Cardiovascular biology of the incretin system

Abstract

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that enhances glucose-stimulated insulin secretion and exerts direct and indirect actions on the cardiovascular system. GLP-1 and its related incretin hormone, glucose-dependent insulinotropic polypeptide, are rapidly inactivated by the enzyme dipeptidyl peptidase 4 (DPP-4), a key determinant of incretin bioactivity. Two classes of medications that enhance incretin action, GLP-1 receptor (GLP-1R) agonists and DPP-4 inhibitors, are used for the treatment of type 2 diabetes mellitus. We review herein the cardiovascular biology of GLP-1R agonists and DPP-4 inhibitors, including direct and indirect effects on cardiomyocytes, blood vessels, adipocytes, the control of blood pressure, and postprandial lipoprotein secretion. Both GLP-1R activation and DPP-4 inhibition exert multiple cardioprotective actions in preclinical models of cardiovascular dysfunction, and short-term studies in human subjects appear to demonstrate modest yet beneficial actions on cardiac function in subjects with ischemic heart disease. Incretin-based agents control body weight, improve glycemic control with a low risk of hypoglycemia, decrease blood pressure, inhibit the secretion of intestinal chylomicrons, and reduce inflammation in preclinical studies. Nevertheless, there is limited information on the cardiovascular actions of these agents in patients with diabetes and established cardiovascular disease. Hence, a more complete understanding of the cardiovascular risk to benefit ratio of incretin-based therapies will require completion of long-term cardiovascular outcome studies currently underway in patients with type 2 diabetes mellitus.

Figure 1. GLP-1 targets multiple organs to improve glucose control in T2DM

GLP-1 acts directly and indirectly on several peripheral tissues that contribute to lowering of blood glucose levels. These include potent effects on the pancreatic β-cell to stimulate insulin secretion, inhibition of α-cell glucagon secretion that reduces hepatic glucose production, a decrease in gastric motility, and a reduction in appetite that contributes to weight loss, reduced levels of adipocytokines and decreased inflammation.

Figure 2. GLP-1R–Dependent Intracellular Signal Transduction Pathways in the Cardiomyocyte

The signalling pathways engaged downstream of the cardiomyocyte GLP-1R lead to a reduction in apoptosis and increase in glucose uptake independent of the classical insulin-dependent pathway.

Figure 3. Anti-Atherosclerotic potential of GLP-1 action

The direct actions of GLP-1 on blood vessels, macrophages, and on the regulation of plasma lipid profiles may impact the development and/or progression of atherosclerotic plaques.

Figure 4. Indirect Cardiac Actions of GLP-1

In addition to direct actions on the cardiomyocyte, GLP-1 may also influence cardiac function indirectly through its actions on pancreatic islets to enhance glucose-dependent insulin secretion and inhibit glucagon secretion, thereby changing levels of islet hormones, glucose and fatty acids, all of which may also directly impact the heart.

Figure 5. DPP-4 Substrates that directly or indirectly regulate cardiovascular function

Multiple DPP-4 substrates have been identified that act on multiple peripheral tissues that influence the cardiovascular system. For a summary of these direct effects on target tissues refer to Table 1.