Article date: June 2014
By: K Ramachandran, X Peng, K Bokvist, L Stehno‐Bittel in Volume 171, Issue 12, pages 3010-3022
Background and Purpose
Insulin secretion from isolated pancreatic islets is a pivotal assay in developing novel insulin secretagogues, given its good correlation with in vivo efficacy. Because the supply of human islets is limited, this assay is typically run with rodent islets, which do not address species differences and are low‐throughput, because of the size matching or volume normalization required. Here we have evaluated the suitability of human re‐aggregated islets for this assay.
Experimental Approach
We generated re‐aggregated human islets of a consistent size, using micromolds and compared their responses with those of native human and rat islets, to known secretagogues and inhibitors of insulin release.
Key Results
Insulin secretion from rat islets, human islets and human re‐aggregated cell clusters was concentration‐dependently increased by glucose. The calcium channel agonist, Bay K 8644, stimulated insulin secretion in native rat islets and human re‐aggregated islets, but not native human islets. Glibenclamide and tolbutamide were more effective and potent in re‐aggregated human clusters compared with the other two preparations. Rat islets outperformed both human preparations of islets in response to caffeine, carbachol and glucagon‐like peptide‐1. Re‐aggregated human islet clusters were more sensitive to somatostatin, diazoxide and sodium azide, but rodent islets were more sensitive to nifedipine.
Conclusions and Implications
Human re‐aggregated clusters of islet cells, of a constant size were more responsive to all compounds tested than native human islets. Importantly, the assay variability was less in the re‐aggregated cluster preparations, which suggests that such re‐aggregated cells could be useful for drug development.
DOI: 10.1111/bph.12622
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