways positions it as a key regulator in the neuro-immune-endocrine axis. These findings highlight the therapeutic potential of targeting CgA-derived peptides, especially CST, for managing diabetes and metabolic-inflammatory diseases through precise peptide-based interventions.
嗜铬粒蛋白A（CgA）是一种神经内分泌前体激素，经蛋白水解切割产生生物活性肽，特别是抑癌素（CST）和胰抑制素（PST），它们对代谢和炎症过程具有相反的作用。本研究利用CgA和CST基因敲除（KO）小鼠，研究了它们在胰腺内分泌功能、形态、神经递质动力学和全身葡萄糖稳态中的作用。CST缺乏会导致胰岛素抵抗、胰岛结构改变以及儿茶酚胺水平升高，而同时缺乏CST和PST的CgA基因敲除小鼠由于不存在PST而表现出胰岛素敏感性提高。CST抑制糖异生并增强胰高血糖素调节，而PST促进胰岛素抵抗和葡萄糖生成。空间质谱分析显示胰岛中的神经递质和多胺谱发生改变，这表明神经-免疫-胰岛相互作用受到破坏。CST对儿茶酚胺能和炎症途径的调节使其成为神经-免疫-内分泌轴中的关键调节因子。这些发现突出了靶向CgA衍生肽，特别是CST，通过精确的基于肽的干预措施来治疗糖尿病和代谢性炎症疾病的治疗潜力。
