Incretin-based Therapies
Incretin-based Therapies
The human incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide are released by the intestine following nutrient exposure. In normal individuals, incretin activity is estimated to be responsible for around 70% of post-prandial insulin secretion; however, the incretin effect is impaired in individuals with type 2 diabetes. Human GLP-1 has many important actions that could directly benefit patients with type 2 diabetes, such as: stimulating insulin secretion and suppressing glucagon secretion in a glucosedependent manner; promoting glucose uptake and glycogen synthesis by muscle, liver and adipose tissue; protecting β-cell function; and inducing feelings of satiety and reducing appetite. Human GLP-1 has a short half-life of around two minutes in circulation, as it is rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4), minimising its therapeutic potential. Therefore, therapies are based on two main approaches. One approach has been the development of GLP-1 receptor agonists that are more resistant to DPP-4-mediated degradation than native GLP-1. This increases their circulating half-life in vivo and enables pharmacological levels of GLP-1 activity to be achieved. Another approach is taken by the group of DPP-4 inhibitors, which restore physiological GLP-1 activity by reducing the degradation of endogenous GLP-1.
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