Dipeptidyl Peptidase IV Inhibition Prevents the Formation and Promotes the Healing of Indomethacin-Induced Intestinal Ulcers in Rats

Inoue, Takuya; Higashiyama, Masaaki; Kaji, Izumi; Rudenkyy, Sergiy; Higuchi, Kazuhide; Guth, Paul H.; Engel, Eli; Kaunitz, Jonathan D.; Akiba, Yasutada

doi:10.1007/s10620-013-3001-6

Cited by 21 publications

(33 citation statements)

References 56 publications

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“…The GLP-2 (3-33) form lacks in vivo activity [41,42]; however it can weakly activate the GLP-2 receptor (GLP-2R) when administered at supraphysiological doses [43]. Because of GLP-2's short (approximately 7-min) half-life in humans [44], administration of DPP-IV inhibitors has been used to enhance the therapeutic effects of GLP-2 [45][46][47], and synthetic GLP-2 analogs that are resistant to DPP-IV degradation have been used to prolong and increase its biological activity. Modifications include replacing the Ala (2) residue with Gly [40,42], which increases the half-life of GLP-2 to approximately 3 h in humans [48], or conjugating the peptide to various polymers, which extends the half-life in humans to as great as 10 d, based on theoretical projections from animal models [49][50][51].…”

Section: Glp-2 Synthesis and Degradationmentioning

confidence: 99%

“…Of interest, taste receptor T1R1-T1R3 activation by both L-glutamate and inosine 5 0 -monophosphate increases GLP-2 release in rat duodenum [100], and both GLP-2 administration and a combined treatment of L-alanine with inosine 5 0 -monophosphate increase the healing rate of intestinal ulcers in rats [47]. In addition, Bauchart-Thevret et al [101] demonstrated that dietary monosodium glutamate supplementation of preterm pigs dose-dependently increases plasma GLP-2 concentration.…”

Section: Potential Uses Of Glp-2 and Stimulators Of Glp-2 Secretion Imentioning

confidence: 99%

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Glucagon-like peptide 2 and its beneficial effects on gut function and health in production animals

Connor

Evock‐Clover

Wall³

et al. 2016

Domestic Animal Endocrinology

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Numerous endocrine cell subtypes exist within the intestinal mucosa and produce peptides contributing to the regulation of critical physiological processes including appetite, energy metabolism, gut function, and gut health. The mechanisms of action and the extent of the physiological effects of these enteric peptides are only beginning to be uncovered. One peptide in particular, glucagon-like peptide 2 (GLP-2) produced by enteroendocrine L cells, has been fairly well characterized in rodent and swine models in terms of its ability to improve nutrient absorption and healing of the gut after injury. In fact, a long-acting form of GLP-2 recently has been approved for the management and treatment of human conditions like inflammatory bowel disease and short bowel syndrome. However, novel functions of GLP-2 within the gut continue to be demonstrated, including its beneficial effects on intestinal barrier function and reducing intestinal inflammation. As knowledge continues to grow about GLP-2's effects on the gut and its mechanisms of release, the potential to use GLP-2 to improve gut function and health of food animals becomes increasingly more apparent. Thus, the purpose of this review is to summarize: (1) the current understanding of GLP-2's functions and mechanisms of action within the gut; (2) novel applications of GLP-2 (or stimulators of its release) to improve general health and production performance of food animals; and (3) recent findings, using dairy calves as a model, that suggest the therapeutic potential of GLP-2 to reduce the pathogenesis of intestinal protozoan infections.

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Section: Glp-2 Synthesis and Degradationmentioning

confidence: 99%

Section: Potential Uses Of Glp-2 and Stimulators Of Glp-2 Secretion Imentioning

confidence: 99%

Glucagon-like peptide 2 and its beneficial effects on gut function and health in production animals

Connor

Evock‐Clover

Wall³

et al. 2016

Domestic Animal Endocrinology

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“…Since DPP-4 rapidly degrades and deactivates GLP-2, DPP-4 inhibitors are viewed as a novel method for treating of intestinal inflammation (15,16). It has previously been shown that DPP-4 inhibitors have a protective effect on indomethacin-induced intestinal damage in rats (17,18). However, in terms of colon carcinogenesis, exogenous and endogenous GLP-2 has been identified as a factor that increases colon carcinogenesis in azoxymethane-treated mice (19).…”

