1 International Diabetes Monitor Volume 21, Number 1, 2009 Abstract Type 2 diabetes is characterized by insulin resis- tance, impaired glucose-induced insulin secre- tion and inappropriately regulated glucagon secretion, which in combination eventually result in hyperglycemia and in the longer term in microvascular and macrovascular complications affecting multiple organ systems. Traditional treatment modalities — even multidrug approaches — for type 2 diabetes are often unsatisfactory at achieving glycemic goals as the disease progresses due to a steady, relentless decline in pancreatic β-cell function. Further- more, current treatment modalities are often limited by inconvenient dosing regimens, safety and tolerability issues, the latter including hypo- glycemia, body weight gain, edema and gastro- intestinal side effects. The incretin hormones glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) are intestinal hormones that augment insulin secretion in response to the ingestion of nutrients. The actions of GLP-1 and GIP, which also include trophic effects on the β- cells, have attracted a lot of interest. GLP-1 also inhibits glucagon secretion and suppresses food intake and appetite. Recently, an entirely new therapeutic modality for the treatment of type 2 diabetes based on the effect of GLP-1 was intro- duced onto the market. Incretin-based therapies fall into two groups: (1) GLP-1 receptor agonists, i.e. injectable pep- tide preparations with actions similar to the nat- ural incretin hormone GLP-1; and (2) the incretin enhancers, which are orally available agents that inhibit the degradation of the incretin hormones and thereby increase their plasma concentrations and biological actions. This review outlines the scientific basis for the development of GLP-1 receptor agonists and incretin enhancers, assesses the clinical experi- ence gathered so far and discusses future expec- tations for incretin-based therapy. Key words: Incretin hormones, dipeptidyl peptidase-4 (DPP-4), glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), incretin mimetics, GLP-1 receptor agonists, type 2 diabetes Incretin hormones: secretion, effect and degradation The ‘incretin effect’ refers to the amplification of glucose-stimulated insulin secretion elicited by hormones secreted from the gastrointestinal tract. In the strictest sense, it is quantified by comparing insulin responses to oral and intra- venous glucose administration where the intra- venous infusion is adjusted so as to result in the same (isoglycemic) plasma glucose concentra- tions as the oral stimulus [1, 2]. In healthy sub- jects, oral administration causes a two- to threefold larger insulin response compared with the isoglycemic intravenous stimulus. The incretin hormones GLP-1 and GIP are intestinal hormones that augment insulin secretion in response to the ingestion of nutrients This discrepancy in insulin secretion between the two stimuli is due to the actions of incretin hormones, glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 is a 30-amino acid polypeptide produced in the endocrine L-cells of the intesti- nal epithelium as a product of glucagon gene expression. The GLP-1 moiety is liberated from proglucagon by the action of prohormone convertase 1/3 (PC1/3). This is in contrast to proglucagon processing in the pancreatic α-cells, where prohormone convertase 2 cleaves out glucagon but leaves the GLP-1 molecule embedded in a large inactive fragment [3]. The L-cells are found throughout the intestinal REVIEW ARTICLES Glucagon-like peptide-1 and diabetes treatment Tina Vilsbøll, Kristine J. Hare, Jonatan O. Bagger and Filip K. Knop Department of Internal Medicine F, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark (t.vilsboll@dadlnet.dk)