Recent major accomplishments include: elucidation of a major gene in fibrocalculous pancreatic diabetes ( SPINK1 ); demonstration that gene to gene interactions determine glucose tolerance; confirmation of the importance of calpain-10 gene polymorphism in diabetes and the novel discovery that it is a key molecule in insulin trafficking in the pancreatic b -cell and hormone secretion from other endocrine cell types; mutations of the TNF receptor ( TNFRSF1A ) lead to a defect in NF k B signalling; the study of hereditable traits in type 1 diabetes and the identification of genetic components to intracellular protein glycation in different proteins including haemoglobin and advanced glycation end-products using healthy and diabetic twins which could be used to predict diabetic complication risk; identification and characterisation of familial defects in monocytes in type 1 diabetes; the characterisation of latent onset diabetes of the adults (LADA) in terms of epidemiology with Europe where the disease pattern is distinct from that found in childhood onset type 1 diabetes; evidence from twin studies that the genetic basis of type 1 diabetes in childhood is substantially greater than that of adult-onset type 1 diabetes; the development of novel therapies using two distinct vaccination-based peptide immunomodulations in type 1 diabetes which are now progressing from the successfully completed Phase 2 to Phase 3 trials; evidence for the novel concept that members of the family of pyruvate dehydrogenase kinases serve as metabolic allostats to counter abnormal lipid handling; identification of key roles for signalling via the lipo-oxidative and lipogenic transcription factors peroxisome proliferator-activated receptor (PPAR)s - a and - g ; demonstration of the importance of fatty acid and glycerol kinetics and sympathetic nervous system activity in human adipose tissue by in vivo techniques; establishing that all diabetics benefit from statin treatment to reduce cardiovascular events (CARDS) that has subsequently influenced guideline development. The newly formed stem cell group has demonstrated the role of bone marrow in fibrosis and vasculogenesis in pancreatic and gastrointestinal tract pathology.

The strength and uniqueness of the Centre is the clinical focus of the work spanning from basic science to clinical application. The Centre continues to consolidate the research base and explores common themes amongst our research groups, for instance in functional genomics, cell signalling and autoimmunity whilst capitalising on data that will emerge from genome wide association and epigenomic scans that members of the Centre are investigators or will have access to pre-publication data. An emerging interest is in the prevention of diabetes that is especially relevant to our local community. Clinical translational research that interfaces with the Trust and Primary Care have been strengthened by several initiatives including the setting up of the North East London Local Diabetes Research Network (co-leads Hitman and Feder) and a recent award of an MRC, National Prevention Research Initiative (NPRI; Hitman as PI) grant to pilot methods for identification of people at risk of diabetes and prevention strategies in the local Bangladeshi population. This therefore mirrors our prevention work in type 1 diabetes and LADA (Leslie and Pozzilli). Moreover, the pathogenesis of type 1 diabetes (T1D) is influenced by both genetic and environmental factors. However, the high degree of discordance for T1D observed between monozygotic (MZ) twins, who are genetically identical and share similar environments, has prompted the exploration that T1D may be associated with aberrant epigenetic modifications of the DNA. Dr. Vardhman Rakyan, a newly appointed lecturer, in collaboration with Prof. David Leslie (Director of the British Diabetic Twin Study) has generated genome-wide DNA methylation profiles for T1D-discordant MZ twins. The findings from this study could have a major impact on our understanding of the aetiology of complex diseases such as T1D.

The cell biology links to the genetic work with major interests in insulin secretory granule trafficking, pancreatic b -cell metabolism and stem cells. In particular we are focussing work on calpain-10 and the receptors for tumour necrosis factor (TNF) in health and disease, and on regulatory mechanisms influencing nutrient-stimulated insulin secretion and the regulation of tissue glucose oxidation by pyruvate dehydrogenases (PDKs). Studies of the regulation of nutrient-stimulated insulin secretion currently focus on the role of the peroxisome proliferator-activated receptors (PPARs), lipid-responsive transcription factors, in modifying the characteristics of compensatory hypersecretion of insulin that is invoked to counteract the development of insulin resistance in extra-islet tissues (liver, skeletal muscle) in response to altered lifestyle interventions (pregnancy, altered dietary lipid intake), and endocrine states (glucocorticoid excess, hyperthyroidism) which are associated with altered lipid-buffering by white adipose tissue.

The stem cell work is focussing on identifying intrapancreatic stem cells using novel Attenuated Total Reflection (ATR) infrared microspectroscopy and Photothermal imaging; performed in conjunction with The Department of Physics at Lancaster (one of only three RAE 5* Physics Departments). These studies are being complimented by projects searching for clonogenic cells in pancreatic cancer cell lines and tracing cell lineages in normal pancreas through the study of cells bearing passive but unique mitochondrial mutations, providing for the first time a way of lineage tracing in human tissues. Extending previous work on the relationship between the bone marrow and end-stage liver fibrosis, tumour desmoplasia and inflammatory bowel disease, the stem cell group is exploring the role of bone marrow in pancreatitis and examining the proposition that the genotype of the bone marrow might alter the pancreatic fibrosis phenotype. In conjunction with Paolo Pozzilli's group, the group is exploring the therapeutic potential of mesenchymal stem cells (MSCs) derived from adipocytes in the treatment of T1D, using the non-obese diabetic (NOD) murine model of T1D.