Evidence for neural contribution to islet effects of DPP-4 inhibition in mice

Ahlkvist, Linda; Omar, Bilal; Pacini, Giovanni; Åhrén, Bo

doi:10.1016/j.ejphar.2016.03.030

Cited by 8 publications

(6 citation statements)

References 33 publications

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“…10n ). This is in consistent with previous reports that neural pathways contribute to the effect of GLP-1 and DPP-4 inhibitors on food intake and glucose metabolism 22 , 23 , 25 , 46 . This vagal afferent-mediated link of endogenous GLP-1 to food intake and glucose metabolism is consistent with several previous reports.…”

Section: Discussionsupporting

confidence: 94%

GLP-1 release and vagal afferent activation mediate the beneficial metabolic and chronotherapeutic effects of D-allulose

et al. 2018

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Overeating and arrhythmic feeding promote obesity and diabetes. Glucagon-like peptide-1 receptor (GLP-1R) agonists are effective anti-obesity drugs but their use is limited by side effects. Here we show that oral administration of the non-calorie sweetener, rare sugar d-allulose (d-psicose), induces GLP-1 release, activates vagal afferent signaling, reduces food intake and promotes glucose tolerance in healthy and obese-diabetic animal models. Subchronic d-allulose administered at the light period (LP) onset ameliorates LP-specific hyperphagia, visceral obesity, and glucose intolerance. These effects are blunted by vagotomy or pharmacological GLP-1R blockade, and by genetic inactivation of GLP-1R signaling in whole body or selectively in vagal afferents. Our results identify d-allulose as prominent GLP-1 releaser that acts via vagal afferents to restrict feeding and hyperglycemia. Furthermore, when administered in a time-specific manner, chronic d-allulose corrects arrhythmic overeating, obesity and diabetes, suggesting that chronotherapeutic modulation of vagal afferent GLP-1R signaling may aid in treating metabolic disorders.

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Section: Discussionsupporting

confidence: 94%

GLP-1 release and vagal afferent activation mediate the beneficial metabolic and chronotherapeutic effects of D-allulose

et al. 2018

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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%

“…Furthermore, administration of a DPP‐4 inhibitor in a dose that increased portal, but not systemic, intact GLP‐1 levels was associated with improved glucose‐lowering and insulinotropic effects in rats, with the effects being attenuated by vagotomy . The mechanism has been suggested to involve muscarinic signalling, as the insulinotropic effects of DPP‐4 inhibition in mice were reduced (by 35%) by atropine . However, while rodent data support the notion that vagal signalling may be involved in the anti‐hyperglycaemic actions of endogenous GLP‐1 and DPP‐4 inhibitors, the situation in non‐rodent species is less clear.…”

Section: Mechanism Of Actionmentioning

confidence: 97%

“…33 The mechanism has been suggested to involve muscarinic signalling, as the insulinotropic effects of DPP-4 inhibition in mice were reduced (by 35%) by atropine. 34 However, while rodent data support the notion that vagal signalling may be involved in the anti-hyperglycaemic actions of endogenous GLP-1 and DPP-4 inhibitors, the situation in non-rodent species is less clear.…”

Section: Local Neural Signalling Pathwaymentioning

confidence: 99%

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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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“…2 In addition to serving as building blocks for the synthesis of pharmaceuticals 3 and natural products, 4 α-chiral nitriles also represent a structural motif in a wide spectrum of natural products, pharmaceuticals, and bioactive compounds. 5 As exemplified in Figure 1, the α-aminonitrile moiety is distributed in alkaloids such as lahadinine A (1), 6 and dnacin A 1 (2), 7 as well as in drugs such as NVP-DPP-728 (3), 8 vildagliptin (4), 9 and saxagliptin (5). 10 The cyanohydrin moiety is present in remdesivir (6), which is a nucleoside analogue with effective antiviral activity, 11 and fenvalerate (7), 12 which is one of the pyrethroid class of insecticides.…”

Section: Introductionmentioning

confidence: 99%

Catalytic Enantioselective Cyanation: Recent Advances and Perspectives

Zhou

2020

ACS Catal.

103

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α-Chiral nitriles are prevalent structural motifs in natural products, drugs, and pharmaceutically active compounds. In addition, because the cyano group can undergo various diversifying reactions, they are very versatile chiral building blocks for the synthesis of optically active aldehydes, ketones, carboxylic acids, carboxamides, amines, and N-heterocycles such as tetrazolium. Accordingly, the catalytic enantioselective cyanation reaction, as one of the most important C–C bond forming reactions, has been intensely studied in the past three decades. While traditional efforts mainly focus on the addition of the cyanide to highly polarized electrophiles as well as alkene hydrocyanation, intriguing directions in enantioselective cyanations have been opened, including the development of enantioselective alkene cyanofunctionalization, cyanation via C–H bond functionalization, and C–C bond cleavage, as well as the invention of bifunctional cyanating agents to design asymmetric tandem synthesis and to exploit enantioselective cyanide-free cyanation reactions. Additionally, significant advances have also been made in developing unprecedented chiral catalysts to address a long-term challenge, the catalytic enantioselective synthesis of structurally diverse C α-tetrasubstituted or quaternary α-chiral nitriles. This perspective aims to highlight these impressive advances, illustrates their key advantages and future applications, and provides some inspiration for related research.

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Evidence for neural contribution to islet effects of DPP-4 inhibition in mice

Cited by 8 publications

References 33 publications

GLP-1 release and vagal afferent activation mediate the beneficial metabolic and chronotherapeutic effects of D-allulose

GLP-1 release and vagal afferent activation mediate the beneficial metabolic and chronotherapeutic effects of D-allulose

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

Catalytic Enantioselective Cyanation: Recent Advances and Perspectives

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