Limits...
Cardiovascular benefits of GLP-1-based herapies in patients with diabetes mellitus type 2: effects on endothelial and vascular dysfunction beyond glycemic control.

Forst T, Weber MM, Pfützner A - Exp Diabetes Res (2012)

Bottom Line: Beside more or less comparable glucose lowering efficacy, some of them have shown limited or probably even unfavorable effects on the cardiovascular system and overall mortality.Beside the effects of GLP-1 on insulin secretion, glucagon secretion, and gastrointestinal motility, recent studies suggested a couple of direct cardiovascular effects of GLP-1-based therapies.The goal of this paper is to provide an overview about the current knowledge of direct GLP-1 effects on endothelial and vascular function and potential consequences on the cardiovascular outcome in patients with T2DM treated with GLP-1 receptor agonists or DPP-IV inhibitors.

View Article: PubMed Central - PubMed

Affiliation: Institute for Clinical Research and Development, 55116 Mainz, Germany. thomasf@ikfe.de

ABSTRACT
Type 2 diabetes mellitus (T2DM) is a progressive multisystemic disease accompanied by vascular dysfunction and a tremendous increase in cardiovascular mortality. Numerous adipose-tissue-derived factors and beta cell dysfunction contribute to the increased cardiovascular risk in patients with T2DM. Nowadays, numerous pharmacological interventions are available to lower blood glucose levels in patients with type 2 diabetes. Beside more or less comparable glucose lowering efficacy, some of them have shown limited or probably even unfavorable effects on the cardiovascular system and overall mortality. Recently, incretin-based therapies (GLP-1 receptor agonists and DPP-IV inhibitors) have been introduced in the treatment of T2DM. Beside the effects of GLP-1 on insulin secretion, glucagon secretion, and gastrointestinal motility, recent studies suggested a couple of direct cardiovascular effects of GLP-1-based therapies. The goal of this paper is to provide an overview about the current knowledge of direct GLP-1 effects on endothelial and vascular function and potential consequences on the cardiovascular outcome in patients with T2DM treated with GLP-1 receptor agonists or DPP-IV inhibitors.

Show MeSH

Related in: MedlinePlus

Schematic illustration of GLP-1-receptor-dependent and GLP-1-receptor-independent pathways in the signalling of GLP-1 associated cardiovascular effects (PI3K: phosphatidylinositol 3 kinase; cAMP: cyclic adenosine monophosphate, PKA: protein kinase A, PKB: protein kinase B, GSK3ß: glycogen synthase kinase 3 beta, MEK1/2: components of the MAP kinase cascade, ERK: extracellular-signal-regulated kinase, NO: nitric oxide, eNOS: endothelial nitric oxide synthase, cGMP: cyclic guanosine monophosphate, PKG: protein kinase G; adapted to [69]).
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3345223&req=5

fig4: Schematic illustration of GLP-1-receptor-dependent and GLP-1-receptor-independent pathways in the signalling of GLP-1 associated cardiovascular effects (PI3K: phosphatidylinositol 3 kinase; cAMP: cyclic adenosine monophosphate, PKA: protein kinase A, PKB: protein kinase B, GSK3ß: glycogen synthase kinase 3 beta, MEK1/2: components of the MAP kinase cascade, ERK: extracellular-signal-regulated kinase, NO: nitric oxide, eNOS: endothelial nitric oxide synthase, cGMP: cyclic guanosine monophosphate, PKG: protein kinase G; adapted to [69]).

Mentions: GLP-1 acts through a distinct heptahelical G-protein-coupled receptor, which has been located not only in beta cells and the gastrointestinal tract, but also in the nervous system, heart, vascular smooth muscle cells, endothelial cells, and macrophages [45, 58, 70, 71]. GLP-1 appears to modulate a wide range of physiological effects, not only regulating blood glucose and metabolic control, but also directly affecting several cardiovascular pathways involved in atherogenesis. Binding of GLP-1 to the GLP-1 receptor in the myocardium leads to an increase in the production of cyclic adenosine monophosphate (cAMP) and an activation of protein kinase A (PKA), which results in an increase in glucose uptake and the inotropic effects in myocardial tissue. GLP-1 knockout mice exhibit reduced resting heart rate, elevated left ventricular and diastolic pressure, and increased left ventricular thickness compared with normal controls [58]. In agreement with this findings, treatment with GLP-1 or the GLP-1 receptor agonists was found to improve left ventricular function [72, 73] and to reduce circulating levels of brain natriuretic peptide (BNP) [74, 75]. GLP-1 increased functional cardiomyocyte viability in an isolated mouse heart reperfusion model but, unexpectedly, many of these actions were preserved in the GLP-1 knockout mouse model, suggesting cardiovascular effects that are independent of the GLP-1-receptor-mediated activation of cAMP/PKA [50]. Ban et al. studied the myocardial effects of GLP-1 (7-39) and GLP-1(9-39) under postischemic conditions in both wild-type and GLP1r (−/−) (GLP-1 receptor knockout mice) [58]. In wild-type mice, some of the effects of GLP-1 (7-39) could be reproduced by the truncated peptide GLP-1 (9-39). Those effects could also be induced by GLP1 (7-39) and GLP-1 (9-39) in the GLP1r (−/−) knockout mouse model. In addition, the beneficial effects of GLP-1 in the knockout mouse model could be abolished by the addition of the DPP-IV inhibitor Sitagliptin and by the administration of the NO-synthase blocker L-NNA (NG-nitro-arginine). This leads to the hypothesis of a two pathway mechanism for the protective cardiovascular action of GLP-1. One that depends on the GLP-1 receptor mediated action with inotropic, glucose uptake stimulating, ischemic preconditioning effects, and one, receptor independent vasodilatatory pathway, which is mediated by NO (Figure 4).


