Beta cells of the pancreas, which make and secrete insulin, do not respond like those of non-diabetic subjects when type 2 diabetes is present. Specifically, subjects suffering from type 2 diabetes have a blunted or even absolute loss of first phase and a severely blunted second phase insulin release in response to glucose. In conjunction with this, and despite all treatments currently available to treat diabetes, beta cell function continues to deteriorate over time. With the data now available from the United Kingdom Prospective Diabetes Study (Sept. 1998) this point was brought home even more forcefully. Despite continual monitoring of patients enrolled in the study, euglycemia could not be maintained even with intensive therapy, because of declining beta cell function. We have been working for some time with GLP-1, a naturally occurring incretin peptide produced and released from the gut in response to food. The amount released depends on the amount of glucose and fat that has been ingested. After its plasma levels increase, GLP-1 binds to the GLP-1 receptor (GLP-1R) on beta cells, and increases PKA activity because of adenylyl cyclase (AC) activation and cAMP generation. Downstream of the increased PKA activity, glucose-induced insulin secretion is enhanced. The end result is a restoration of plasma glucose back to baseline. Consequently, GLP-1 analogs and GLP-1R agonists are under intense study as treatments for type 2 diabetes. A naturally occurring GLP-1R agonist, exendin-4, is now available for treatment. However, there are cellular and hormonal mechanisms within islets that negatively impact beta-cell secretion and proliferation, which cannot be fully overcome with incretin receptor agonists. Another incretin, GIP, also enhances glucose-induced insulin secretion, however, unlike GLP-1, when it is given in pharmacological concentrations to patients with type 2 diabetes it actually worsens post-prandial glucose because in also increases glucagon secretion. As regards inhibitors of insulin secretion, somatostatin production from delta cells in islets, for example, could serve to inhibit insulin secretion, though there is no evidence for its over-activity in type 2 diabetes and there are very few delta cells in adult islets to begin with ( about 100:1, beta to delta cells, respectively). We looked for other potential adenylyl cyclase inhibitors that may be produced within islets and found that endogenous cannabinoids are produced exclusively in beta cells. When cannabinoid 1 receptors (CB1R) are inhibited or genetically removed, insulin secretion and beta-cell function is enhanced because a brake on AC activity is lifted. We are now evaluating CB1R antagonists that have effects solely in the periphery for their ability to improve beta-cell function in type 2 diabetes.