Selective elevation of cAMP in the pancreatic islet b cell will augment insulin secretion and lower blood glucose. Our work indicates that, although several cAMP phosphodiesterases are present in islet b cells, it is the PDE3 isoform that is functionally relevant to insulin secretion. The further characterisation of the islet b cell PDEs is in progress, together with an analysis of their functions. It may be possible to target these enzymes to develop novel oral hypoglycaemic agents for the treatment of non-insulin dependent diabetes.
Cardiovascular disease remains the main cause of the increased mortality seen in diabetics.
We are investigating the susceptibility of the diabetic heart to developing arrhythmias and damage following myocardial ischaemia. In particular we are interested in determining if ischaemic preconditioning, an important endogenous protective mechanism, is modified by diabetes. Septic shock is associated with peripheral vascular failure, secondary to impaired responsiveness to endogenous vasoconstrictors. Endothelium-dependent vasodilation is also impaired. One mechanism underlying these changes, at least in gram-negative septicaemia, is an increased nitric oxide production following induction of nitric oxide synthase by bacterial lipopolysaccharide.