Download Fumarate- the elusive link between diabetes and cancer?

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.