The pathophysiology of type 2 diabetes involves the combined effects of reduced insulin action (insulin resistance) and defective insulin secretion (beta cell dysfunction). Progressive beta cell failure is a strong driver for the escalating hyperglycaemia during advancement of the disease. Therapeutic interventions to preserve beta cell function and increase insulin secretion require a controlled to avoid episodes of hypoglycaemia. Sulphonylureas and meglitinides can initiate insulin secretion and enhance nutrient-induced insulin secretion, but with little effect on insulin biosynthesis. Sulphonylureas bind to the cytosolic face of a transmembranal complex of the sulphonylurea receptor SUR1 with the adenosine-triphosphate (ATP)-sensitive Kir6.2 potassium efflux channel. This closes the channels, depolarises the membrane, opens voltage-dependent calcium channels and raises intracellular free calcium concentrations. This in turn activates calcium-dependent exocytotic pathways regulating phasic insulin exocytosis. Meglitinides are more rapidly-acting and shorter-acting insulin secretagogues that bind to a ‘benzamido’ site on the SUR1-Kir6.2 complex. Recently, therapeutic attention has turned to the endocrine components of the entero-insular axis (‘incretins’)that enhance the physiological insulin response to a meal. The incretin effect is reduced in type 2 diabetes, and the meal-stimulated gut hormone glucagon-like peptide-1 (GLP-1) is particularly attractive as a therapy because it exerts a glucose-dependent insulinotropic effect, reduces glucagon secretion, slows gastric emptying and exerts a satiety effect. GLP-1 acts on the beta cell via a G-protein linked receptor to potentiate nutrient-induced insulin secretion and insulin biosynthesis. Animal and in vitro studies have suggested that GLP-1 might assist the preservation of beta cell mass. However, GLP-1 is rapidly degraded by the enzyme dipepidyl peptidase IV (DPP-4) which breaks the peptide at the N2 alanine residue. To counter the effect of DPP-4, GLP-1 analogues have been developed with a different N2 residue that confers resistance to DPP-4. Additional modifications have been introduced to further extend the biological half-life. The first DPP-4 resistant GLP-1 analogue in clinical use, exenatide, retains the biological effects of GLP-1. As a peptide it is delivered by twice daily subcutaneous injection, lowering HbA1c without causing significant hypoglycemia and usually accompanied by a reduction in body weight. Longer-acting formulations of GLP-1 analogues such as liraglutide (GLP-1 linked to albumin via a fatty acid) are advanced in development. As an alternative approach to prevent the rapid degradation of endogenous GLP-1, several inhibitors of DPP-4 (termed ‘gliptins’) have been developed. These agents reduce HbA1c, carry low risk of hypoglycemia and do not cause weight gain.