Section: Introductionmentioning

confidence: 99%

Sitagliptin, a dipeptidyl peptidase-4 inhibitor, suppresses CXCL5 and SDF-1 and does not accelerate intestinal neoplasia formation in ApcMin/+ mice fed a high-fat diet

et al. 2017

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Abstract.The relationship between type 2 diabetes mellitus and intestinal neoplasia has been shown epidemiologically. A high-fat diet (HFD) is also known to promote insulin resistance, which is a risk factor for intestinal neoplasia. Dipeptidyl peptidase-4 (DPP-4) inhibitors are used in the clinic for the treatment of type 2 diabetes and also to prolong the effects of glucagon-like peptide-1 (GLP-1). However, since the intestinotrophic hormone GLP-2 and chemokines, such as CXCL5 and stromal cell-derived factor-1 (SDF-1), are also substrates of DPP-4, DPP-4 inhibitors may increase the risk of intestinal carcinogenesis. In this study, we evaluated the impact of a DPP-4 inhibitor on intestinal tumorigenesis in Apc Min/+ mice fed a HFD. Six-week-old male Apc Min/+ mice were randomized to either a normal diet (10 kcal% fat) group, a HFD (60 kcal% fat) group, or a HFD group treated with sitagliptin (STG). The mice were euthanized nine weeks after the start of treatment. Daily treatment with STG did not increase number of intestinal tumors in the HFD group; however, this increase was not statistically significant. The mucosal concentration of total GLP-2 was significantly increased in the HFD group. The chemokine protein array showed elevated plasma concentrations of CXCL5 and SDF-1 in the HFD group. The administration of STG significantly suppressed the levels of plasma CXCL5 and SDF-1 in mice fed a HFD. Since CXCL5 expression is increased in patients with type 2 diabetes, and GLP-2, CXCL5 and SDF-1 are associated with tumor progression, DPP-4 inhibition may have potential as an agent for decreasing the risk of cancer in obese or diabetic patients.

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“…Additionally, recent preliminary trial by another researcher have shown some efficacy of lubiprostone (a bicyclic fatty acid derived from PGE1) [35], mesalazine (treatment of inflammatory bowel disease) [36] and dipeptidyl peptidase IV (treatment of diabetes mellitus) [37] for treatment of NSAID-induced injuries in experimental models, and further study will be needed.…”

Section: Current Strategy For Nsaid-induced Small Intestinal Injuriesmentioning

confidence: 99%

Current Topics of Strategy of NSAID-Induced Small Intestinal Lesions

et al. 2015

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Small intestinal mucosal injuries have been recently recognized as common complications associated with non-steroidal anti-inflammatory drugs (NSAIDs) because video capsule endoscopy and balloon enteroscopy are now available for the detection of small intestinal lesions. Small intestinal injury occurs not in an acid-dependent mechanism but by various factors such as enteric bacteria, bile acids, prostaglandin (PG) deficiency and topical factors (abnormal intestinal mucosal permeability, mitochondrial dysfunction, reactive oxygen species, endoplasmic reticulum stress and so on), and there is no well-established prophylactic approach. Several experimental and clinical studies found the effectiveness of some of the mucoprotective drugs, PG analogs, but not that of acid suppressants. Considering the effect of proton pump inhibitors (PPIs) for upper gastrointestinal (GI) disease and in the small intestine, the following 2 kinds of strategies against NSAID-induced GI injuries may be recommended. In patients with a high risk of upper GI disease (peptic ulcer etc.), simultaneous administration of a PPI (for upper GI disease) and a mucoprotective drug (for small intestine) is needed to prevent NSAID-induced GI injury. In other cases, an effective mucoprotective drug is enough for the protection of the entire digestive tract, that is, starting from the esophagus to the small intestine. These strategies may fulfill both economical and curative effects.

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Dipeptidyl Peptidase IV Inhibition Prevents the Formation and Promotes the Healing of Indomethacin-Induced Intestinal Ulcers in Rats

Cited by 21 publications

References 56 publications

Glucagon-like peptide 2 and its beneficial effects on gut function and health in production animals

Glucagon-like peptide 2 and its beneficial effects on gut function and health in production animals

Sitagliptin, a dipeptidyl peptidase-4 inhibitor, suppresses CXCL5 and SDF-1 and does not accelerate intestinal neoplasia formation in ApcMin/+ mice fed a high-fat diet

Current Topics of Strategy of NSAID-Induced Small Intestinal Lesions

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