Pseudoislets as a model system to study beta cell dysfunction in diabetes

Islets of Langerhans are aggregates of endocrine cells dispersed throughout the pancreas. The majority of islet cells are insulin-secreting beta-cells, but islets also contain glucagon-secreting alpha-cells and somatostatin-secreting delta-cells. The importance of pancreatic beta-cell function in the development of diabetes mellitus, and the search for new therapies for diabetes, has driven a great deal of research into every aspect of islet/beta-cell biology. This area of research has been greatly assisted by the development of methods for isolating islets from experimental animals (predominantly rodents), but this has required the use of a considerable number of animals - we calculate that data published from islet studies in 2006 alone may have used 30-40,000 rodents as a source of islets.

This project proposes to reduce the numbers of animals used by developing useful in vitro substitutes for primary islets. A number of rodent islet hormone-secreting cell lines are currently available, but they lack the differentiated functions of primary islets, which limits their usefulness in many studies. We have demonstrated that the function of insulin-secreting cell lines is much improved by configuring them as three-dimensional islet-like structures (which we call pseudoislets), and we have now incorporated a glucagon-secreting cell line (alphaTC1) into the pseudoislet model – preliminary results show that our endocrine cell lines retain ability to self-organise into anatomically-appropriate islet-like structures, and that this is important for their function. We have also demonstrated that interactions through cell-surface adhesion molecules influence the proliferative capacity and the differentiated function of cells within pseudoislet structures, suggesting that islet-like structures generated in vitro can offer a viable experimental alternative to islets isolated from experimental animals. We propose a series of studies to refine the pseudoislet model to ensure that it more closely approximates a mouse primary islet in anatomy and function such that it offers a valid alternative to islets in many experimental protocols. We also propose an extensive programme of dissemination of information to UK and international groups that currently use animals as their source of islet material for experiments. The impact of this model to the 3Rs will be in replacement of animals that would otherwise be used as a source of primary pancreatic islets of Langerhans.

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Reers C,  Hauge-Evans AC, Morgan NG, Willcox A,  Persaud SJ, Jones PM (2011) Down-regulation of proliferation does not affect the secretory function of transformed beta-cell lines regardless of their anatomical configuration. Islets 3 (3): 80-88 doi:10.4161/isl.3.3.15428

Persaud SJ, Arden C, Bergsten P, Bone AJ, Brown J, Dunmore S, Harrison M, Hague-Evans A, Kelly C, King A, Maffucci T, Marriottt CE, McClenaghan N, Morgan NG, Reers C, Russell MA, Turner MD, Willoughby E, Younis MYG, Zhi ZL & Jones PM (2010) Pseudoislets as primary islet replacements for research. Islets 2 (4): 1-4 doi:10.4161/isl.2.4.12557

Zhi Z-L, Liu B, Jones PM, Pickup JC (2010) Polysaccharide multilayer nanoencapsulation of insulin-producing beta-cells grown as pseudo-islets for potential cellular delivery of insulin Biomacromolecules 11 (3): 610-616  Read the abstract doi: 10.1021/bm901152k.

Menichini F, Tundis R, Loizzo RL, Bonesi M, Liu B, Houghton PJ, Persaud SJ, Jones PM, Mastellone V, Lombardi P, Avallone L, Menichini F (2010) C. medica cv Diamante peel chemical composition and influence on glucose homeostasis and metabolic parameters. Food Chemistry 124 (3): 1083-1089  doi:10.1016/j.foodchem.2010.07.083.

Al-Romaiyan A, Jayasri MA, Mathew TL, Huang GC, Amiel SA, Persaud SJ, Jones PM (2010) Costus Pictus extracts enhance insulin secretion from mouse and human islets in vitroCell Physiol Biochem 26 (6): 1051-8 Read the abstract doi:10.1159/00032400.

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Project grant

Status:

Closed

Principal investigator

Professor Peter Jones

Institution

King's College London

Co-Investigator

Dr Shanta Persaud

Grant reference number

G0700557/1

Award date:

May 2008 - Jun 2011

Grant amount

£387,722