Michael TitheradgeEmeritus Professor (Brighton and Sussex Medical School)
Research
Control of carbohydrate metabolism in response to bacterial endotoxins and pro-inflammatory cytokines and the role of dimethyl arginine derivatives in vascular disease.
A major characteristic of overwhelming sepsis in animals is a fall in blood glucose arising from an inhibition of gluconeogenesis and decreased capacity of the liver to store and mobilize glycogen. It is evident that the presence of bacterial endotoxins in the bloodstream cause the release of proinflammatory cytokines (IL-1b, IL-6, TNF-a and IFN-g) and the overproduction of nitric oxide and this is a crucial element of the pathophysiology observed at the onset of septic shock We have provided evidence that overproduction of nitric oxide can partially account for the inability of the liver to carry out gluconeogenesis and also the liver damage observed in response to cytokines, but not the inability to make and release glycogen during periods of falling blood glucose. Our research is directed at understanding the mechanisms by which glycogen metabolism in both the liver and muscle is controlled by proinflammatory cytokines and the mechanisms by which these may interfere with signaling in response to insulin during sepsis. In addition to being a potentially toxic agent, nitric oxide production is essential for maintaining vascular tone causing relaxation. Related research is investigating the potential role of asymmetric dimethyl arginine (a natural inhibitor of nitric oxide production produced in our bodies) to inhibit nitric oxide production rendering the vasculature more susceptible to damage and the development of vascular disease.