The role of efferent cholinergic transmission for the insulinotropic and glucagonostatic effects of GLP-1

Plamboeck, Astrid; Veedfald, Simon; Deacon, Carolyn F.; Hartmann, Bolette; Vilsbøll, Tina; Knop, Filip K.; Holst, Jens J.

doi:10.1152/ajpregu.00123.2015

Cited by 21 publications

(19 citation statements)

References 57 publications

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“…Subjects with a truncal vagotomy (associated with previous surgery for duodenal ulcer or oesophageal cancer) also have an intact incretin effect, but there was some impairment in GI‐mediated glucose disposal and in the ability of DPP‐4 inhibition to enhance insulin secretion, while the effects of exogenous GLP‐1 on food intake were lost . However, in contrast to rodent studies, atropine did not attenuate the insulinotropic actions of exogenous GLP‐1 in healthy subjects . Taken together, the data could point towards a potential role for vagal signalling in the actions of GLP‐1 under some circumstances, although the relative importance of this mechanism for the anti‐diabetic effects of DPP‐4 in humans is far from clarified.…”

Section: Mechanism Of Actionmentioning

confidence: 89%

“…38 However, in contrast to rodent studies, 34 atropine did not attenuate the insulinotropic actions of exogenous GLP-1 in healthy subjects. 39 Taken together, the data could point towards a potential role for vagal signalling in the actions of GLP-1 under some circumstances, although the relative importance of this mechanism for the anti-diabetic effects of DPP-4 in humans is far from clarified.…”

Section: Local Neural Signalling Pathwaymentioning

confidence: 98%

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Do we know the true mechanism of action of the DPP‐4 inhibitors?

Andersen

Deacon

Holst

2017

Diabetes Obesity Metabolism

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The prevalence of type 2 diabetes is increasing, which is alarming because of its serious complications. Anti-diabetic treatment aims to control glucose homeostasis as tightly as possible in order to reduce these complications. Dipeptidyl peptidase-4 (DPP-4) inhibitors are a recent addition to the anti-diabetic treatment modalities, and have become widely accepted because of their good efficacy, their benign side-effect profile and their low hypoglycaemia risk. The actions of DPP-4 inhibitors are not direct, but rather are mediated indirectly through preservation of the substrates they protect from degradation. The two incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, are known substrates, but other incretin-independent mechanisms may also be involved. It seems likely therefore that the mechanisms of action of DPP-4 inhibitors are more complex than originally thought, and may involve several substrates and encompass local paracrine, systemic endocrine and neural pathways, which are discussed here. and, thereby, to enhance its antihyperglycaemic actions. 5,6 GLP-1 is a gut hormone, released in response to digestion and absorption of food in the small intestine, which is responsible for an important part of postprandial insulin secretion. 7 This, the so-called incretin effect, is markedly reduced in patients with type 2 diabetes (T2D), which is believed to contribute to the inferior glucose tolerance seen after food ingestion in these individuals. 7 An additional incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), is also degraded by DPP-4, 2,4,8 but given that the insulinotropic, and hence glucose-lowering, effect of GIP is almost entirely absent in patients with T2D, 9 it was originally thought that anti-hyperglycaemic actions of DPP-4 inhibitors were mediated entirely by GLP-1 escaping DPP-4 degradation. Clinical studies have consistently shown that DPP-4 inhibitors increase the circulating concentrations of intact endogenous GLP-1 (and GIP) by about 2-to 4-fold. 10,11 Although considerably less than the 10-fold increase predicted from the observation that only about 10% of exogenously administered GLP-1 survives in the intact form, 12 this is nevertheless sufficient to cause a relative (in relation to plasma glucose levels) increase in insulin and reduction in glucagon concentrations. 11,13Accordingly, the mechanism by which DPP-4 inhibitors improve glycaemic control was believed to be simply due to their ability to enhance the endocrine actions of GLP-1. However, evidence now suggests that this is unlikely to be the only mechanism, and that other pathways and mediators may be involved.

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Section: Mechanism Of Actionmentioning

confidence: 89%

Section: Local Neural Signalling Pathwaymentioning

confidence: 98%

Do we know the true mechanism of action of the DPP‐4 inhibitors?

Andersen

Deacon

Holst

2017

Diabetes Obesity Metabolism

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“…Such a direct GLP-1 mechanism is supported by studies using native GLP-1 and exenatide in healthy people and patients with T2DM showing that the acute increase of HR was not preceded by a decrease in blood pressure, was not associated with changes in plasma levels of adrenaline or noradrenaline, and was independent of GLP-1 glucoregulatory effects [11, 34, 35]. A further possibility is that the positive chronotropic effect could be, at least partially, mediated by sympathetic nervous system enhancement, related to the inhibition of the autonomic nervous system [18, 36, 37]. In subjects with T2DM, 24-h Holter ECG and power spectrum analysis of HR variability were conducted before and after liragutide or lixisenatide administration.…”