Cardiovascular benefits of GLP-1-based herapies in patients with diabetes mellitus type 2: effects on endothelial and vascular dysfunction beyond glycemic control.

Forst T, Weber MM, Pfützner A - Exp Diabetes Res (2012)

Schematic illustration of GLP-1-receptor-dependent and GLP-1-receptor-independent pathways in the signalling of GLP-1 associated cardiovascular effects (PI3K: phosphatidylinositol 3 kinase; cAMP: cyclic adenosine monophosphate, PKA: protein kinase A, PKB: protein kinase B, GSK3ß: glycogen synthase kinase 3 beta, MEK1/2: components of the MAP kinase cascade, ERK: extracellular-signal-regulated kinase, NO: nitric oxide, eNOS: endothelial nitric oxide synthase, cGMP: cyclic guanosine monophosphate, PKG: protein kinase G; adapted to [69]).
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3345223&req=5

fig4: Schematic illustration of GLP-1-receptor-dependent and GLP-1-receptor-independent pathways in the signalling of GLP-1 associated cardiovascular effects (PI3K: phosphatidylinositol 3 kinase; cAMP: cyclic adenosine monophosphate, PKA: protein kinase A, PKB: protein kinase B, GSK3ß: glycogen synthase kinase 3 beta, MEK1/2: components of the MAP kinase cascade, ERK: extracellular-signal-regulated kinase, NO: nitric oxide, eNOS: endothelial nitric oxide synthase, cGMP: cyclic guanosine monophosphate, PKG: protein kinase G; adapted to [69]).
Mentions: GLP-1 acts through a distinct heptahelical G-protein-coupled receptor, which has been located not only in beta cells and the gastrointestinal tract, but also in the nervous system, heart, vascular smooth muscle cells, endothelial cells, and macrophages [45, 58, 70, 71]. GLP-1 appears to modulate a wide range of physiological effects, not only regulating blood glucose and metabolic control, but also directly affecting several cardiovascular pathways involved in atherogenesis. Binding of GLP-1 to the GLP-1 receptor in the myocardium leads to an increase in the production of cyclic adenosine monophosphate (cAMP) and an activation of protein kinase A (PKA), which results in an increase in glucose uptake and the inotropic effects in myocardial tissue. GLP-1 knockout mice exhibit reduced resting heart rate, elevated left ventricular and diastolic pressure, and increased left ventricular thickness compared with normal controls [58]. In agreement with this findings, treatment with GLP-1 or the GLP-1 receptor agonists was found to improve left ventricular function [72, 73] and to reduce circulating levels of brain natriuretic peptide (BNP) [74, 75]. GLP-1 increased functional cardiomyocyte viability in an isolated mouse heart reperfusion model but, unexpectedly, many of these actions were preserved in the GLP-1 knockout mouse model, suggesting cardiovascular effects that are independent of the GLP-1-receptor-mediated activation of cAMP/PKA [50]. Ban et al. studied the myocardial effects of GLP-1 (7-39) and GLP-1(9-39) under postischemic conditions in both wild-type and GLP1r (−/−) (GLP-1 receptor knockout mice) [58]. In wild-type mice, some of the effects of GLP-1 (7-39) could be reproduced by the truncated peptide GLP-1 (9-39). Those effects could also be induced by GLP1 (7-39) and GLP-1 (9-39) in the GLP1r (−/−) knockout mouse model. In addition, the beneficial effects of GLP-1 in the knockout mouse model could be abolished by the addition of the DPP-IV inhibitor Sitagliptin and by the administration of the NO-synthase blocker L-NNA (NG-nitro-arginine). This leads to the hypothesis of a two pathway mechanism for the protective cardiovascular action of GLP-1. One that depends on the GLP-1 receptor mediated action with inotropic, glucose uptake stimulating, ischemic preconditioning effects, and one, receptor independent vasodilatatory pathway, which is mediated by NO (Figure 4).

Bottom Line: Beside more or less comparable glucose lowering efficacy, some of them have shown limited or probably even unfavorable effects on the cardiovascular system and overall mortality.Beside the effects of GLP-1 on insulin secretion, glucagon secretion, and gastrointestinal motility, recent studies suggested a couple of direct cardiovascular effects of GLP-1-based therapies.The goal of this paper is to provide an overview about the current knowledge of direct GLP-1 effects on endothelial and vascular function and potential consequences on the cardiovascular outcome in patients with T2DM treated with GLP-1 receptor agonists or DPP-IV inhibitors.

View Article: PubMed Central - PubMed

Affiliation: Institute for Clinical Research and Development, 55116 Mainz, Germany. thomasf@ikfe.de

ABSTRACT
Type 2 diabetes mellitus (T2DM) is a progressive multisystemic disease accompanied by vascular dysfunction and a tremendous increase in cardiovascular mortality. Numerous adipose-tissue-derived factors and beta cell dysfunction contribute to the increased cardiovascular risk in patients with T2DM. Nowadays, numerous pharmacological interventions are available to lower blood glucose levels in patients with type 2 diabetes. Beside more or less comparable glucose lowering efficacy, some of them have shown limited or probably even unfavorable effects on the cardiovascular system and overall mortality. Recently, incretin-based therapies (GLP-1 receptor agonists and DPP-IV inhibitors) have been introduced in the treatment of T2DM. Beside the effects of GLP-1 on insulin secretion, glucagon secretion, and gastrointestinal motility, recent studies suggested a couple of direct cardiovascular effects of GLP-1-based therapies. The goal of this paper is to provide an overview about the current knowledge of direct GLP-1 effects on endothelial and vascular function and potential consequences on the cardiovascular outcome in patients with T2DM treated with GLP-1 receptor agonists or DPP-IV inhibitors.

Show MeSH
Related in: MedlinePlus