Glucagon-like peptide-1 (GLP-1) is a naturally produced peptide hormone which is secreted from the jejunum and ilium following food intake. It is the most potent insulinotropic agent in humans, i.e., it synergizes with glucose to augment insulin secretion. In contrast to the effects of incretins in glucose tolerant states, GLP-1 has been shown to be insulinotropic in Type II diabetic subjects, unlike the other well-known incretin, glucose-dependent insulinotropic peptide (GIP). In addition, several studies have implicated an independent role for GLP-1 similar to that of insulin, i.e., the ability to enhance glucose uptake independent of its insulinotropic effect. Thus, GLP-1 has the potential to be a therapeutic agent in Type II diabetic states. However, before it becomes an acceptable therapy, more basic work needs to be done. Studies so far have been carried out with intravenous infusions of GLP-1 and none have been done with long-term infusions. We have given subcutaneous infusions to animals for up to 5 days by osmotic pumps. We have shown that GLP-1 is capable of reversing the age-related decline in insulin secretion that occurs in Wistar rats. It also increases insulin mRNA and total islet insulin content. We propose to deliver GLP-1 subcutanelously to Type II diabetic subjects for 48 hours, checking insulin secretion and sensitivity, before and after the influsions, in response to glucose delivered by the way of clamp technology. We previously performed a short (one hour) influsion of GLP-1 intraveneously and were not able to demonstrate extrapancreatic effects. By this longer influsion, we should be able to decisively demonstrate whether there are in fact any extrapancreatic effects of the GLP-1. This will give information as to whether GLP-1 delivered subcutaneously is a viable option for trearing Type II diabetes.