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J H Jaggar, E A Harding, B J Ayton, and M J Dunne


The hyperglycaemia-inducing sulphonamide diazoxide has been previously shown to mediate its effects upon insulin secretion by opening K+ channels and hyperpolarizing the β-cell membrane. The target site has been characterized as the ATP-regulated K+ (K+ ATP) channel protein. In the present study, a detailed investigation of interactions of diazoxide and another K+ channel opener, cromakalim, with K+ ATP channels has been performed in individual insulin-secreting cells using patchclamp techniques. In agreement with previous studies, diazoxide and cromakalim were found to be effective only when ATP was present upon the inside face of the plasma membrane. The ability of both diazoxide and cromakalim to open channels was, however, found to diminish with time following isolation of inside-out patches. Within seconds of forming the recording configuration, the actions of both compounds were potent, and were found to decline steadily as the number of operational channels decreased ('run-down'). In open cells, where the plasma membrane remains partially intact, the rate of run-down was significantly reduced, and effects of channel openers were recorded up to 80 min following cell permeabilization. We also demonstrated that in the absence of ATP, but in the presence of ADP, both diazoxide and cromakalim were able to open K+ ATP channels. Interestingly, once the effects of diazoxide and cromakalim on K+ ATP channels in the presence of ATP were lost, both compounds opened channels in the presence of ADP. One implication of these data is that the actions of diazoxide and cromakalim involve regulatory proteins associated with the ion channel; this molecule is able to bind ATP, ADP and possibly other cytosolic nucleotides.

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A Stevens, C De Leonibus, D Hanson, A W Dowsey, A Whatmore, S Meyer, R P Donn, P Chatelain, I Banerjee, K E Cosgrove, P E Clayton, and M J Dunne

Systems biology is the study of the interactions that occur between the components of individual cells – including genes, proteins, transcription factors, small molecules, and metabolites, and their relationships to complex physiological and pathological processes. The application of systems biology to medicine promises rapid advances in both our understanding of disease and the development of novel treatment options. Network biology has emerged as the primary tool for studying systems biology as it utilises the mathematical analysis of the relationships between connected objects in a biological system and allows the integration of varied ‘omic’ datasets (including genomics, metabolomics, proteomics, etc.). Analysis of network biology generates interactome models to infer and assess function; to understand mechanisms, and to prioritise candidates for further investigation. This review provides an overview of network methods used to support this research and an insight into current applications of network analysis applied to endocrinology. A wide spectrum of endocrine disorders are included ranging from congenital hyperinsulinism in infancy, through childhood developmental and growth disorders, to the development of metabolic diseases in early and late adulthood, such as obesity and obesity-related pathologies. In addition to providing a deeper understanding of diseases processes, network biology is also central to the development of personalised treatment strategies which will integrate pharmacogenomics with systems biology of the individual.