The underlying mechanisms and causes of Diabetes are unknown. Opportunities exist for diabetes research in many areas including electrophysiological studies of hormone action and secretion. This proposal involves the application of ion-selective microelectrodes to: (1) insulin release (i.e., stimulus-secretion coupling) in pancreatic islet cells and (2) the role of insulin in glucose and ion transport by "insulin sensitive" cells. Many studies have demonstrated that the onset of secretion is associated with a number of electrophysiological events e.g., membrane depolarization, the development of "action potentials" analogous to those seen in excitable tissue. The exact nature of the ionic processes involved is unclear, and the use of Na ion, K ion, and Ca ions microelectrodes should yield valuable insight into the basic mechanisms of stimulus-secretion coupling. These electrodes will be used in comparing the electrical responses of normal and diabetic animals, i.e., with defective or impaired secretion. An investigation of the somatostatin inhibition of glucose induced electrical activity in the Beta-islet cells with ion-selective microelectrodes is planned to study the mechanisms by which somatostatin influences the transmembrane ionic fluxes which block the effect of intracellular Ca ions on the secretory processes. Insulin directly affects the membrane transport of glucose in "insulin sensitive cells"; it hyperpolarizes the membrane. The complexity of the mechanism comprising these electrical potentials precludes, at this time, a single hypothesis explaining the effect of insulin upon these potentials. Nevertheless, these recently developed ion-selective microelectrodes (Ca ions and Na ion) offer a unique approach to the study of insulin action on the cell membrane and to demonstrate the electrochemical driving force involved in the insulin induced active accumulation of sugar. This proposal offers a new vantage point for the study of diabetes mellitus: (1) the investigation of cellular defects such as insulin resistant membranes that occur at the onset of obesity, (2) evaluation of the mode of action of the sulphonylurea drugs on "insulin sensitive cells" and on the Beta-islet cell of the pancreas and (3) the study of the role of Ca ions as second messenger in response to insulin as an anabolic agent.