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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.

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Related in: MedlinePlus

Postprandial proinsulin/insulin ratio in patients treated with sulfonylurea, insulin Glargine, or DPP-IV inhibitors compared to nondiabetic healthy controls (*: P < 0.05 versus nondiabetic controls adapted to [67]).
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Related In: Results  -  Collection


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fig3: Postprandial proinsulin/insulin ratio in patients treated with sulfonylurea, insulin Glargine, or DPP-IV inhibitors compared to nondiabetic healthy controls (*: P < 0.05 versus nondiabetic controls adapted to [67]).

Mentions: Recently, it has been reported that the vulnerability of the beta cell to release the prohormone intact proinsulin, instead of insulin and C-peptide, is linked to beta cell polymorphisms observed in three different risk alleles [22]. The mechanisms by which these risk alleles (HHEX, CDKN2A/B, and IGF2BP2) influence proinsulin processing are still a matter of debate. Loos et al. demonstrated that the genes of pro-protein convertases 1 and 2, which are key proteins in the conversion from proinsulin to insulin, exhibit binding sites for the T-cell transcription factor [60]. Therefore, an interaction with these pro-protein convertases may be a mechanism leading to increased proinsulin levels in carriers of the risk alleles [22]. As GLP-1 infusion is able to normalize reduced proinsulin conversion, and GLP-1 signaling is impaired in carriers of the risk alleles in TCF7L2, it is conceivable that an attenuated GLP-1 signaling might lead to an impaired proinsulin processing [61]. Several clinical studies have shown an improvement in the Proinsulin/Insulin Ratio during treatment with GLP-1 receptor agonists [62, 63] and DPP-IV inhibitors [64–66]. In a cross-sectional study, postprandial intact proinsulin levels were significantly higher in sulfonylurea-treated patients compared to insulin and DPP-IV-inhibitor-treated patients and a non-diabetic control group [67]. As shown in Figure 3, the proinsulin/insulin ratio was comparable in between the DPP-IV-inhibitor-treated group and the nondiabetic control group, while it was evaluated in the sulfonylurea- and the insulin-treated group. In a recent study, the introduction of liraglutide treatment caused a pronounced decrease in intact proinsulin levels, which was found in parallel with a reduction in E-Selectin, asymmetric-dimethyl-arginine (ADMA), and PAI-1 levels, and an improvement in endothelial function [68]. Therefore, it seems conceivable that GLP-1-based treatments do not only improve beta cell function by an induction of the proinsulin convertases but also reduce vascular risk by the reduction in circulating absolute proinsulin levels.


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)

Postprandial proinsulin/insulin ratio in patients treated with sulfonylurea, insulin Glargine, or DPP-IV inhibitors compared to nondiabetic healthy controls (*: P < 0.05 versus nondiabetic controls adapted to [67]).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig3: Postprandial proinsulin/insulin ratio in patients treated with sulfonylurea, insulin Glargine, or DPP-IV inhibitors compared to nondiabetic healthy controls (*: P < 0.05 versus nondiabetic controls adapted to [67]).
Mentions: Recently, it has been reported that the vulnerability of the beta cell to release the prohormone intact proinsulin, instead of insulin and C-peptide, is linked to beta cell polymorphisms observed in three different risk alleles [22]. The mechanisms by which these risk alleles (HHEX, CDKN2A/B, and IGF2BP2) influence proinsulin processing are still a matter of debate. Loos et al. demonstrated that the genes of pro-protein convertases 1 and 2, which are key proteins in the conversion from proinsulin to insulin, exhibit binding sites for the T-cell transcription factor [60]. Therefore, an interaction with these pro-protein convertases may be a mechanism leading to increased proinsulin levels in carriers of the risk alleles [22]. As GLP-1 infusion is able to normalize reduced proinsulin conversion, and GLP-1 signaling is impaired in carriers of the risk alleles in TCF7L2, it is conceivable that an attenuated GLP-1 signaling might lead to an impaired proinsulin processing [61]. Several clinical studies have shown an improvement in the Proinsulin/Insulin Ratio during treatment with GLP-1 receptor agonists [62, 63] and DPP-IV inhibitors [64–66]. In a cross-sectional study, postprandial intact proinsulin levels were significantly higher in sulfonylurea-treated patients compared to insulin and DPP-IV-inhibitor-treated patients and a non-diabetic control group [67]. As shown in Figure 3, the proinsulin/insulin ratio was comparable in between the DPP-IV-inhibitor-treated group and the nondiabetic control group, while it was evaluated in the sulfonylurea- and the insulin-treated group. In a recent study, the introduction of liraglutide treatment caused a pronounced decrease in intact proinsulin levels, which was found in parallel with a reduction in E-Selectin, asymmetric-dimethyl-arginine (ADMA), and PAI-1 levels, and an improvement in endothelial function [68]. Therefore, it seems conceivable that GLP-1-based treatments do not only improve beta cell function by an induction of the proinsulin convertases but also reduce vascular risk by the reduction in circulating absolute proinsulin levels.

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