Abstract 1489: Mechanisms Underlying Cardioprotective Effects Of Glucagon-like Peptide-1 In Ischemia-reperfusion Injury

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.

Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies.

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Should diabetes patients be on these new incretin drugs long term?

Gastroenterology. 2011 Jul;141(1):150-6. Epub 2011 Feb 18.


Abstract


BACKGROUND & AIMS: Glucagon-like peptide-1-based therapy is gaining widespread use for type 2 diabetes, although there are concerns about risks for pancreatitis and pancreatic and thyroid cancers. There are also concerns that dipeptidyl peptidase-4 inhibitors could cause cancer, given their effects on immune function.



METHODS:

• We examined the US Food and Drug Administration's database of reported adverse events for those associated with the dipeptidyl peptidase-4 inhibitor sitagliptin and the glucagon-like peptide-1 mimetic exenatide, from 2004-2009; data on adverse events associated with 4 other medications were compared as controls.
• The primary outcomes measures were rates of reported pancreatitis, pancreatic and thyroid cancer, and all cancers associated with sitagliptin or exenatide, compared with other therapies.

RESULTS:

• Use of sitagliptin or exenatide increased the odds ratio for reported pancreatitis 6-fold as compared with other therapies (P<2×10(-16)).
• Pancreatic cancer was more commonly reported among patients who took sitagliptin or exenatide as compared with other therapies (P<.008, P<9×10(-5)).
• All other cancers occurred similarly among patients who took sitagliptin compared with other therapies (P=.20).

CONCLUSIONS: These data are consistent with case reports and animal studies indicating an increased risk for pancreatitis with glucagon-like peptide-1-based therapy. The findings also raise caution about the potential long-term actions of these drugs to promote pancreatic cancer.

Can GLP-1 really be classified as an incretin?

Erythromycin Antagonizes the Deceleration of Gastric Emptying by Glucagon-Like Peptide 1 and Unmasks Its Insulinotropic Effect in Healthy Subjects

In this study Nauk reveals some interesting things:
1. the predominant GLP-1 effect in the lowering of blood sugar comes from the lowering of GI motility and not the stimulation of insulin.
2. GLP-1 physiologically doesn't cause an increase in insulin. Rather, since it has such a strong effect of reducing GI motility, it actually lowers the postprandial insulin level.

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Are there hidden dangers in GLP-1 analogs?

Incretin analogs have been a very powerful tool in the management of type 2 diabetes. Despite it's rapid acceptance and pervasive use, we have very limited understanding of any pathology that may arise from the dysregulation of this system.

One described phenomenon has been postprandial hypoglycemia after gastric bypass. Could the hypoglycemia that had been termed dumping syndrome be from the dysregulation or overstimation of this system?

An article in JCEM by Palladino tries to address this issue. He evaluated patients with fundoplication for an abnormal incretin response.

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