Ghrelin: a new incretin enhancer therapy?

Abstract

The overarching goal of diabetes therapies is to get patients under good glycemic control using therapies that lower abnormally elevated plasma glucose, thereby reducing glucose toxicity, oxidative stress, and inflammation, conditions that promote cardiovascular disease (CVD) and chronic kidney disease. Unfortunately, some conventional diabetes therapies, although effective at controlling glycemia, induce weight gain and actually increase the risk of hypoglycemic episodes and associated CVD events. To this end, the development of novel, safe, and effective therapies that improve long-term glycemic control, that minimize the risk of hypoglycemia, that do not increase weight gain (or induce therapeutic weight loss), and that promote cardiovascular (CV) health is a better way forward (1). The ongoing development of incretin-enhancing therapies may be an example of such an approach. The gut-derived incretin hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide, are secreted in response to the postprandial increase in glucose and act to augment glucose-dependent pancreatic insulin secretion, suppress glucagon release, slow gastric emptying, enhance satiety, and modulate the so-called gut-brain axis (2,3). The action of incretin hormones is short-lived due to rapid degradation by the ubiquitous enzyme, dipeptidyl peptidase-4 (DPP-4). Earlier studies showed that the incretin axis in individuals with type 2 diabetes mellitus (T2DM) is impaired (4,5), and this has led to the development of novel incretin-enhancing therapies, such as the stable (i.e., DPP-4–resistant) receptor (GLP-1R) agonists and DPP-4 inhibitors. Accumulating evidence suggests that modulation of incretin signaling by GLP-1R agonists or DPP-4 inhibitors is not only beneficial for improving glycemic control but confers neutral or modest CV protection (6,7). Given the complexity …