Non-insulin-dependent diabetes mellitus (NIDDM), type II diabetes) is one of the most common diseases in the elderly population of the USA, and is especially common among minority population. NIDDM is caused by 1) impaired insulin secretion from islets of Langerhans in the pancreas, and 2) impaired sensitivity of peripheral tissues (such as muscle, fat, and liver) to insulin. A promising new approach for treatment of NIDDM is the use of incretin hormones such as glucagon-like peptide (GLP). Incretins have many desirable effects which may help NIDDM patients. Incretins stimulate insulin secretion and inhibit glucagon secretion. In addition we have found that GLP stimulates insulin action at insulin target tissues. For example, glucose uptake and lipid synthesis are stimulated by GLP in cultured adipocytes, and GLP stimulates glucose oxidation and glycogen synthesis in rat myotubes in culture. We have found that GLP receptor mRNA is present in many different tissues from rat, further suggesting extrapancreatic effects of GLP. Our data also suggest the presence of different GLP receptor isoforms in pancreas versus extrapancreatic tissues. We have evidence that GLP receptor signaling cascade acts differently in pancreas versus extrapancreatic tissues. Further, different agonist specificity for GLP analogues are noted in pancreas versus extrapancreatic tissues. This suggests the exciting possibility that it may be possible to selectively activate GLP receptor isoforms in different tissues in NIDDM therapy. Our goal is to devote effort to molecular cloning of GLP receptor isoforms and the study of signal transduction involved in GLP action to help develop new therapeutic agents for NIDDM.