Assessment of Re-Aggregated Human Pancreatic Islets for Secondary Drug Screening

Br J Pharmacol. 2014 Jun;171(12):3010-22. doi: 10.1111/bph.12622.

Abstract

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.

Keywords: GLP-1; Insulin; elisa; glibenclamide; human; islets; rat; re-aggregate; somatostatin; tolbutamide.

Publication types

  • Comparative Study
  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Cell Communication*
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical / methods*
  • Female
  • Glucose / metabolism
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • Insulin / metabolism*
  • Insulin Secretion
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / metabolism
  • Male
  • Rats, Sprague-Dawley
  • Reproducibility of Results
  • Species Specificity

Substances

  • Hypoglycemic Agents
  • Insulin
  • Glucose