Insulin and chromogranin B secretory granules in β cell lines under physiological and stress conditions

Giordano, Tiziana (2006). Insulin and chromogranin B secretory granules in β cell lines under physiological and stress conditions. PhD thesis The Open University.



The present work provides insights into several aspects of the regulated secretion in pancreatic β cells. We demonstrated a partial intracellular dissociation of two secretory granule (SG) markers, insulin (Ins) and chromogranin B (CgB), implicating distinct SG populations. In addition, we observed for the first time a redistribution of CgB, shifting from the SG core to the halo upon secretagogues application. We also found that upon ionomycin stimulation, CgB was preferentially released, possibly reflecting a higher sensitivity to Ca2+. These findings suggest a differential regulation of Ins and CgB at multiple levels.
Furthermore, we observed heterogeneous Ins and CgB expression levels in the rat insulinoma Rin-5AH cell line. Among the sub-clones isolated therefrom, two displayed interesting features. The D2 sub-clone, showing nearly undetectable CgB levels and a lower Ins release compared to parental cells, suggested that CgB expression or secretion might affect Ins release. The Q2 sub-clone displayed high CgB content, accumulation of Ins and CgB in the Golgi complex and a poor secretion of both proteins; in addition, it showed a proportion of constitutively released Ins, suggesting a partial impairment of the secretory pathway. Q2 cells also displayed some features suggestive of oxidative stress, i.e. impaired ATP production upon stimulation of Ins secretion and altered mitochondrial morphology and functionality. Such features were also observed in patients with type 2 diabetes (T2D), thus we propose the Q2 sub-clone as a model of T2D.
Next, we assessed whether a cell model bearing oxidative stress is more susceptible to endoplasmic reticulum (ER) stress. We induced a sub-lethal ER stress in Q2 cells and compared them to INS1-E. Our results showed a higher sensitivity of Q2 cells to activation of apoptosis. Further studies of this sub-clone might shed light on the still unclear correlation between oxidative and ER stress in diabetes.

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