Figure 4.

Illustrations of the endocrine (A) and nerve‐stimulating (B) elements of the mode of action of glucagon‐like peptide‐1 (GLP‐1) and of the predominant modes of action of GLP‐1 receptor agonists (GLP‐1RAs) (C) and DPP‐4 inhibitors (D). (A) GLP‐1 (depicted by red ovals) is released from L‐cells in the gut mucosa, and is partially degraded and inactivated by DPP‐4 in the vicinity of L‐cells in the gut mucosa and other compartments (circulatory system and other tissues). GLP‐1 surviving in its intact, biologically active form reaches target cells expressing the GLP‐1 receptor (GLP‐1R) via the bloodstream. (B) Afferent vagal nerve endings with GLP‐1Rs respond to GLP‐1 immediately after its release from L‐cells. The signal reaches the brain via ganglia belonging to the parasympathetic nervous system. The brain then sends efferent impulses to target organs for GLP‐1 activity, such as the endocrine pancreas, where insulin secretion is stimulated and glucagon secretion is suppressed. The endocrine and nerve‐stimulating elements of the mode of action of GLP‐1 co‐exist and may vary in their relative importance. (C) GLP‐1RAs (yellow ovals) are injected into the adipose tissue compartment and, from there, mainly reach target cells via the general circulation. (D) For DPP‐4 inhibitors, a substantial proportion of the effects may be mediated through enhanced interactions of GLP‐1 maintained in its intact, biologically active form, with receptors on afferent vagal fibres (i.e. the neural pathway).