This study discuss the mechanism of incretin benefit in the heart.
This also is from the expert of incretin in the west side of the hemisphere, Daniel Drucker. This shows that the DPPIV blunts the benefit of GLP-1.
Kiwon Ban ; Judith Hoefer ; Steffen S Bolz ; Daniel J Drucker ; Mansoor Husain
Depts of Medicine and Physiology, Heart & Stroke Richard Lewar Cntr of Excellence, Banting & Best Diabetes Cntr, Samuel Lunenfeld Rsch Institute, Univ of Toronto, Toronto, Canada
Background: GLP-1 is a member of the gut incretin hormone family, and a GLP-1 receptor agonist (exendin-4) is approved for the treatment of Type-II diabetes. Studies in man post-MI, and in rat and dog models suggest that GLP-1 is cardioprotective. However, the mechanisms underlying the effects of structurally diverse GLP-1 peptides in the heart have not been fully elucidated.
Methods & Results: GLP-1(7–36) (i.e. GLP-1), its cleavage product GLP(9–36), and the degradation-resistant GLP-1R agonist exendin-4 were examined in 30 min of global ischemia followed by 40 min of reperfusion (I/R) in Langendorff isolated heart preparations from both wild-type (WT) and GLP-1 receptor knockout (GLP-1R–/–) mice. In WT mice, recovery of left ventricular developed pressure (LVDP) following I/R was higher in GLP-1 pre-infused hearts than in untreated controls (79±9 vs. 42±1%; p<0.01). Pre-treatment with 5 nM but not with 0.3~3 nM exendin-4 also protected the heart from I/R injury. Although pre-infusion of GLP(9–36) induced lower recovery than untreated controls (21.4±1%), post-infusion of either GLP(9–36) or GLP-1 augmented functional recovery to a similar extent (59.1±6% and 53.3±6%). Surprisingly, the cardioprotective effects of pre- and post-treatments with both molecular forms of GLP-1 were detected in studies with GLP-1R–/– hearts (80.1±6% and 55.8±8). Of note, both GLP-1 and GLP(9–36) treatments also demonstrated potent vasodilatory effects, as manifested by increased coronary flow rates in isolated hearts and increased diameters of pre-constricted mesenteric arteries isolated from both WT and GLP-1R–/– mice. The cardioprotective effects on isolated hearts and vasodilatory effects on isolated mesenteric arteries, induced by GLP-1 was blunted by co-treatment with a dipeptidyl peptidase-4 (DPP-4) enzyme inhibitor, that blocked conversion of GLP-1 to GLP(9–36). Increased cGMP release in the coronary effluents was also observed following addition of GLP-1 and GLP(9–36) to hearts isolated from WT and GLP-1R–/– mice.
Summary: These data expand the complexity of GLP-1 biology by illustrating that the beneficial effects of GLP-1 in I/R injury are mediated in part by GLP(9–36) via a NO/cGMP-dependent vasodilatory effect that is independent of the known GLP-1R.