Genetics and trafficking in insulin secreting b-cells

Group Leaders:

Prof Graham A Hitman MBBS, MD, FRCP

Dr Mark Turner BSc PhD

Research field

There is a major interest in studying genetic susceptibility to diabetes, related disorders and periodic fevers. Barts and The London is at the forefront of the international gene discovery programs in these disorders (including genome scans, candidate genes, functional genomics and applied physiology) and many seminal discoveries have been made. The current program is focusing on genes important to the pancreatic beta cell and endoplasmic reticulum stress in a number of major resources including British/Irish as part of the Diabetes UK/MRC Warren2 collections and from the South Asian subcontinent including younger adult patients from Bangladesh . The cell biology links to the genetic work with major interests in pancreatic beta cell metabolism and insulin secretory granule trafficking. In particular we are focussing work on PPARg, calpain-10 and the receptor for tumour necrosis factor in health and disease. We recently discovered that calpain-10 is a trigger for insulin release; current studies are extending to actions on the cytoskeleton and into other endocrine cell types.

Key research papers

Recent key research papers including prevention

1 Marshall C, Hitman GA , Partridge CJ et al. Evidence that an isoform of calpain-10 is a regulator of exocytosis in pancreatic beta-cells. Mol Endocrinol 2005; 19(1):213-224.

2 Yousaf N., Gould DJ, Aganna E. et al. TNF-R1 from periodic syndrome patients interact with wild-type TNF-R1 inducing TNF-independent NFkB activation. Arthritis Rheum. 2005 52: 2906-2916.

3 Colhoun HM, Betteridge DJ, Durrington PN et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004; 364(9435):685-696.

4 Jackson AE, Cassell PG, North BV et al. Polymorphic variations in the neurogenic differentiation-1, neurogenin-3, and hepatocyte nuclear factor-1alpha genes contribute to glucose intolerance in a South Indian population. Diabetes 2004; 53(8):2122-2125.

5 Turner MD. Fatty acyl CoA-mediated inhibition of endoplasmic reticulum assembly. Biochim. Biophys. Acta. 2004; 1693: 1-4.

6 Aganna E, Martinon F, Hawkins PN et al. Association of mutations in the NALP3/CIAS1/PYPAF1 gene with a broad phenotype including recurrent fever, cold sensitivity, sensorineural deafness, and AA amyloidosis. Arthritis Rheum 2002; 46(9):2445-2452.

7 Hassan Z, Mohan V, Ali L et al. SPINK1 is a susceptibility gene for fibrocalculous pancreatic diabetes in subjects from the Indian subcontinent. Am J Hum Genet 2002; 71(4):964-968.

8 Ogunkolade BW, Boucher BJ, Prahl JM et al. Vitamin D receptor (VDR) mRNA and VDR protein levels in relation to vitamin D status, insulin secretory capacity, and VDR genotype in Bangladeshi Asians. Diabetes 2002; 51(7):2294-2300.

9 Cassell PG, Jackson AE, North BV et al. Haplotype combinations of calpain 10 gene polymorphisms associate with increased risk of impaired glucose tolerance and type 2 diabetes in South Indians. Diabetes 2002; 51(5):1622-1628.