The pro-hormone chromogranin A (CgA) and its cleavage product, the neuropeptide catestatin (CST) are linked to various cardiovascular and autoimmune diseases (T1D, IBD, RA) as biomarkers for disease severity. In these diseases, CgA and CST seem to affect inflammation, nerve communication, insulin resistance and hypertension. Since we found various CgA cleavage products leading towards CST in the pancreatic islet, we investigated how CgA and CST may modulate the pancreatic islet microenvironment and function. We show that CgA-KO and CST-KO mice have fewer insulin producing cells per islet and altered physiological islet function. To map the neurotransmitter microenvironment in the pancreatic islet and exocrine tissue we used spatial mass spectrometry that allowed us to identify neurotransmitter levels in and outside of the islets. Using this method, we show that endocrine cell homeostasis and insulin regulating pathways are disturbed in the pancreatic islets upon CgA or CST deletion. Thus, absence of CgA or CST in mice affects the endocrine composition and microenvironment of the pancreatic islet. Our findings contribute to understanding the role of CgA and CST in the pancreas with possible implications for the pathology of both type 1 and type 2 diabetes.

Loss of chromogranin A and catestatin affect pancreatic islet homeostasis, endocrine function, and neurotransmitters