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Fumarate- the elusive link between diabetes and cancer? Supervisors: Prof Patrik Rorsman Dr Julie Adam Department: Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Radcliffe Department of Medicine Background Type-2 diabetes (T2D) is a progressive disorder of deteriorating glucose homeostasis and insulin secretion, often combined with reduced insulin sensitivity and hypersecretion of the hyperglycaemic hormone glucagon. Diabetes is also associated with a wide spectrum of co-morbidities: macro- and microvascular complications (that in turn precipitate heart disease, stroke, blindness, renal disease, and peripheral neuropathies), an increased risk of neurodegenerative disorders (Parkinson’s and Alzheimer’s) and certain cancers (liver, pancreas, uterus and colon/rectum). Identifying the molecular link between these disorders is a major challenge in diabetes research. Our recent data suggest that the Krebs cycle enzyme fumarate hydratase (Fh1; FH in man) may play a key role in the development of the hormone secretion defects and co-morbidities of diabetes. Reduced activity of FH leads to elevated intracellular fumarate levels. This has multiple cellular consequences including the posttranslational modification of cysteine residues in proteins to form (S)-2-succinocysteine (2SC); an irreversible chemical process termed ‘succination’ which can lead to loss of activity of some proteins. We found that succination was strongly increased in pancreatic islets from T2D patients. Hyperglycaemia also resulted in increased succination in the kidney and fat of a murine model, two tissues that become dysregulated in T2D. Succination screens of diabetic murine and human islets revealed some interesting targets, notably Park7 (also known as DJ1), which acts as a sensor for oxidative stress and is known to be reduced in T2D. Fumarate is also known as an ’oncometabolite’; elevated intracellular concentrations of fumarate lead to stabilisation of the transcription factor HIF1-alpha and this may contribute to tumorigenesis. It is therefore intriguing that we found intense 2SC labelling (indicative of high intracellular fumarate) in colorectal tissue obtained from T2D patients. Strong 2SC labelling was also seen in colorectal tumours and was significantly stronger in tumours from T2D patients. Hypothesis The effects of T2D on protein succination and fumarate content are recapitulated in vitro by longterm (24h) exposure of cells/tissues to ‘diabetic’ levels of glucose. We therefore hypothesise that hyperglycaemia reduces FH activity and that this, via increased intracellular fumarate and protein succination, mediates the adverse effects associated with diabetes. Aims We will explore: 1) how hyperglycaemia reduces FH activity (reduced gene expression or via metabolic regulation?); 2) in which tissues increased succination can be detected in T2D; 3) the mechanisms by which reduced FH activity affects pancreatic hormone release; 4) if increased FH activity exerts an anti-diabetic effect and whether it can be pharmacologically targeted; 5) which proteins become succinated in different cells and if tissues affected by T2D exhibit a distinct ‘succinome’; and 6) the ‘tumorigenic’ effects of fumarate and the signalling pathways involved. Proposed research We will generate cell-specific Fh1 knockout models (mice and cells) and study the functional consequences. In parallel, tissues from diabetic versus non-diabetic individuals, including pancreatic islets, kidneys, muscle, fat and cancer biopsies, will be analysed to investigate whether there is evidence for similar phenotypes in human samples. An extensive range of technologies will be used to answer these questions including histology, molecular biology, proteomics, metabolomics, advanced microscopy and cell physiology. The research will be conducted within the framework of existing collaborations (local and international). Recent relevant publications 1. Zhang Q, Ramracheya R, Lahmann C, Tarasov A, Bengtsson M, Braha O, Braun M, Brereton M, Collins S, Galvanovskis J, Gonzalez A, Groschner LN, Rorsman NJ, Salehi A, Travers ME, Walker JN, Gloyn AL, Gribble F, Johnson PR, Reimann F, Ashcroft FM, Rorsman P. Role of KATP channels in glucoseregulated glucagon secretion and impaired counterregulation in type 2 diabetes. Cell Metab. 18:87182, 2013. 2. Rosengren AH, Braun M, Mahdi T, Andersson SA, Travers ME, Shigeto M, Zhang E, Almgren P, Ladenvall C, Axelsson AS, Edlund A, Pedersen MG, Jonsson A, Ramracheya R, Tang Y, Walker JN, Barrett A, Johnson PRV, Lyssenko V, McCarthy MI, Groop L, Salehi A, Gloyn AL, Renström E, Rorsman P, Eliasson L. Reduced insulin exocytosis in human pancreatic beta-cells with gene variants linked to type-2 diabetes. Diabetes 61: 1726-33, 2012. 3. Adam J, Yang M, Bauerschmidt C, Kitagawa M, O'Flaherty L, Maheswaran P, Özkan G, Sahgal N, Baban D, Kato K, Saito K, Iino K, Igarashi K, Stratford M, Pugh C, Tennant DA, Ludwig C, Davies B, Ratcliffe PJ, El-Bahrawy M, Ashrafian H, Soga T, Pollard PJ. A role for cytosolic fumarate hydratase in urea cycle metabolism and renal neoplasia. Cell Rep. 3:1440-8, 2013.