The glucagon-like peptides: a double-edged therapeutic sword? TracyAnn Perry and Nigel H. Greig Section of Drug Design and Development, Laboratory of Neurosciences, Gerontology Research Center, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA Glucagon-like peptide-1(7 – 36)-amide (GLP-1) is an endogenous peptide that is secreted from the gut in response to the presence of food. Recent studies have established that GLP-1 and its longer-acting analog exendin-4 have multiple synergistic effects on glucose- dependent, insulin secretion pathways of the pancreatic b-cell and on plasticity in neuronal cells. Recent interest has focused on the development of these peptides as a novel therapeutic strategy for non-insulin-dependent (type 2) diabetes mellitus and associated neuropathy. This is with a view to developing lead compounds, based on neurotrophic action, for central and peripheral degenerative disorders such as stroke and Alzheimer’s disease in addition to the peripheral neuropathy associ- ated with type 2 diabetes mellitus. Here, we address recent advances in the biological action of GLP-1 and its related analogs. Non-insulin-dependent (type 2) diabetes mellitus is a progressive disease that is prevalent in the elderly. Unlike type 1 diabetes, people with type 2 diabetes might make healthy, even high, levels of insulin, but there is a decrease in insulin action at insulin-sensitive tissues. Thus, the control of glucose levels in the blood is impaired. This resistance to insulin is often caused by obesity (reviewed by [1]). Approximately 90–95% of people with diabetes have type 2 diabetes [2]. There is also evidence to indicate that type 2 diabetes, or at least impaired glucose tolerance, is associated with impaired cognition, independent of age. Therefore, the normal, age-related decline in cognitive function might be exacerbated by the development of impaired glucose tolerance and insulin resistance. The age-related decline in pancreatic b-cell function results in , 19% of those over 65 in the US being diagnosed with type 2 diabetes. Although type 2 diabetes is associated typically with older people, it has become much more prevalent among children and young adults, in line with the alarming rise of obesity in the general population. Present treatments are less than satisfactory. Diabetes has become the major cause of peripheral neuropathy, afflicting some 20–30% of type 2 diabetics, for which there is currently no treatment other than strict control of blood glucose levels. A major focus of endocrin- ology research over the past 5 years has been the development of a new therapeutic strategy for type 2 diabetes and neuropathy, based on the insulinotropic actions of endogenous peptides. Specifically, glucagon-like peptide-1(7 – 36)-amide (GLP-1) and glucose-dependent insulinotropic peptide (GIP) (reviewed in [3]) are released from entero-endocrine cells of the gastrointestinal mucosa following the ingestion of nutrients. They regulate nutrient metabolism via effects on insulin release from pancreatic islets (insulinotropic release), gastric motility and acid secretion, islet cell proliferation and nutrient disposal [4,5]. Infusions (either intravenous or subcu- taneous) of GLP-1, at pharmacological concentrations, lower blood glucose in type 2 diabetic and non-diabetic subjects [6,5]. An important regulator of the biological activity of GLP-1 and GIP is N-terminal degradation by the common, endogenous, aminopeptidase enzyme, dipeptidyl pepti- dase IV (DPP-IV). This enzyme cleaves GLP-1 at the alanine residue at position 2 [7], which not only inactivates GLP-1, but might turn it into an antagonist at the GLP-1 receptor (Box 1) [8]. Several studies confirm that DPP-IV- mediated inactivation of these peptides is a crucial control mechanism that regulates the biological activity of both GIP and GLP-1 in rodents [9] and humans [7,10]. Indeed, it is this rapid inactivation that poses important challenges for therapeutic efforts directed at enhancing GIP and GLP-1 activity in vivo. Thus, a continuous infusion of peptide is required to maintain steady-state levels of active GLP-1 in plasma. The finding that the glucose-lowering effects of GLP-1 are preserved in type 2 diabetic individuals, irrespective of patient age and the duration of diabetes [11], and that it can preserve and augment b-cell mass [12,13] has provided the impetus for develop- ing GLP-1-based pharmaceuticals with more suitable pharmacokinetics than those of native GLP-1. Insulinotropic action GLP-1 exerts its insulinotropic activity via interaction with a specific receptor, the GLP-1 receptor, on the cell membrane of pancreatic b-cells. The GLP-1 receptor has been cloned [14] and is a G-protein-coupled receptor of the subfamily that includes receptors for the related peptides, secretin, vasoactive intestinal peptide, pituitary adenylyl cyclase activating peptide and GIP. The GLP-1 receptor is coupled positively to the adenylyl cyclase system [15]. Ligand activation of the GLP-1 receptor stimulates adenylyl cyclase (Fig. 1), leading to an increase in intracellular cAMP in pancreatic b-cells [16], rat Corresponding author: TracyAnn Perry (perryt@grc.nia.nih.gov). Review TRENDS in Pharmacological Sciences Vol.24 No.7 July 2003 377 http://tips.trends.com 0165-6147/03/$ - see front matter. Published by Elsevier Science Ltd. doi:10.1016/S0165-6147(03)00160-3