Effects of GLP-1 and Incretin-Based Therapies on Gastrointestinal Motor Function

Marathe, Chinmay S.; Rayner, Christopher K.; Jones, Karen L.

doi:10.1155/2011/279530

Cited by 88 publications

(79 citation statements)

References 106 publications

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“…In addition to its well-known glucoregulatory effects, GLP1 is able to affect the motor functions of the gastrointestinal tract in different species, including humans (Marathe et al 2011). In fact, it inhibits gastric emptying, relaxes the antral region of the stomach, and reduces the motility of the upper intestine (Wettergren et al 1993, Giralt & Vergara 1999, Miki et al 2005, Nagell et al 2006, Schirra et al 2006, Amato et al 2010, Rotondo et al 2011.…”

Section: Discussionmentioning

confidence: 99%

“…The GLP1 effects on the stomach and small intestinal motility have been investigated, although the action on lower gut motility is less clear (Marathe et al 2011). Few studies have analyzed the role of GLP1 in the regulation of colonic contractility, and the results remain controversial because both GLP1 stimulatory (Gülpinar et al 2000, Ayachi et al 2005 and inhibitory (Byrne et al 2001, Amato et al 2010 effects have been described.…”

Section: Introductionmentioning

confidence: 99%

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Exogenous glucagon-like peptide 1 reduces contractions in human colon circular muscle

Amato¹,

Baldassano²,

Liotta

et al. 2014

Journal of Endocrinology

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Glucagon-like peptide 1 (GLP1) is a naturally occurring peptide secreted by intestinal L-cells. Though its primary function is to serve as an incretin, GLP1 reduces gastrointestinal motility. However, only a handful of animal studies have specifically evaluated the influence of GLP1 on colonic motility. Consequently, the aims of this study were to investigate the effects induced by exogenous GLP1, to analyze the mechanism of action, and to verify the presence of GLP1 receptors (GLP1Rs) in human colon circular muscular strips. Organ bath technique, RT-PCR, western blotting, and immunofluorescence were used. In human colon, exogenous GLP1 reduced, in a concentration-dependent manner, the amplitude of the spontaneous contractions without affecting the frequency and the resting basal tone. This inhibitory effect was significantly reduced by exendin (9-39), a GLP1R antagonist, which per se significantly increased the spontaneous mechanical activity. Moreover, it was abolished by tetrodotoxin, a neural blocker, or N u -nitro-L-arginine -a blocker of neuronal nitric oxide synthase (nNOS). The biomolecular analysis revealed a genic and protein expression of the GLP1R in the human colon. The double-labeling experiments with anti-neurofilament or anti-nNOS showed, for the first time, that immunoreactivity for the GLP1R was expressed in nitrergic neurons of the myenteric plexus. In conclusion, the results of this study suggest that GLP1R is expressed in the human colon and, once activated by exogenous GLP1, mediates an inhibitory effect on large intestine motility through NO neural release.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Exogenous glucagon-like peptide 1 reduces contractions in human colon circular muscle

Amato¹,

Baldassano²,

Liotta

et al. 2014

Journal of Endocrinology

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“…The amount of gastric distension due to food intake is partly influenced by the rate of gastric emptying, which affects postprandial glycaemic excursions. The role of gastric motility in appetite and satiation regulation and the effects of GLP-1/GLP-1RA on gastric and gut motility has been extensively reviewed (Janssen et al 2011, Marathe et al 2011. GLP-1 delays gastric emptying and gut motility not only in healthy lean but also in obese subjects and patients with T2DM (Nauck et al 1997, Naslund et al 1998, Schirra et al 2002, Meier et al 2003, Little et al 2006.…”

Section: Glp-1 Effects On the Regulation Of Appetite: The Role Of Delmentioning

confidence: 99%

Effects of glucagon-like peptide 1 on appetite and body weight: focus on the CNS

Bloemendaal¹,

Kulve²,

Fleur

et al. 2013

Journal of Endocrinology

219

176

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The delivery of nutrients to the gastrointestinal tract after food ingestion activates the secretion of several gut-derived mediators, including the incretin hormone glucagon-like peptide 1 (GLP-1). GLP-1 receptor agonists (GLP-1RA), such as exenatide and liraglutide, are currently employed successfully in the treatment of patients with type 2 diabetes mellitus. GLP-1RA improve glycaemic control and stimulate satiety, leading to reductions in food intake and body weight. Besides gastric distension and peripheral vagal nerve activation, GLP-1RA induce satiety by influencing brain regions involved in the regulation of feeding, and several routes of action have been proposed. This review summarises the evidence for a physiological role of GLP-1 in the central regulation of feeding behaviour and the different routes of action involved. Also, we provide an overview of presently available data on pharmacological stimulation of GLP-1 pathways leading to alterations in CNS activity, reductions in food intake and weight loss.

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“…Dipeptidyl peptidase-4 (DPP-4) inhibitors enhance the activity of endogenous glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide (10), which have emerged as important prandial stimulators of insulin secretion and have many physiological actions (10,11). Additionally, DPP-4 is distributed throughout the body and cleaves numerous substrates other than incretin hormones (10).…”

mentioning

confidence: 99%

Linagliptin-Mediated DPP-4 Inhibition Ameliorates Kidney Fibrosis in Streptozotocin-Induced Diabetic Mice by Inhibiting Endothelial-to-Mesenchymal Transition in a Therapeutic Regimen

et al. 2014

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Kidney fibrosis is the final common pathway of all progressive chronic kidney diseases, of which diabetic nephropathy is the leading cause. Endothelial-to-mesenchymal transition (EndMT) has emerged as one of the most important origins of matrix-producing fibroblasts. Dipeptidyl peptidase-4 (DPP-4) inhibitors have been introduced into the market as antidiabetes drugs. Here, we found that the DPP-4 inhibitor linagliptin ameliorated kidney fibrosis in diabetic mice without altering the blood glucose levels associated with the inhibition of EndMT and the restoration of microRNA 29s. Streptozotocin-induced diabetic CD-1 mice exhibited kidney fibrosis and strong immunoreactivity for DPP-4 by 24 weeks after the onset of diabetes. At 20 weeks after the onset of diabetes, mice were treated with linagliptin for 4 weeks. Linagliptin-treated diabetic mice exhibited a suppression of DPP-4 activity/protein expression and an amelioration of kidney fibrosis associated with the inhibition of EndMT. The therapeutic effects of linagliptin on diabetic kidneys were associated with the suppression of profibrotic programs, as assessed by mRNA microarray analysis. We found that the induction of DPP-4 observed in diabetic kidneys may be associated with suppressed levels of microRNA 29s in diabetic mice; linagliptin restored microRNA 29s and suppressed DPP-4 protein levels. Using cultured endothelial cells, we found that linagliptin inhibited TGF-β2–induced EndMT, and such anti-EndMT effects of linagliptin were mediated through microRNA 29 induction. These results indicate the possible novel pleiotropic action of linagliptin to restore normal kidney function in diabetic patients with renal impairment.

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Effects of GLP-1 and Incretin-Based Therapies on Gastrointestinal Motor Function

Cited by 88 publications

References 106 publications

Exogenous glucagon-like peptide 1 reduces contractions in human colon circular muscle

Exogenous glucagon-like peptide 1 reduces contractions in human colon circular muscle

Effects of glucagon-like peptide 1 on appetite and body weight: focus on the CNS

Linagliptin-Mediated DPP-4 Inhibition Ameliorates Kidney Fibrosis in Streptozotocin-Induced Diabetic Mice by Inhibiting Endothelial-to-Mesenchymal Transition in a Therapeutic Regimen

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