Section: Discussionmentioning

confidence: 99%

Differential effects of glucagon-like peptide-1 receptor agonists on heart rate

Lorenz

Lawson

Owens

et al. 2017

Cardiovasc Diabetol

123

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While glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are known to increase heart rate (HR), it is insufficiently recognized that the extent varies greatly between the various agonists and is affected by the assessment methods employed. Here we review published data from 24-h time-averaged HR monitoring in healthy individuals and subjects with type 2 diabetes mellitus (T2DM) treated with either short-acting GLP-1 RAs, lixisenatide or exenatide, or long-acting GLP-1 RAs, exenatide LAR, liraglutide, albiglutide, or dulaglutide (N = 1112; active-treatment arms). HR effects observed in two independent head-to-head trials of lixisenatide and liraglutide (N = 202; active-treatment arms) are also reviewed. Short-acting GLP-1 RAs, exenatide and lixisenatide, are associated with a transient (1–12 h) mean placebo- and baseline-adjusted 24-h HR increase of 1–3 beats per minute (bpm). Conversely, long-acting GLP-1 RAs are associated with more pronounced increases in mean 24-h HR; the highest seen with liraglutide and albiglutide at 6–10 bpm compared with dulaglutide and exenatide LAR at 3–4 bpm. For both liraglutide and dulaglutide, HR increases were recorded during both the day and at night. In two head-to-head comparisons, a small, transient mean increase in HR from baseline was observed with lixisenatide; liraglutide induced a substantially greater increase that remained significantly elevated over 24 h. The underlying mechanism for increased HR remains to be elucidated; however, it could be related to a direct effect at the sinus node and/or stimulation of the sympathetic nervous system, with this effect related to the duration of action of the respective GLP-1 RAs. In conclusion, this review indicates that the effects on HR differ within the class of GLP-1 RAs: short-acting GLP-1 RAs are associated with a modest and transient HR increase before returning to baseline levels, while some long-acting GLP-1 RAs are associated with a more pronounced and sustained increase during the day and night. Findings from recently completed trials indicate that a GLP-1 RA-induced increase in HR, regardless of magnitude, does not present an increased cardiovascular risk for subjects with T2DM, although a pronounced increase in HR may be associated with adverse clinical outcomes in those with advanced heart failure.

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“…; Plamboeck et al. ). Here, we measured the plasma levels of active GLP‐1, total PYY, and active amylin in lean rats 45 min after onset of IV infusions of anorexigenic doses of GLP‐1, PYY(3‐36), and amylin (~ED 50 and threefold higher doses).…”

Section: Discussionmentioning

confidence: 97%

“…; Plamboeck et al. ). Here, we used a DDP4 inhibitor, plasma extraction, and specific assays for active GLP‐1 to show that a large chow meal increased plasma GLP‐1 from below the detection limit of 8.6 to 46 ± 8.2 pg/mL, and that a ~ED 50 dose of GLP‐1 produced 30‐fold higher levels.…”

Section: Discussionmentioning

confidence: 97%

Effects of solid-phase extraction of plasma in measuring gut metabolic hormones in fasted and fed blood of lean and diet-induced obese rats

et al. 2016

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Glucagon‐like peptide‐1 (GLP‐1), peptide YY (3‐36) [PYY(3‐36)], amylin, ghrelin, insulin, and leptin are thought to act as hormonal signals from periphery to brain to control food intake. Here, we determined the effects of solid‐phase extraction of plasma in measuring these hormones in blood of lean and diet‐induced obese rats. Individual enzyme‐linked immunoassays and a multiplex assay were used to measure active GLP‐1, total PYY, active amylin, active ghrelin, insulin, leptin, and total GIP in response to (1) addition of known amounts of the peptides to lean and obese plasma, (2) a large meal in lean and obese rats, and (3) intravenous infusions of anorexigenic doses of GLP‐1, PYY(3‐36), amylin, and leptin in lean rats. Extraction of lean and obese plasma prior to assays produced consistent recoveries across assays for GLP‐1, PYY, amylin, ghrelin, and insulin, reflecting losses inherent to the extraction procedure. Plasma extraction prior to assays generally revealed larger meal‐induced changes in plasma GLP‐1, PYY, amylin, ghrelin, and insulin in lean and obese rats. Plasma extraction and the multiplex assay were used to compare plasma levels of GLP‐1, PYY, and amylin after a large meal with plasma levels produced by IV infusions of anorexigenic doses of GLP‐1, PYY(3‐36), and amylin. Infusions produced dose‐dependent increases in plasma peptide levels, which were well above their postprandial levels. These results do not support the hypothesis that postprandial plasma levels of GLP‐1, PYY(3‐36), and amylin are sufficient to decrease food intake by an endocrine mechanism.

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The role of efferent cholinergic transmission for the insulinotropic and glucagonostatic effects of GLP-1

Cited by 21 publications

References 57 publications

Do we know the true mechanism of action of the DPP‐4 inhibitors?

Do we know the true mechanism of action of the DPP‐4 inhibitors?

Differential effects of glucagon-like peptide-1 receptor agonists on heart rate

Effects of solid-phase extraction of plasma in measuring gut metabolic hormones in fasted and fed blood of lean and diet-induced obese rats

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