It is well recognized that treatment of non-insulin-dependent diabetes mellitus (NIDDM) is complicated by the risks of hypoglycemia, as well as large swings in the blood glucose level, inherent to insulin and sulfonylurea therapy. Recent clinical studies of NIDDM indicate the usefulness of incretin hormone glucagon-like peptide-1-(7-37) (INSULINOTROPIN, GLP-1) as the alternative treatment for this disorder. When administered during a meal to patients with NIDDM, GLP-1 restores the missing first phase component of insulin secretion and delays the post-prandial hyperglycemic excursion. Since the insulinotropic action of GLP-1 is self-terminating as blood glucose levels begin to fall, hypoglycemia is not a significant complicating factor. Although it is generally accepted that NIDDM is characterized by ineffective coupling of beta-cell glucose uptake to insulin secretion, it is not yet understood how short-term administration of GLP-1 corrects this defective secretory response. Here we report preliminary findings indicating rapid conversion of glucose-insensitive beta-cells to fully responsive cells by GLP-1, a phenomenon we term glucose competence. The objective of this study is to determine the mechanism by which GLP-1 renders pancreatic beta-cells glucose-competent, as assessed by patch clamp electrophysiological analysis. Perforated patch, cell-attached patch, and excised patch recordings will be used to study modulation of Ik GLP, an inwardly-rectifying potassium current that is inhibited by GLP-1, and which mediates the depolarizing action of this hormone on beta-cells. The biophysical and pharmacologic properties of Ik GLP will be characterized and an assessment made as to whether it represents a previously unrecognized beta-cell potassium current. since inhibition of Ik GLP by GLP-1 is contingent on the simultaneous application of glucose, the synergistic interaction of these two agents to depolarize beta-cells will be quantified by dose-response analysis. This will allow a direct test of the hypothesis that induction of glucose competence by GLP-1 results from a shift in the dose-dependence of the glucose response so that concentrations of glucose normally considered to be substimulatory become fully effective. Since cross-talk between the GLP- 1 and glucose signalling systems is a requirement for inhibition of Ik GLP, experiments will be directed at identifying the cytosolic second messenger that mediates the action of GLP-1. Understanding the molecular events that underlie the response to GLP-1 will provide insight into why this hormone is of therapeutic value in the treatment of NIDDM, as well as further our understanding of the glucose-sensing mechanism of beta- cells.