DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1262
Proglucagon
GRPP Glucagon IP-1 GLP-1 IP-2 GLP-2
Pancreatic Islet α-cells
(PC2 dominant)
IP-1
IP-2
Intestinal L-cells and STN neurons
(PC1/3 dominant)
GRPP
Glucagon
GLP-1
IP-2
GLP-2
GRPP
Glucagon IP-1
GLP-1
GLP-2
Major Proglucagon
Fragment
Glicentin
SECTION V
HORMONES AND HORMONE ANTAGONISTS
treatment diabetic patients in the U.S. and several others
in advanced phases of development. Exendin-4 is a
naturally occurring reptilian peptide of 39 amino acids
with considerable homology to GLP-1. It is a potent
GRPP
Glucagon
IP-1
Oxyntomodulin
Figure 43–9. Processing of proglucagon to glucagon, GLP1. GLP-2, and GRPP. Proglucagon is synthesized in islet α cells, intestinal
enteroendocrine cells (L cells) and a subset of neurons in the hindbrain. In α cells, prohormone processing is primarily by proconvertase
2, releasing glucagon, glicentin-related pancreatic polypeptide (GRPP), and a major proglucagon fragment, containing the two
glucagon-like peptides (GLPs). In L cells and neurons, proglucagon cleavage is mostly through proconvertase 1/3, giving the larger
C-terminal peptides, glicentin and oxyntomodulin, and the smaller GLP-1 and GLP-2. STN, solitary tract nucleus.
Intact incretins
GLP-1 [7-36]
GLP-1 receptor agonist that shares many of the physiological
and pharmacological effects of GLP-1. It is not
metabolized by DPP-4 and so has a plasma t 1/2
of 2-3
hours following subcutaneous injection. Importantly,
Incretin
metabolites
GIP-1 [1-42] Capillaries
GLP-1 [9-36]
GIP-1 [3-42]
Intact GLP-1
Meal
DPP-4 inhibitor
No drug
Intact GIP
Meal
DPP-4
inhibitor
No drug
Time
Time
Figure 43–10. Pharmacological effects of DDP-4 inhibition. DPP-4, an ectoenzyme located on the luminal side of capillary endothelial
cells metabolizes the incretins, glucagon-like peptide 1 (GLP-1). and glucose-dependent insulinotropic polypeptide (GIP), by removing
the two N-terminal amino acids. The target for DPP-4 cleavage is a proline or alanine residue in the second position of the primary
peptide sequence. The truncated metabolites GLP-1[9-36] and GIP[3-42] are the major forms of the incretins in plasma and are inactive
as insulin secretagogues. Treatment with a DPP-4 inhibitor increases the concentrations of intact GLP-1 and GIP.