Chromogranin B regulates early-stage insulin granule trafficking from the Golgi in pancreatic islet β-cells

Abstract

Chromogranin B (CgB, also known as CHGB) is abundantly expressed in dense core secretory granules of multiple endocrine tissues and has been suggested to regulate granule biogenesis in some cell types, including the pancreatic islet β-cell, though the mechanisms are poorly understood. Here, we demonstrate a critical role for CgB in regulating secretory granule trafficking in the β-cell. Loss of CgB impairs glucosestimulated insulin secretion, impedes proinsulin processing to yield increased proinsulin content, and alters the density of insulin-containing granules. Using an in situ fluorescent pulse-chase strategy to track nascent proinsulin, we show that loss of CgB impairs Golgi budding of proinsulin-containing secretory granules, resulting in a substantial delay in trafficking of nascent granules to the plasma membrane with an overall decrease in total plasma membrane-associated granules. These studies demonstrate that CgB is necessary for efficient trafficking of secretory proteins into the budding granule, which impacts the availability of insulin-containing secretory granules for exocytic release. This article has an associated First Person interview with the first author of the paper.

Insulin granule biogenesis and exocytosis

“…Numerous proteins of importance for proinsulin condensation have been identified, including chromogranin A (CHGA), chromogranin B (CHGB) and VGF. Mice lacking CHGB exhibit reduced glucose-stimulated insulin secretion, and similar defects are seen in islets and clonal β-cells following transient knockdown of CHGB [ 12 , 13 ]. Mechanistically, loss of CHGB does not affect ISG biogenesis but it impairs proinsulin processing, leading to reduced insulin content [ 12 ].…”

Strain-based and sex-biased differences in adrenal and pancreatic gene expression between KK/HlJ and C57BL/6 J mice

“…Furthermore, the biogenesis of DCVs are under the control of Chromogranin B (CHGB) [66], which also exhibited increased gene expression in the adrenal and pancreatic tissues of the KK/ HlJ mice. Recent studies have shown that siRNAtargeted loss of CHGB in vitro impairs glucosestimulated insulin secretion and reduces the density of insulin-containing granules [67]. Additionally, in the adrenal gland loss of CHGB in knockout mice was shown to reduce chromaffin granule abundance by approximately 35% which promoted deregulation of catecholamine release; whereas lentiviral over-expression led to a greater abundance of DCVs [68], suggesting a key role for CHGB and PTPRN in endocrine secretion.…”

Lower serum chromogranin B level is associated with type 1 diabetes and with type 2 diabetes patients with intensive conservative insulin treatment

“…CgB derives from numerous neurons, endocrine and neuroendocrine cell types throughout the human body [ 1 ]. CgB contributes to the physiological secretion of insulin in pancreatic beta cells [ 9 – 11 ], moreover, it may take part in the signal transduction of insulin secretion [ 19 ]. Furthermore, the messenger RNA quantity of CgB is reduced in pancreatic islets of type 2 diabetes patients than that of non-diabetic control subjects [ 20 ].…”

“…Chromogranins are associated with the carbohydrate metabolism: CgA is known to play a significant role in the development and pathogenesis [ 5 – 7 ] of type 1 diabetes and it is associated with some type 1 diabetes complications, which could develop into neuroendocrine tumors [ 8 ]. Animal and cellular models have shown that CgB is mostly related to the physiological insulin secretion [ 9 – 11 ], however, human clinical study investigating the connection between CgB and diabetes has not been conducted yet.…”